\r\n\tThis book aims to comprise the current state of the art of the drying operations, at a laboratory and industrial scale, through the presentation of chapters that cover the fundamentals and applications of the different drying methods such as convective, freeze (lyophilization), osmotic, supercritical, vacuum- and irradiation-assisted drying. The comparison, analysis, modeling, and scale-up of the diverse type of dryers are also topics under the scope of the book. Besides, the engineering aspects of drying are considered, specifically the drying kinetics and the transport phenomena during the process, as well as energy consumption, operating costs, equipment safety, and environmental controls.
",isbn:"978-1-83880-110-6",printIsbn:"978-1-83880-109-0",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"3ebb761607fa27f2d32dd269ee2f2c0f",bookSignature:"Dr. Israel Pala-Rosas",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8540.jpg",keywords:"convective drying, freeze drying, supercritical drying, cabinet tray dryer, drum dryer, equilibrium moisture, bound moisture, drying kinetics, drying constant, dryer design, dryer scale-up",numberOfDownloads:112,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 1st 2019",dateEndSecondStepPublish:"August 22nd 2019",dateEndThirdStepPublish:"October 21st 2019",dateEndFourthStepPublish:"January 9th 2020",dateEndFifthStepPublish:"March 9th 2020",remainingDaysToSecondStep:"4 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,editors:[{id:"284261",title:"Dr.",name:"Israel",middleName:null,surname:"Pala-Rosas",slug:"israel-pala-rosas",fullName:"Israel Pala-Rosas",profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:"Israel Pala-Rosas is Biochemical Engineer by the Instituto Tecnológico de Tehuacán (ITT), Master in Chemical Engineering by the Benemérita Universidad Autónoma de Puebla (BUAP) and Doctor in Sciences in Chemical Engineering by the Escuela Superior de Ingeniería Química e Industrias Extractivas del Instituto Politécnico Nacional (ESIQIE-IPN). \r\n\r\nCurrently, Israel Pala develops research at ESIQIE-IPN and at the Laboratorio de Procesos Catalíticos of the Universidad Autónoma Metropolitana-Azcapotzalco (UAM-A).\r\n\r\n His interest lies in, but is not limited to, the research and development of catalytic and biotechnological processes for the transformation of biomass to value-added compounds and biofuels, regarding the synthesis, characterization, and testing of catalysts, as well as the design and analysis of (bio)chemical reactors. Areas related to the catalytic processes, such as chemical thermodynamics and unit operations, are also under his scope.",institutionString:"Instituto Politécnico Nacional",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Instituto Politécnico Nacional",institutionURL:null,country:{name:"Mexico"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:[{id:"69858",title:"The Study of Fabric Drying Using Direct-Contact Ultrasonic Vibration",slug:"the-study-of-fabric-drying-using-direct-contact-ultrasonic-vibration",totalDownloads:10,totalCrossrefCites:0,authors:[null]},{id:"69050",title:"Convective Drying in the Multistage Shelf Dryers: Theoretical Bases and Practical Implementation",slug:"convective-drying-in-the-multistage-shelf-dryers-theoretical-bases-and-practical-implementation",totalDownloads:73,totalCrossrefCites:0,authors:[null]},{id:"69796",title:"Kinetics of Drying Medicinal Plants by Hybridization of Solar Technologies",slug:"kinetics-of-drying-medicinal-plants-by-hybridization-of-solar-technologies",totalDownloads:29,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"270941",firstName:"Sandra",lastName:"Maljavac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/270941/images/7824_n.jpg",email:"sandra.m@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"54440",title:"NeuroPharmacology: As Applied to Designing New Chemotherapeutic Agents",doi:"10.5772/67591",slug:"neuropharmacology-as-applied-to-designing-new-chemotherapeutic-agents",body:'\n
\n
1. Introduction
\n
A basic assumption in cancer management is that all cancer cells must be killed or removed. When surgical and radiotherapies fail to achieve this goal, anticancer agents become the hope for control of the advanced disease.
\n
Classically, when a drug is injected or orally administrated, ideally it is 100% absorbed and enters the systemic circulation and distributed into the various body compartments. The drug then develops equilibrium (distribution) between metabolism, storage, target tumors, nontumor organs, and final elimination [1].
\n
The various body components and physiological barriers, which a cancer chemotherapeutic agent encounters from the time of administration until reaching the target site—the tumor—are depicted in Figure 1 [2, 3].
\n
Figure 1.
Drug distribution.
\n
The intensity and duration of drug action at any one site depends upon absorption, distribution, affinity, excretion, and metabolism for the drug.
\n
It is anticipated that the drug’s tumor selectively will be such that it is absorbed preferentially, with relatively low toxicity to the host organs, such as bone marrow, liver, kidney, gastrointestinal tract, etc. In addition, the accumulation of drug in the tumor will depend upon lipid storage, metabolic activation, and elimination. The liver has a principal role in the metabolism of cancer chemotherapeutic agents, but the other organs such as bone marrow, liver, intestines, kidneys, and even brain also contain low levels of drug-metabolizing enzymes [1, 2].
\n
\n\nTable 1\n outlines the major types of biotransformation which anticancer drugs can be expected to undergo. These include oxidative, reductive, and conjugation reactions, which usually result in increased product polarity. The resulting product(s) are either activated or detoxified metabolites of the parent drug. The conjugated reactions usually result in water-soluble products, which are excreted via the biliary and urinary systems.
Cancer cells are the target of cancer chemotherapeutic \x3c!--\n
Please check the section ‘Cancer cells’or provide suitable title for heading 2.
\n--\x3eagents, and the rate at which cancer cells interact with these agents is controlled by the hierarchy of molecular organization shown in \nFigure 2\n.
\n
Figure 2.
Hierarchy of cellular components. Molecular organization of cells.\n
\n
However, for tumor cells colonized in the brain and associated central nervous system structures, drugs/chemicals have an “additional hurdle,” they must penetrate the blood brain barrier (BBB) before classical interactions and pharmacological principles can be applied. Evidence supports anticancer agents exerting their antitumor activities via cytotoxic, cytostatic and/or initiating immunotherapeutic mechanisms of action resulting in cancer cell death. All the chemotherapeutics interfere/interact with pathways in the cellular organization (\nFigure 2\n), thus inhibiting the synthesis of cancer cell DNA, RNA, proteins, and initiating lymphocyte—cancer cell recognition.
\n
Although chemotherapeutics have their initial interactions on the molecular levels, they must first reach their targets. Thus, the abilities of chemotherapeutic agents to reach and interact with their targets are controlled by the hierarchy of distribution (\nFigure 1\n) and disposition (\nTable 1\n). These responses or changes are then transmitted to the respective molecular and/or cellular levels of cells (\nFigure 2\n).
\n
\n
\n
3. Clark’s correlates
\n
In his classic work on general pharmacology, A.J. Clark divided the possible quantitative drug action(s) into five types [4]:
\n
Relationship between:
\n
Time and the production of some quantitative response.
Time and the incidence of some “all-or-none effect.”
Concentration and time of appearance of a selected action.
Concentration and amount of quantitative response.
Concentration and incidence of all-or-none effects.
\n
The first three classes of Clark’s correlates are expressions of kinetics and are the rate(s) of actions for drugs, while the last two classes summarize equilibrium conditions between drugs and their target sites. The reactivity of an agent with a molecular target in a biological system, is dependent upon the concentration of the “active therapeutic available” and often more important, is the rate at which the active form of the drug finds its way to the therapeutic sites/targets.
\n
The selection of an optimal drug source requires consideration of:
\n
The qualitative and quantitative nature of the drug’s known toxicity.
The influence of drug concentration with time on tumor cell kill.
The drug’s pharmacology.
\n
Consideration is also required for recovery time for the target organ, as well as nontarget organs, such as the bone marrow and gastrointestinal tract to recover prior to the administration of additional drugs. This depends on the pharmacologic disposition of the drug, since absorption, distribution, elimination, and metabolism affect the toxicity and efficacy, which can be achieved in the treatment of cancer.
\n
\n
\n
4. Pharmacokinetics
\n
Since most aspects of pharmacology involve dynamic processes, it is necessary to consider the rates or time courses for this process [5]. Pharmacokinetics is the quantitative measurement of concentration vs. time for drug and metabolite(s) in respective biological fluids, tissues, and for excretion. Pharmacokinetics is not the measurement of a solution to a problem; it is merely the scientific analysis of a drug’s chemobiodynamics— the distribution of a drug in an organism [6].
\n
Common questions in which applications of pharmacokinetics have proven to be useful include:
\n
How a drug is eliminated and how fast?
What factors affect the rate of elimination?
What is the optimal drug regimen for a drug?
How can drugs and radiotherapy be combined?
Is the pharmacological response due to the parent drug or a metabolite?
Does drug distribution change with multiple dosing?
How do the pharmacokinetics of chemically related drugs compare?
How are the pharmacokinetics of a drug altered by the simultaneous administration of a second drug or radiation?
\n
The initial step in a pharmacokinetic study is to determine if a drug is distributed by first or second-order reactions. The second step is to develop models for documentation.
\n
\n
4.1. First Order Kinetic Reactions
\n
\n\x3c!--\n
Please check the section heading ‘First-order reactions’ or provide suitable title for heading 4.1.
\n--\x3eFirst-order reactions usually produce parallel curves for different doses of a drug with proportional shifts in the ordinate. If not, one must determine, which saturation processes or enzymatic reactions or zero order reactions are present.
\n
Once the reaction kinetics is found to be first order, a model must be formulated. Models are based on the concepts of compartments. The simplest first order pharmacokinetics normally fits a one compartment model; for example, a drug is administered by intravenous injection and eliminated only in the urine or some other single route.
\n
The rate of disappearance of the drug from the blood is proportional to the actual concentration of drug (x) in the blood (\nFigure 3\n).
\n
Figure 3.
Pharmacokinetics of a one-compartment system.
\n
Plotting the log [x] vs. time produces a slope equal to: −k/2.303.
\n
The half-life (t\n1/2) of the drug (x) is the time in which the concentration in the primary compartment decreases by 50%:
The half-life is only meaningful as long as there is a one compartment model and the reaction is first-order. The half-life is also related to the clearance (Cl) and distribution (V\nd) of the drug:
\n\n\n\n\n\n\n\n\nV\n\nd \n=\n\n\ndose/\n\nx\n0\n\n;\n\n\nx\n0\n\n\nis obtained by extrapolating the curve to\n\nt\n=\n0.\n\n\n\n\n\n\nAlso \n−\n\nt\n\n1\n/\n2\n\n\n=\n06.93\n/k\n=\n0.693\n\n\nV\nd\n\n/\nC\nl\n,\n\nwhere\n:\nC\nl\n=\nk\n\nV\nd\n\n\nand\n\n\nV\nd\n\n=\ndose\n/\n\nx\n0\n\n.\n\n\n\n\n\n\n\n\nE3
\n
Thus, the elimination is calculated as – dx/dt = −kx (with k = elimination constant)
\n
\n
\n
\n\x3c!--\n
Please check the section heading ‘Second-order reactions’ or provide suitable title for heading 4.2.
\n--\x3e4.2. Second Order Kinetic Reactions
\n
Second-order reactions are best described in models where there are both elimination and distribution to other compartments and the curve would look like \nFigure 4\n. The upper portion of the curve represents distribution, while the lower flatter portion represents elimination [7].
\n
Figure 4.
Pharmacokinetics of a two-compartment system [2].
\n
The slope of the elimination phase or β is calculated by extending or extrapolating the lower portion of the curve to the ordinate (intercept) at B. The slope of the distribution phase or α is calculated by taking the differences between times for actual curve A and extrapolating to (B) back to T\n0.
There are some disadvantages to this type of feathering—data can be biased when converting from linear to log scale and objectivity lost (too much importance placed on the terminal part of the curve where there is often least confidence). Computer models are best employed, if possible.
\n
In this type of example, it is meaningless to speak of T\n1/2, since the whole curve is determined by two T\n1/2 values analogous to K\n1 and K\n2, and one cannot combine these two values directly. It is no longer true that the T\n1/2 values remain constant for greater than two compartments.
\n
\n
\n
4.3. Drug Distribution
\n
Another \x3c!--\n
Please provide suitable title for headings 4.3, 4.4, 5.1, 6.1 and 6.2.
\n--\x3ereason for the success or failure in drug activity is related to the pharmacologic disposition of drugs in subjects. Even if the tumor is sensitive to a drug, the latter is not useful unless it reaches the tumor site and remains there in cytotoxic (therapeutic) concentrations long enough to kill the tumor cells. In general, the purpose of pharmacology studies is to inform the treating physicians what is an effective concentration (C) of the drug that can be administered by a certain route and be present (available) for a sufficient period of time (T) to bring about the desired effect. This is referred to as the “optimal C × T,” and in most diseases, this can be approximated for dosing in humans through preclinical studies in animal models. Generally, 10% of the LD10 in mice is the acceptable starting dose [1].
\n
\n
\n
4.4. Correlation of Pharmacokinetic Profile
\n
What makes cancer different from other diseases is the need to relate optimal C × T to the phases of the cell cycle [1]. First, the optimal C × T for the tumor must be estimated for the real target—the tumor cells that are susceptible to be killed by the drug. Second, calculations are required to define the optimal C × T for human safety (e.g., the C × T that will be tolerated by normal organ tissues (bone marrow or gastrointestinal tract in most cases). Third, the cell population kinetics of both tumor cells and normal cells will be perturbed as a result of the drug’s administration; however, the cancer cell growth fraction should be reduced to a greater degree, with sparing of normal tissues. Thus, the potential for drug’s usefulness is a balance between anticancer activity and damage to healthy organs/tissues. Understanding the failure of active drugs to cause regression of cancer will depend to a significant extent upon successful delineation of this complex pharmacology.
\n
Thus, the effectiveness of an antitumor agent is directly related to C × T, which is markedly affected by dose, schedule, and its pharmacokinetics discussed above. The sensitivities of the cancer cells, as well as, normal tissue to drugs are the variable factors, which determine the potential usefulness of a drug. Documentation of the optimal C × T is usually conducted in Phase I studies and will relate clinical responses to acceptable doses and schedules necessary to standardize drug use in humans.
The C × T product is also known as the area under the curve (AUC) and discussed and illustrated latter in this chapter.
\n
\n
\n
\n
5. Blood brain barrier
\n
The chemobiodynamic relationship of a drug with the blood brain barrier (BBB) evaluated using in vivo, in vitro, and in silico (computational) models in attempt to appreciate the best design for novel anticancer agents to be used in subjects with malignant tumors involving the brain and central nervous system.
\n
The blood brain barrier was discovered over 100 years ago by Paul Ehrlich who found that water soluble dyes stained all organs of animals except for their brains and central nervous system (CNS) [8]. Subsequently, other researchers found that Ehrlich’s dye injected into the brain did not enter the blood stream and hence a barrier existed between the two compartments. These compartments could be traversed by more lipophilic substances however [9]. In general, more lipid soluble drugs can traverse the blood brain barrier by passive diffusion, while other molecules can cross the blood brain barrier (BBB) by active transport by proteins such as P-glycoprotein (P-gp) [10].
\n
The BBB differs from normal capillaries in that it has tight junctions in the endothelial cell walls with specialized pores and junctions (formed by terminal surfaces of endothelial cells, neurons, astrocytes, etc.) that allow selective transport through the openings. The BBB is also highly electrically resistant confirming that it is very fatty and free of aqueous electrolytes [5].
\n
To treat cancers involving the CNS, the BBB is the protective “no man’s land” must be penetrated by anticancer agents. Figure 5 depicts two modes of drug transport into the brain and intracerebral cancers. Figure 5(a) requires drug to penetrate via diffusion or a transfer pathway [12]. Figure 5(b) allows drugs to penetrate the CNS via the association with RBCs or transport through cancer-associated breaks in the BBB [11].
\n
Figure 5a.
Primary tumor mass involving the CNS. Drugs \n\n\n can only penetrate the BBB by passive diffusion or active transport.
\n
Figure 5b.
Breaks (leaks) in the BBB 2° to cancer cell \n\n\n penetration and tumor growth allow RBCs \n\n\n and associated drugs \n\n\n easily penetration into tumors growing in the brain.
\n
\n
5.1. Calculation of Log P\n
\n
Measuring or calculating log P is the most important molecular attribute to defining lipophilicity and the ability of the drug to diffuse across the lipophilic BBB. This is measured by dissolving the drug in octanol and then shaking with equal volumes of water. The concentration of drug is then measured in both phases and the ratio of octanol-water is calculated according to Eq. (1) [6].
Since, very lipophilic compounds tend to be highly lipoprotein bound and associate/bind to lipid membranes, thus the ideal octanol-water partition coefficient for a neurotargeted drug (at pH 7.4) to diffuse from the serum into BBB into the CSF should be ≤ log P 5 [2, 12].
\n
The estimation or determination of BBB permeability as log\nBBB\n (the concentration of drug in the brain is divided by concentration in the blood) is accomplished as follows:
\n
\nIn vitro kits to measure log\nBBB\n in monkey or rat brain cells [13].
\nIn vivo during a clinical trial (Phase I).
\n\x3c!--\n
Ref. [14] was not cited in the text, please cite text in sequence.
\n--\x3e\nIn silico computer models that simulate human BBB and are validated by correlating with drugs of known and measured log\nBBB\n values [5]. For example, for DM-CHOC-PEN, temozolomide and others, log P can be calculated from their structure and from Eq. (2) log\nBBB\n\n\n calculated [13–15].
\n\nTable 2\n lists compounds with known brain and/or CNS activity and from their structure log P is calculated. From this value and Eq. (2) log\nBBB\n is calculated; the latter is compared to literature values in \nTable 2\n. The calculated and literature values are in good agreement indicating that log P is a good predictor of passive diffusion through the BBB. However, one must realize that this is just a predictor of drug penetration across the BBB. Some drugs have higher cytotoxicity and selectivity than others and as such are active at lower concentrations than other drugs, e.g., temozolomide. Other caveats include the fact that drugs that penetrate the BBB can be “pumped out” — P-glycoprotein (GgP), thus the log P is not predictive that all drugs will be active [10, 15].
\n
Table 2.
Calculated and structure related activities for molecules with known intracerebral activity [15].
\n
\n
\n
\n
6. Clinical applications
\n
The above introductory information provides the general principles, which must be considered when designing or planning on using a drug to treat cancer involving the brain.
\n
\n\x3c!--\n
Please check the in-text citation for Figure 6 and correct if necessary.
\n--\x3e4-Demethyl-4-cholesteryoxycarbonylpenclomedine (DM-CHOC-PEN) [\nFigure 6\n] is a lipophilic cholesterol carbonate polychlorinated pyridine that is cytotoxic and penetrates the BBB, both because of its log\nBBB\n (\nTable 2\n), as well as an affinity for red blood cells (RBCs) [16–18].
\n
Figure 6.
DM-CHOC-PEN and metabolite DMPEN.
\n
\n
6.1. DM-CHOC-PEN PK Profile With Cell Cycle
\n
DM-CHOC-PEN‘s PK profile is best modeled via a two compartment model with ~5% being excreted unchanged in the urine [17]. The use of plasma pharmacokinetics is of great importance in considering its use. The drug has produced excellent responses in primary cancers (glioblastomas) as well as metastatic (lung, melanoma, breast) cancers involving the CNS [18]. DM-CHOC-PEN is lipophilic and penetrates the BBB, as well as transported and activated in metastatic cancers involving the CNS through a 4-tier mechanism: (1) transport per RBCs into the brain via breaks in the BBB; (2) entry into cancer cells per the l-glutamine (GLM) transfer system; (3) activation to DM-PEN (active molecule) in situ in the acidic microenvironment of cancer cells; and (4) bis-alkylation of DNA at N7-guanine and N4-cytosine—with cellular death [11].
\n
It’s a large molecule and if there are liver metastases or other hepatic disease involving the liver there can be biliary congestion resulting in reversible jaundice [17].
\n
The pharmacokinetics of DM-CHOC-PEN’s disappearance from plasma after a single intravenous dose consist of an initial phase having a T\n1/2 of 5 hours and a final phase T\n1/2 of 245 hours (\nFigures 7\n and \n12\n). The slow, final phase of DM-CHOC-PEN elimination is the reason for the single high dose schedules that are currently being employed [18].
\n
Figure 7.
Plasma decay curve for DM-CHOC-PEN: 85.8 mg/m2 IV once.
\n
Figure 8.
DM-CHOC-PEN + DM-PEN plasma and urine levels.
\n
Figure 9.
AUC—1 subject–doses of 39 mg/m2, then 21 days later—55 mg/m2.
\n
Figure 10.
Area under the curve (AUC) for DMCHOCPEN (decadron patients excluded) as a function of DMCHOCPEN dose.
\n
\n
\n
6.2. DM-CHOC-PEN Degradation
\n
It has been found that the hydrolysis of DM-CHOC-PEN to DM-PEN (\nFigure 7\n) is the principle route of degradation and elimination of the drug in animals and humans [16].
\n
Results vary with individual patients but on a mass balance analysis 1–10% of DM-CHOC-PEN are excreted unchanged and the metabolite, DM-PEN is excreted 10–100% in the urine. \nFigure 8\n shows a pattern seen for 12 subjects treated once with 70–85.8 mg/m2 plasma and urine drug and metabolite levels [17].
\n
\n
\n
6.3. Area under the curve
\n
Increasing the dose of DM-CHOC-PEN increases the plasma concentration of drug and metabolites. The Cmax increased with the dose giving rise to an increase in area under the curve (AUC) (\nFigure 9\n). \nFigures 9\n and \n10\n combine and summarize the AUCs for DM-CHOC-PEN vs. time [16, 17].
\n
\n
\n
6.4. Distribution and elimination
\n
DM-CHOC-PEN follows a standard two compartment model for elimination [17].
\n
The preclinical and Phase I trial results suggest that the brain and central nervous system is targeted, but that all tissues including cancer tumors will absorb drug [17, 19]. So the second step in decreasing DM-CHOC-PEN blood levels is drug elimination. From bioavailability kinetic studies, this has found to be about 4%. The third step of elimination is after the metabolic degradation to a more water soluble and excreted as DM-CHOC-PEN. For DM-CHOC-PEN, the drug is primarily eliminated as DMPEN in the urine, which accounts for 57% of the dose on a mass balance basis. The metabolite on average has maximal plasma concentration 14 hours after drug administration (\nFigure 8\n) [17, 19].
\n
The whole point of the above discussion is to illustrate that there are differing kinetic processes involved in drug elimination such that elimination is not linear with time. In classical pharmacokinetics, this is described as two compartment model and you know you have one when you plot Log Drug Plasma Concentration vs. time and you see two slopes (\nFigure 12\n).
\n
Thus, from the DM-CHOC-PEN and DM-PEN study, the drug is eliminated in a two compartment model (see \nFigures 11\n and \n12\n). In addition, DM-CHOC-PEN has been identified in the CNS and tumors as DNA adducts [17, 19].
\n
Figure 11.
Distribution of DM-CHOC-PEN into the CNS and Cancer Cells.
\n
\nFigure 12.
Elimination of DM-CHOC-PEN identified as two-compartment model as log plasma concentration vs. time is bi-linear two slopes evident initial α or distribution phase: terminal β or elimination phase.
\n
\n
\n
\n
7. Conclusion
\n
An attempt to review neuropharmacology and distribution of anticancer agents in the central nervous system has been made. However, actually little is known about the interactions of drugs with the various levels of the CNS. We combined drugs in neurooncology but actually know little about the neuropharmacology of any single agent. In fact, Clark’s basic pharmacological questions that should have been answered for all the agents we use but have been answered in only a few cases. With the current interests in neurooncology, we may finally make some progress in the specialty—but let’s do it correctly.
\n
\n
Acknowledgments
\n
Supported by NCI/SBIR grants – 5R44CA85021 and 3R43CA132257.
\n
\n',keywords:"neurooncology, pharmacology, chemotherapeutics in clinical trials",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/54440.pdf",chapterXML:"https://mts.intechopen.com/source/xml/54440.xml",downloadPdfUrl:"/chapter/pdf-download/54440",previewPdfUrl:"/chapter/pdf-preview/54440",totalDownloads:564,totalViews:112,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"June 12th 2016",dateReviewed:"January 24th 2017",datePrePublished:null,datePublished:"March 23rd 2017",readingETA:"0",abstract:"Neurooncology anticancer drugs are no exception—their distribution and tissue interactions follow the general rules of classical pharmacology. In an attempt to assist with the new therapeutic approaches to manage cancers involving the central nervous system, classical chemobiodynamic compartment and pharmacokinetic models are discussed and illustrated. In addition, strategies and approaches for penetrating the blood brain barrier (BBB) are reviewed and modeled. Finally, in support of classical pharmacology, a new anticancer agent in clinical trial for brain tumors is reviewed as an example of clinical onco-neuropharmacology.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/54440",risUrl:"/chapter/ris/54440",book:{slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors"},signatures:"Andrew H. Rodgers and Lee Roy Morgan",authors:[{id:"158053",title:"Dr.",name:"Lee Roy",middleName:null,surname:"Morgan",fullName:"Lee Roy Morgan",slug:"lee-roy-morgan",email:"lrm1579@aol.com",position:null,institution:null},{id:"193557",title:"Ph.D.",name:"Andrew",middleName:null,surname:"Rodgers",fullName:"Andrew Rodgers",slug:"andrew-rodgers",email:"ahrodgers@gmail.com",position:null,institution:{name:"University of New Orleans",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Cancer Cells Involving CNS",level:"1"},{id:"sec_3",title:"3. Clark’s correlates",level:"1"},{id:"sec_4",title:"4. Pharmacokinetics",level:"1"},{id:"sec_4_2",title:"4.1. First Order Kinetic Reactions",level:"2"},{id:"sec_5_2",title:"\n4.2. Second Order Kinetic Reactions",level:"2"},{id:"sec_6_2",title:"4.3. Drug Distribution",level:"2"},{id:"sec_7_2",title:"4.4. Correlation of Pharmacokinetic Profile",level:"2"},{id:"sec_9",title:"5. Blood brain barrier",level:"1"},{id:"sec_9_2",title:"5.1. Calculation of Log P\n",level:"2"},{id:"sec_11",title:"6. Clinical applications",level:"1"},{id:"sec_11_2",title:"6.1. DM-CHOC-PEN PK Profile With Cell Cycle",level:"2"},{id:"sec_12_2",title:"6.2. DM-CHOC-PEN Degradation",level:"2"},{id:"sec_13_2",title:"6.3. Area under the curve",level:"2"},{id:"sec_14_2",title:"6.4. Distribution and elimination",level:"2"},{id:"sec_16",title:"7. Conclusion",level:"1"},{id:"sec_17",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\nMorgan, L.R., Principles of Pharmacology, Practical Oncology Today. Part II. Adra Labs, 1977.\n'},{id:"B2",body:'\nMorgan, L.R. and Weatherall, T.J., “Pharmacology and drug distribution. In: Combined Modalities. Chemotherapy/Radiotherapy.” Phillips, T.L. (ed.) Int. J. Radit. Oncol., Biol. Phys., 17, 20–24,1974.\n'},{id:"B3",body:'\nOliverio, V.T. and Guarino, A.M., “Absorption, protein binding, distribution, and excretion of antineoplastic drugs.” Biochem. Pharmacol. 23, Supp 2:9–20, 1974.\n'},{id:"B4",body:'\nClarke, A.J., General Pharmacology, in A. Heffter (ed.), “Handbuch der experimentellen Pharmakologie,” vol. 4, Springer-Verlag, Berlin, 1937, pp. 63–65.\n'},{id:"B5",body:'\nGoodman & Gilman’s The Pharmacological Basis of Therapeutics, edition 11, Brunton, LL, Lazo, JS, Parker, KL, McGraw-Hill, New York, 2006,.\n'},{id:"B6",body:'\nSchuler, F.W., Chemobiodynamics and Drug Design, McGraw-Hill Book Co. New York, 1960.\n'},{id:"B7",body:'\nGermain, R., Bastian, G., Serota, D., Struck, R.F., Morgan, L.R., Isophosphoramide mustard (IPM): preclinical pharmacology and toxicology in rodents, dogs and primates. Cancer Chemother. Pharmacol., 51, 1204–1212, 2004.\n'},{id:"B8",body:'\n\n\x3c!--\n
Please replace the other language title with English title in Ref. [8].
\n--\x3eEhrlich, P., Das Sauerstoff-Bedurfniss des Organismus. Eine farbenanalytische Studie. Verlag von August Hischwald 1–167, 1885.\n'},{id:"B9",body:'\n\n\x3c!--\n
Please provide the publisher location for Ref. [9].
\n--\x3eThe Davis Lab. History of the Blood Brain Barrier, University of Arizona, Tucson, AZ 85721, 2014.\n'},{id:"B10",body:'\nHartz, A.M.S. and Bauer, B., Regulation of ABC transporters at the blood brain barrier: new targets for CNS therapy. Mol. Interv., 10(5), 293–304, 2010.\n'},{id:"B11",body:'\nMorgan, L.R., Benes, E., Rodgers, A.H., Mahmood, T., Weiner, R.S., Cosgriff, T.S., Influence of L-Glutamine on DM-CHOC-PEN Activity in NSLC, 16th Int.Lung Cancer Congress, 2015.\n'},{id:"B12",body:'\nCarpenter, T.S., Kirshner, D.A., Lau, E.Y., Wong, S.E., Nilmeier, J.P., Lightstone, F.C., A method to predict blood brain barrier permeability of drug like compounds using molecular dynamic simulations. Index of compounds with data indicating they either cross or do not cross the BBB (or are found in CSF). Biophys. J., 107, 630–641, 2014.\n'},{id:"B13",body:'\nhttp://www.pharmacocell.co.jp/en/bbb/index_e.html\n'},{id:"B14",body:'\nhttp://www.molinspiration.com\n'},{id:"B15",body:'\nhttp://www.brynmawr.edu/chemistry/Chem/mnerzsto/bbb_index_of_compound-optimized.pdf\n'},{id:"B16",body:'\nMorgan, L.R., Struck, R.F., Rodgers, A.H., Jursic, B.S. Waud, W.R., Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer agents. Cancer Chemother. Pharmacol., 64, 829–835, 2009.\n'},{id:"B17",body:'\nWeiner, R.S., Ware, M.L., Bastian, G., Rodgers, A.H., Urien, S., Morgan, L.R., Comparative pharmacokinetics of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in humans, Proc. Amer. Assoc. Cancer Res., 53, 758, 2012.\n'},{id:"B18",body:'\nWeiner, R.S., Friedlander, P., Gordon, C., Saenger, Y., Ware, R.L., Mahmood, T., Rodgers, A.H., Bastian, G., Urien, S., Morgan, L.R., Early clinical trial for 4-demethyl-4-cholesteryl-oxycarbonylpenclomedine (DM-CHOC-PEN) in patients with advanced cancer. Proc. Am. Assoc. Cancer Res., 56, 246, 2015.\n'},{id:"B19",body:'\nMorgan, L.R., Rodgers, A.H., Bastian, G., Benes, E., Waud, W.S., Papagiannis, C., Krietlow, D., Jursic, B.S., Struck, R.F., LaHoste, G., Thornton, M., Luttrell, M., Stevens, E., Thompson, R., Comparative preclinical pharmacology and toxicology for 4-demethyl-4-cholestryloxylcarbonylpenclomedine (DM-CHOC-PEN) – a potential neuro-alkylating agent for glioblastoma (GBM) and metastatic cancers involving the central nervous system. In: Morgan, LR (ed.): Tumors of the Central Nervous System\n – Primary and Secondary, Rijeka, InTech; 2014, pp. 239–263.\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Andrew H. Rodgers",address:"ahrodgers@gmail.com",affiliation:'
DEKK-TEC, Inc. New Orleans, LA, USA
'},{corresp:null,contributorFullName:"Lee Roy Morgan",address:null,affiliation:'
DEKK-TEC, Inc. New Orleans, LA, USA
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Rodgers and Lee Roy Morgan",authors:[{id:"158053",title:"Dr.",name:"Lee Roy",middleName:null,surname:"Morgan",fullName:"Lee Roy Morgan",slug:"lee-roy-morgan"},{id:"193557",title:"Ph.D.",name:"Andrew",middleName:null,surname:"Rodgers",fullName:"Andrew Rodgers",slug:"andrew-rodgers"}]},{id:"53032",title:"Role of Pathologist in Driver of Treatment of CNS Tumors",slug:"role-of-pathologist-in-driver-of-treatment-of-cns-tumors",totalDownloads:818,totalCrossrefCites:0,signatures:"Serdar Altınay",authors:[{id:"185324",title:"Associate Prof.",name:"Serdar",middleName:null,surname:"Altınay",fullName:"Serdar Altınay",slug:"serdar-altinay"}]},{id:"54453",title:"A Review of Current Radiation Therapies for the Treatment of Metastatic Brain Tumors",slug:"a-review-of-current-radiation-therapies-for-the-treatment-of-metastatic-brain-tumors",totalDownloads:673,totalCrossrefCites:0,signatures:"Jonathan S. 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Strong and Marcus L. 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Rodgers, Gerard Bastian, Edmund\nBenes, William S. Waud, Christopher Papagiannis, Dan Krietlow,\nBranko S. Jursic, Robert F. Struck, Gerald LaHoste, Melissa Thornton,\nMelody Luttrell, Edward Stevens and Rodger Thompson",authors:[{id:"158053",title:"Dr.",name:"Lee Roy",middleName:null,surname:"Morgan",fullName:"Lee Roy Morgan",slug:"lee-roy-morgan"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"67502",title:"Nanopharmaceuticals: A Boon to the Brain-Targeted Drug Delivery",doi:"10.5772/intechopen.83040",slug:"nanopharmaceuticals-a-boon-to-the-brain-targeted-drug-delivery",body:'\n
\n
1. Introduction
\n
Brain besides being a fascinating organ is also known for its complexity. From outside, this delicate organ is protected by a bony structure called skull while internally it is sheltered from noxious substances via some complex barrier systems. These protective barriers impede the treatment strategies adopted for therapeutic purposes [1]. The management of CNS disorders such as dementia, epilepsy, panic disorders, meningitis, and brain tumors greatly depends on the means of attaining higher drug levels at the targeted sites. Physico-chemical properties of the drug molecule mainly dictate its ability to penetrate these barriers and achieve a therapeutic outcome. Thus the ultimate pharmacological response obtained by the potential drug depends on multiple factors like its effectiveness, its uptake or penetration through protective barriers or its ability to bind with specific carrier proteins for efficient transport across the membrane [2]. Among these barriers, blood-brain barrier (BBB) presents one of the types that hinder the transport of the medicinal compounds for treating brain ailments. BBB serves as both physical and transport barrier and is present at the interface of blood and brain. It is a tight junction made of microvascular endothelial cells, astrocytes, and pericytes [3]. Therefore, the development of newer therapeutic strategies is the need of the hour to overcome these transport hurdles.
\n
\n
1.1. Barriers in delivering drug to brain
\n
\n
1.1.1. The blood-brain barrier (BBB)
\n
It is a tight physical junction present at the interface of CNS and blood circulation. It consists of endothelial cells that do not have fenestrations and thus restrict the influx of ions and other solutes into the brain from surrounding blood capillaries. Astrocytes and pericytes surround endothelial cells and thus make it almost an impermeable barrier. BBB allows paracellular transport of small lipophilic compounds (<400 Da) via passive diffusion. This barrier also offers active transport of some hydrophilic compounds by the means of transport proteins (e.g., P-glycoprotein) present at the junction. The transcellular pathway that is used by some compounds to enter the brain includes different mechanisms such as passive diffusion, specific transporters, and transcytosis [4].
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1.1.2. Other barriers
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Among the primary brain tumors, gliomas are considered the most common. These tumors make a barrier at their early stage termed as blood-brain tumor barrier (BBTB). Although BBTB is permeable at the core of glioblastomas, however, it closely resembles BBB at the peripheral regions. This combination of BBB and BBTB leads to an additional hindrance for drug delivery to reach the glioblastoma cells and thus requires newer drug development strategies to aid drug delivery to the tumor site [5].
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Efflux pumps also serve as additional barriers in drug delivery to the brain that are present in endothelial cells lining. These efflux pumps are made up of protein complexes called adherens junctions primarily regulate the permeability of the endothelial barrier [6].
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Blood-cerebrospinal fluid also acts as a barrier that limits the free movement of molecules and drug compounds across the brain by strictly regulating the transfer of solutes between the blood and CSF [7].
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2. Drug delivery to brain: potential hurdles to overcome
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Mainly lipophilic drugs are used to treat CNS ailments and possess a molecular weight below 400 Da and log P between −0.5 and 6.0 [8, 9]. For drugs that are ionized at physiologic pH, it is their unionized fraction that determines the concentration gradient across the BBB for passive diffusion [2]. By considering these facts, a drug should be designed in such a manner that it has optimal lipid solubility so that it penetrates BBB and maintains a therapeutic concentration in the brain. But this is not that simple because only increasing the lipophilicity of the drug molecule via certain chemical modifications may not attain the desired pharmacokinetic effects as it may lead to decreased systemic solubility and bioavailability. It may also have increased protein binding and higher uptake by liver and reticuloendothelial system which ultimately leads to increased metabolism thus leading to diminished active drug concentration at the target site [2]. There are certain drug molecules that penetrate the BBB besides what their lipid solubility suggest. This penetration is attributed to the carrier-mediated transport of these polar compounds present at the tight junctions [10].
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3. Nanopharmaceuticals: an approach to achieve brain targeting
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Brain targeting is potentially difficult because of multiple barriers. Recent advances in nanotechnology present opportunities to overcome such limitations and to deliver the drug to the brain targets. Nanopharmaceuticals are the relatively newer field that employed “therapeutic containing nanomaterial” with unique physicochemical properties due to their small size (one to several 100 nm), high surface to volume ratio and flexibility to alter their properties [11]. An alternate definition can be pharmaceuticals engineered on the nanoscale for the therapeutic purpose [12]. Nanopharmaceuticals comprised of different nanomaterial like polymers, lipids, amphiphilic material, metals, inorganic elements, carbon nanotubes, dendrimers, etc., to constitute nanocarriers which can be fabricated in different sizes, shapes, morphology, surface charges and surface groups for the brain-specific targeted delivery of the drug across barriers. Nanopharmaceuticals mediated drug delivery system has the power to penetrate drug moieties across CNS, either passively or actively, and improve bioavailability and therapeutic efficacy of the drug even at a lower concentration. Currently, available marketed nanopharmaceuticals for the brain are mentioned in Table 1.
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Route
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Brand
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Nanocarrier
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Indication
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Manufacturer
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\n\n\n
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SC
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Copaxone
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Glatiramer acetate
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Multiple sclerosis
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TEVA
\n
\n
\n
IV
\n
DepoCyt®
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Cytarabine encapsulated in multivesicular liposomes (20 μm)
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Lymphomatous malignant meningitis
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Leadiant Biosciences
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\n
\n
Epidural space injection
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DepoDur®
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Morphine sulfate encapsulated in multivesicular liposomes (17–23 μm)
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Chronic pain
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Pacira Pharmaceuticals
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\n
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IV
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Opaxio®
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Paclitaxel covalently linked to SLN
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Glioblastoma
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Cell Therapeutics
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\n
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Intratumoral Injection
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NanoTherm®
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Aminosilane-coated superparamagnetic iron oxide (15 nm) nanoparticles
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Local ablation in glioblastoma, prostate, and pancreatic cancer
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Magforce
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\n
\n
Oral
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Avinza®
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Morphine sulfate nanocrystals
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Psychostimulant
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Pfizer/King Pharma
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\n
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Oral
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Focalin XR®
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Dexmethylphenidate HCl nanocrystals
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ADHD
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Novartis
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\n
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Oral
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Ritalin LA®
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Methylphenidate HCl nanocrystals
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ADHD
\n
Novartis
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\n
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SC injection
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Plegridy®
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Polymer-protein conjugate (PEGylated IFN Beta-1a)
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Multiple sclerosis
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Biogen
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\n
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IM injection
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Invega Sustenna®
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Paliperidone
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Schizophrenia
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Janssen Pharms
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\n
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IV
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AmBisome®
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Amphotericin B liposome
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Cryptococcal meningitis
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Gilead Sciences, Inc.
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\n
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IV
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Abelcet®
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Amphotericin B liposome
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Cryptococcal meningitis
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Enzon Pharma
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\n
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IV
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DaunoXome®
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Daunorubicin liposome
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Pediatric brain tumors
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Under Phase I trial
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\n
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IV
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Doxil®/Caelyx®
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Doxorubicin HSPC, cholesterol, and DSPE-PEG2,000
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Glioblastoma and Pediatric brain tumors
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Phase II Phase II
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\n
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IV
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Myocet®
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Doxorubicin EPC and cholesterol
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Glioblastoma
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Phase II
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IV
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SGT-53 (SynerGene Therapeutics)
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Cationic liposome with anti-transferrin antibody
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Glioblastoma
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Phase II
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\n
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—
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Cornell Dots
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Silica nanoparticles with a fluorophore, PEG-coated
Nanopharmaceuticals could able to breach blood-brain barriers through various mechanisms. On the simple edge, their smaller size leads to passive delivery of the drugs through transcellular route across brain’s epithelial cells or choroid plexus. Criteria for the simple passive diffusion across the barriers are molecular size less than 400 Da, low hydrogen bonding capacity and lipophilicity [13, 14]. Therefore, lipophilic and tailored nanocarriers could deliver the drug through this mechanism.
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While extremely hydrophobic molecules like nutrients (glucose and amino acids) pass through active diffusion mechanism with the aid of special transporter proteins. On the other hand, hydrophilic and larger molecules like transferrin and insulin pass through receptor-mediated transport across the membrane [15]. BBB majorly comprised of the endothelial layer which possessed tight junctions; the presence of proteins, namely occludins, claudins and adhesion molecules in the tight junction, make it a tougher barrier [16].
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Nanopharmaceuticals are custom-made to surpass the brain barriers through these mechanisms:
Lipophilic nanocarriers (liposomes, solid lipid nanoparticles SLN) fuse with the endothelial cells and transport the drug through the transcellular pathway or endocytosis. Moreover, nanoparticles provide a sustained drug release pattern in the bloodstream, enabling higher drug concentration to cross BBB [17].
Furthermore, nanoparticles are functionalized with ligands or specific surfaces to trigger receptor-mediated transcytosis or carrier-mediated transport across BBB. Attachment of ligands like lactoferrin, transferrin, insulin facilitated receptor-mediated transport. Cationized ligands and peptides like albumin cross through receptor-mediated absorptive transport. Nanoparticles surface can be modified to utilize active transport system comprising P-glycoproteins, L-transporters, nucleoside transporter, ionic transporter, multidrug-resistant proteins that transfer the molecules into the brain by consuming adenosine triphosphate (ATP) [17]
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Liposomes have been extensively studied and even FDA approved nanocarrier for brain disorders. Surface modulation of liposomes with functional proteins, peptides and polyethers aided targeted drug delivery for brain diseases [18]. PEGylated liposomes and glutathione-PEGylated liposomes evade body’s reticuloendothelial system and facilitate enhanced drug uptake across BBB [19]. Moreover, transferrin-modified liposomes [20], TAT peptide-conjugated liposomes [21], glucose-modified liposomes [22], and transferrin-folate bound liposome effectively deliver the drug across the barrier to treat multiple sclerosis [23]. Similarly, transferrin bound SLN and thiamine coated SLN were found to be efficacious in the treatment of cerebral malaria and increased drug uptake in the brain [24]. Mechanisms of transport across BBB are shown in Figure 1.
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Figure 1.
Different pathways for nanopharmaceuticals mediated transport across the blood-brain barrier (Under Creative Commons Attribution License 4.0, https://creativecommons.org/licenses/by/4.0/) [96].
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Polymeric nanoparticles accumulate in the brain tissue by both passive and active mechanisms. Chitosan-poly lactic-co-glycolic acid (PLGA) nanoparticles showed enhanced delivery of coenzyme Q to the brain of transgenic mice through absorption mediated endocytosis [25]. In another study, PLGA was coupled with Tet-1 peptide to achieve neuronal targeting of curcumin in the treatment of Alzheimer’s disease. Retrograde transportation of curcumin across the barriers destroyed amyloid aggregates and scavenges oxidative radicals in the brain [26]. Similarly, ligand attached polymeric-lipidic nanoparticles like nerve growth factor (NGF) loaded poly butyl cyanoacrylate (PBCA) liposomes considerably deliver the drug across the BBB cholinergic system in the amnesic rodent model [27]. Likewise, inorganic nanocarriers show promising outcomes in terms of brain targeting. Amine functionalized multi-walled carbon nanotubes adopted transcytosis mechanism to pass BBB [28]. A natural substance wheat germ agglutinin-horseradish peroxide (WGA-hrp) was conjugated to gold nanoparticles (AuNPs) and administered in the IM injection into the mice. Results were remarkable in terms of drug penetration across BBB [29].
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Dendrimers are the excellent drug carriers; their surface functionalization with folic acid, peptides, aptamers, amino acids, biotin, antibodies facilitated more site-specific targeting. To penetrate CNS barriers, dendrimers were conjugated with transferrin, lactoferrin, D-glucosamine, and leptin for more effective brain drug delivery [30].
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Some other nanoparticulate systems like nanoemulsion and nanogel can be functionalized with targeting moieties (transferrin, insulin, peptides) for CNS drug delivery. Nanogels made up of PEG-polyethylenimine (PEI) and N-vinylpyrrolidone/isopropyl acrylamide have been tested to ensure CNS drug delivery potential [30].
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5. Nanopharmaceuticals classification on the basis of routes of administration
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BBB mediated drug uptake restrictions prompt scientists to investigate drug delivery potential of the nanopharmaceuticals to the brain through various routes. The ultimate objective was to enhance drug penetration across BBB and to reduce disease index. Up till now, the most commonly employed route was systemic administration through Intravenous (IV) injection. Other natural routes like oral, intranasal (IN), intrathecal (IT), intraperitoneal (IP) have been used as well. Some novel strategies like cerebral devices, implants, Ultrasound-guided nanoparticle delivery, osmotic delivery gain much attention in the recent era. Different nanopharmaceuticals are illustrated in Figure 2. List of all nanopharmaceuticals delivered through different routes have been mentioned in Table 2.
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Figure 2.
Nanopharmaceuticals classification on the basis of route and nanocarriers.
The oral route is the most convenient, non-invasive and compliant mode of administration. However, brain targeting through the oral route was not investigated largely mainly due to indirect systemic entry through absorption from the gastrointestinal tract (GIT). Harsh GIT environment, slow onset of action, shorter half-life, first pass elimination and reduced systemic absorption hampered drug therapeutic efficacy and bioavailability. Thus, oral drug delivery failed to deliver the therapeutic moiety to the brain efficiently. In this regard, nanopharmaceuticals must possess the properties to bear harsh enzymatic environment, overcome first pass metabolism and efficiently permeate through the intestinal epithelial barrier to reach the systemic circulation.
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Scientists developed lipid nanocore surrounded by poly (e-caprolactone) and orally administered to the mice. The concentration of the loaded drug, indomethacin, was successively increased in the brain and efficiently treat glioblastoma in the mice model without causing BBB vessel alteration. This could serve as a basis for safe and effective brain targeting via oral route [31].
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Similarly, orally administered saquinavir-loaded nanoemulsion significantly delivers the drug across BBB. Nanoemulsion was stabilized by deoxycholic acid which overpasses first-pass elimination of the drug. The oily phase, polyunsaturated fatty acids (PUFA) facilitates rapid transport to the brain. It laid the foundation for effective brain targeting through oral route [32].
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Researchers formulated poly (butyl cyanoacrylate) nanoparticles, double coated with Tween 80 and polyethylene glycol (PEG)-2000 for the oral delivery of the dalargin to the brain. Dalargin is a hexapeptide, anti-nociceptive agent which could not cross BBB. However, its nanoformulation showed promising analgesic effects in the mice model, which demonstrated the potential of the nanoformulation for brain targeting via oral route [33].
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Orally administered Tween 80 coated PLGA deliver estradiol successfully to the brain. The therapeutic efficacy in elevating Alzheimer’s disease was parallel to the nanoformulation administered intramuscularly [34]. In short, oral delivery of drug-loaded nanopharmaceuticals achieved preliminary success but still need to be further explored in the near future.
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5.2. Intraperitoneal administration (IP)
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Intraperitoneal administration involved peritoneal cavity of the abdomen. The route is still under investigation. It has an advantage of delivering a larger amount of the drug and it is employed when a vein for the IV injection is not easily located. In addition, it can be employed when animals are not ready for oral administration. However, the route is currently limited to pre-clinical research in small animals and need to be scaled up [35].
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Iron oxide nanoparticles were fabricated with the aim to target subcellular compartment of the brain cells. For this purpose, iron oxide nanoparticles with different shapes (round, biconcave, spindle, nanotube) were synthesized and coated with glucose derived fluorescent carbon layer. In-vivo administration through IP route indicated biconcave nanoparticles localized in the nuclei and nanotube-shaped nanoparticles located in the cytoplasm of the brain cells. While the carbon coated surface on iron oxide nanoparticles facilitated attachment of several therapeutic moieties on the nanoparticles for their delivery inside the brain cells [36]. Therefore, the IP route could serve as a major route to deliver the drug across the brain barriers.
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5.3. Intravenous administration (IV)
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Systemic route including IV drug delivery to the brain involves the receptor-mediated and adsorptive mediated transcytosis. It is the most exploited route of administration for the nanoparticles because of the immediate action systemically and locally by targeted delivery. Polybutyl cyanoacrylate (PBCA) was first used for the synthesis of the NPs intended for the brain. Analgesic dalargin was incorporated in the PBCA NPs with Polysorbate 80 coating and a marked level of analgesia was seen in the animal studies after IV administration of the NPs [37]. PBCA NPs with doxorubicin coated with Polysorbate 80 were studied for their brain delivery in the rats and showed the promising result in 2–4 hours as compared to the uncoated NPs after IV drug delivery [38]. In a similar study, Polysorbate 80 coated PBCA NPs with a size of 280 nm were evaluated for the delivery of Loperamide across BBB following IV injection. Results were quite promising in the in-vivo nociceptive studies on mice [39]. Musumeci et al. prepared the docetaxel loaded nanospheres using PLGA and observed the biphasic release of drug following IV administration. An in vitro study using a biomembrane model made of dipalmitoylphosphatidylcholine (DPPC) was conducted and confirmed the significant release of the drug across the membrane, making it a potent drug delivery approach for crossing BBB [40]. An in vitro study was conducted on brain endothelial cell lines and glioma cells using nanocarrier system made with PLGA/PLA and a detailed sketch of cellular uptake, cytotoxicity and therapeutic efficiency were obtained. Furthermore, the animal studies confirmed the uptake of NPs in the brain following IV administration [41]. In one study, male Sprague Dawley rats were used for establishing the efficacy of curcumin as an anticancer drug with neuroprotective properties. The study group demonstrated that how the nanoparticles can increase the circulation time of curcumin in the body and penetration across the BBB, especially the distribution of NPs in the hippocampus. Half-life and mean residence time of curcumin increased after IV administration of NPs across the BBB [42]. Liu et al. demonstrated the effect of breviscapine loaded PLA NPs in rats after IV administration. NPs with an average particle size of 319 nm were distributed in the liver, spleen and brain. The prepared NPs had longer circulation life because they evaded the RES and crossed BBB [43]. Poly (alkyl cyanoacrylate) NPs can deliver several drugs like loperamide, doxorubicin, tubocurarine, etc., across the brain based on the principle of LDL receptor mediate endocytosis after injection of these NPs into the blood by IV administration. Prior to in vivo studies, these NPs were coated with surfactants like Poloxamers and Tween for the enhanced drug uptake by brain blood capillaries [44]. Some of the latest techniques of treating brain disorders include delivery of neurogenic genes, mRNA and siRNA. One such study was reported by Son et al. for the delivery of rabies virus glycoprotein (RVG) labeled disulfide containing polyethyleneimine (PEI) nanomaterial to the brain. In vivo studies revealed promising data after the infusion of RVG peptide linked nanomaterial in 6 weeks old male BALB/c mice. [45] MRI-driven targeting of the brain using iron oxide NPs of around 100 nm was reported by the group of researchers. Mice were injected with the NPs suspension and were kept in the magnetic field for 30 minutes. There was 5-folds increase in the accumulation of NPs in the glioma cells in the presence of a magnetic field as compared to undirected NPs following IV administration. This approach can be used as a non-invasive therapeutic and diagnostic tool in the various dimensions of health [46]. However, the associated issues like rapid body clearance through the reticuloendothelial system and unintended organ distribution must be overcome for appropriate brain-specific drug delivery.
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5.4. Intranasal administration (IN)
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Recently, intranasal (IN) route for the drug delivery to the brain proved to be a reliable and non-invasive mode to cross BBB while possessing the ability to deliver a wide range of drug moieties like smaller molecules, larger macromolecules, growth factors, viral vectors and even stem cells to the brain. The transport involves either olfactory or trigeminal nerve which has a direct link from the brain and terminated in the nasal cavity at respiratory epithelium or olfactory neuroepithelium [47]. The nasal mucosa is the target tissue for the drug administration and possessed features like a larger surface area, porous endothelial membrane, huge blood flow, the absence of first-pass elimination and readily accessible. Olfactory region of nasal mucosa provide nose to brain targeting feature and could able to treat various CNS disorders like depression, pain, Alzheimer’s disease, glioblastoma, multiple sclerosis etc. Several dosage forms, sprays, suspensions, nebulizers, aerosols, gel, solutions can be utilized for IN drug delivery [47]. On the other hand, barriers like mucociliary clearance from nasal mucosa, enzymatic degradation and low degree of permeability across nasal epithelium hinder the drug targeting efficiency to the brain. As a solution, nanopharmaceuticals were used which overcome the clearance and other nasal problems due to their unique nature.
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One of the studies demonstrated IN administration of chitosan nanoparticle to deliver bromocriptine, a dopaminergic agonist, to minimize motor function disorder associated with prolonged levodopa usage in the Parkinson’s disease. Results were promising in terms of motor function [48]. Didanosine-dideoxyinosine (ddI) is an antiretroviral therapy (HAART) and available in oral dosage forms, however, faced extensive degradation and elimination in GIT which decreases its bioavailability. To overcome the issues, dd loaded chitosan nanoparticles were administered through IN route. Results indicated higher brain to plasma, CSF to plasma and olfactory blood to plasma ratios in the case of IN delivered dd nanoparticles. It shows that nanoformulation can be directly delivered to the brain compartment through IN route [49].
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Another research group fabricated rivastigmine loaded chitosan nanoparticle for inhibiting acetylcholinesterase in the brain through IN administration. The free drug had severe bioavailability issues and distributed to the non-targeted site with severe side effects when administered through oral or IV route. Here, chitosan nanocarrier and administration through nasal route enhanced brain uptake with higher brain/blood ratio. It further highlighted the role of nanocarrier and route in brain targeting [50]. Similarly, Venlafaxine (VLF) chitosan nanoparticles were administered to the brain through the nasal route for the treatment of major depressive disorders and anxiety disorder with improved brain uptake and enhanced bioavailability [51].
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Another study showed microemulsion and mucoadhesive delivering clonazepam, an anxiolytic, sedative, hypnotic, anticonvulsant drug to the brain. The brain/blood uptake ratio of the intranasal microemulsion and mucoadhesive microemulsion were significantly higher than the IV administered microemulsion, indicating the effectiveness of IN route for brain-specific drug delivery [52]. Similarly, the microemulsion was used for the IN delivery of nimodipine to the brain cells. The microemulsion leads to 3-fold more drug uptake by the olfactory bulb than the IV route. AUC ratio of brain to plasma and cerebrospinal fluid (CSF) to plasma were higher after IN administration in comparison to IV injection. Thus, it could be a promising approach to treat neurodegenerative disorders [53]. Risperidone nanoemulsion and mucoadhesive nanoemulsion were administered through IN route for the treatment of schizophrenia. The composition of nanoemulsion included glyceryl monocaprylate as an oily phase, tween 80 as a surfactant and mixture of propylene glycol and transcutol as a co-surfactant. While mucoadhesive microemulsion had chitosan polymer which induces mucoadhesive properties. The nanoemulsion and mucoadhesive nanoemulsion improved risperidone bioavailability, prevent first pass metabolism and bypass BBB to achieve desired drug concentration at the targeted site. The brain/blood uptake ratio and drug transport efficiency were found to be significantly higher through nasal administration in comparison to the IV injection [54].
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Furthermore, nanostructured lipid carriers comprising duloxetine was prepared and delivered to the brain via IN route for the treatment of the major depressive disorder. The results revealed prolonged drug release and therapeutic effect as demonstrated from improved behavior analysis after 24 hours [55].
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Furthermore, micellar nanocarrier (amphiphilic nanocarriers) of sumatriptan was developed to treat an acute migraine to improve cerebral blood flow. Limitations of the drug associated with oral dosage forms and subcutaneous administration like poor bioavailability, shorter plasma half-life, and hepatic elimination have been resolved to much extent through incorporation in micellar nanocarrier. And increased brain concentration of the drug and site-retention can be achieved via nose to brain drug delivery [56]. Similarly, zolmitriptan-loaded micellar nanocarriers were prepared to target brain serotonin receptors and inhibit cranial vessel inflammation. Micellar nanocarriers were administered through nasal route with enhanced characteristics like lower particle size, higher permeation across nasal mucosa, appropriate flow rate, ability to load hydrophilic as well as hydrophobic drugs, enhanced site-retention and ultimately enhanced drug therapeutic activity [57].
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Another polymer methoxy-PEG-polycaprolactone was used to encapsulate coumarin with promising brain penetration and myelin binding properties, while administered through nasal route [58]. Bioadhesive nanocarriers reported in the above studies overcome many hurdles associated with a nasal route like protection of drug against enzymatic degradation, enhanced permeability, and avoidance of mucociliary clearance. However, IN delivery of nanopharmaceuticals should be further improved with targeting moieties and incorporation of cost-effective approach.
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6. Alternate routes and strategies
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6.1. Conventional enhanced delivery (CED)
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Potential brain barriers can be by-passed by injecting the drug directly into the tissues using catheter. Such a direct delivery of therapeutic agent to the target site is termed as conventional enhanced delivery (CED). Many pre-clinical studies adapted CED to infuse nano-formulations directly into the brain [59]. C57BL/6 J mice were used to infuse a 10 μL solution of lipid nanocapsules (LNCs) having an average size of 70 nm into their skull at an infusion rate of 0.5 μL/min [60]. An alternate method for direct infusion was also reported in which drug-loaded micelles were injected by making small incisions on the skull. A foremost shortcoming CED technique is its invasiveness which requires high anesthetic doses prior to incisions, which resulted in the death of the experimental rats [61]. This technique also requires the optimization of certain factors like pH and osmolarity to surpass any brain damage [62].
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6.2. Intracarotid delivery
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Administering the drug into the carotid artery provides an alternative solution to direct delivery. This direct systemic delivery requires a catheter to directly inject drugs into the bloodstream. In a study, the efficacy of direct systemic delivery was reported almost twice to that of CED in terms of brain damage [63]. IV route is also used to deliver the drug directly into systemic circulation. Ferrociphenol-loaded lipid nanoparticles were infused to manage glioma via the IV route. The outcomes showed that mean survival of the rats was 28 days while mean survival rate recorded foe CED was of 24 days [62, 64].
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6.3. Intratumor delivery
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Polylactic acid (PLA) and poly-dimethylaminoethyl methacrylate (PDMAEMA) were used to synthesize amphiphilic star-branched co-polymeric nanoparticles for intratumor delivery of the drugs for treating brain tumors. In a study, this system was used to deliver combined DOX and miR-21 inhibitor (miR-21i) into LN229 glioma cells directly. These micelles protected miR-21i from lysosome degradation and the release of DOX to the nucleus, which ultimately decreased the miR-21 expression. This combined DOX and miR-21i delivery surprisingly displayed an anti-proliferative efficiency compared with separate treatment of DOX or the miR-21. The outcomes revealed that this co-polymeric system was a better option for delivering genes and hydrophobic therapeutic agents [65].
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6.4. Other parenteral routes
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Delivering the drug directly into the brain is another way of treating brain disorders. This local drug delivery has been approved by the US FDA [66]. Intrathecal administration of nanopharmaceuticals delivers the nano-drugs in the CSF. However, this route of administration is most commonly used for anesthetics and neurotic pain [67]. This route is under experimental phases in humans. It includes two different ways of delivering the therapeutic moiety, either by infusion in the intralumbar region or intraventricularly using an Ommaya reservoir placed subcutaneously and connected to the brain with a catheter [68]. Thioflavin-T was delivered by intrahippocampal injection for targeting the β amyloid in the brain using the nanoparticles. The data reported localization of thioflavin-T in the intracellular and extracellular spaces of the brain, which prevented the formation of β-amyloid aggregates in the Alzheimer’s disease. This same method can be adapted to deliver the anticancerous drugs as well as other analgesic peptides [69]. In an in situ perfusion study conducted on mice, Polysorbate 80 coated PBCA NPs loaded with the tubocurarine were able to cross the BBB after intraventricular drug administration. There was a marked effect on the EEG epileptiform spikes [70]. Intraarterial drug delivery has an advantage over the other conventional systems of drug delivery because of the increased dose delivery at the desired site of the brain. This route can also be exploited for the immun0-targeting. However, this route has some limitations like a dilution of the drug because of cerebral blood flow [71].
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6.5. Ultrasound guided drug delivery
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Ultrasound facilitated drug penetration through brain barriers is yet another option for safe and reversible targeted drug delivery [72]. In this technique, ultrasound radiations are employed to generate shear stress on the vascular endothelium for a transient and reversible perforation in the BBB which facilitates the nanoscaled drug delivery to the targeted site. It appeared in a research outcome that docosahexaenoic acid binding with low-density lipoprotein NPs can penetrate the BBB by the application of ultrasound sonication. A near IR fluorescent dye examination revealed about 60 times greater accumulation of sonication facilitated drug delivery to the targeted site. The main advantage reported was lack of cytotoxicity or neuronal damage due to pointed ultrasound irradiation [73]. PEGylated PLA nanoparticles delivery to the brain was facilitated via ultrasound-induced perforation. β-specific antibody 6E10 was conjugated on PEG-PLA along with the coumarin 6 and DiR as fluorescent probes to assess the target site accumulation. Ultrasonication facilitated NPs penetration was about 2.5-fold more than the complementary non-sonicating therapy [74]. Ultrasound techniques can be used to aid the enhanced delivery of PEG-b-poly(l-Lysine) coupled with siRNA into glioma cells by 10-fold in conjunction with a newer gas-cored nanobubble [75].
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7. Future prospects for nanopharmaceuticals delivery
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Another targeted approach to the brain for delivering drugs is through the ocular route. The ocular route has so many advantages like reduced peripheral toxicity and direct delivery of therapeutic moiety in the target site [76]. Ocular and intranasal drug delivery for the brain was compared by a group, in which nerve growth factor (NGF) was used for treating Alzheimer’s disease. However, it was found out that intranasal drug administration was more effective and potent for brain disorders and ocular route did not perform well. However, many scientists are working for making the ocular route a success because of it being the compliant and non-invasive route [77]. There has been a huge room for the administration of nanocarrier through ocular route to the brain. Nanocarrier can facilitate drug delivery to the brain because of their size, site-retention properties and enhanced adhesion to the lacrimal fluid. The route can be exploited for the delivery of drugs and genes to CNS by avoiding systemic exposure via nanopharmaceuticals [78].
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8. Conclusion
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Brain-targeted drug delivery is a difficult matter due to anatomic and pathophysiological brain barriers. The current advances in nanotechnology provide a solution in the form of nanopharmaceuticals, drug containing nanocarriers, to cross the CNS barriers and to target the brain tissue in various disorders. Nanopharmaceuticals’ mode of administration into the body is an important aspect, which ultimately effects drug concentration in the brain and drug therapeutic effect. Current chapter highlighted the routes of administration through which nanopharmaceuticals can be delivered to reach the brain. Every route has pros and cons, nanopharmaceuticals overcome the route associated limitations in the delivery of drug to the brain due to their peculiar physicochemical properties and surface modulation. Translation this research area into the clinic still require investigations, as safety is the foremost concern and distribution to other body organs must be eradicated. Moreover, there is a need to control the drug delivery rate when nanopharmaceuticals reach the brain for safer action.
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Conflict of interest
The authors declared no conflict of interest.
\n',keywords:"nanocarriers, nanoparticles, nanopharmaceuticals, ligand, brain diseases, targeted drug delivery, nanomedicine, route of administration",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67502.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67502.xml",downloadPdfUrl:"/chapter/pdf-download/67502",previewPdfUrl:"/chapter/pdf-preview/67502",totalDownloads:337,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 3rd 2018",dateReviewed:"December 5th 2018",datePrePublished:"June 4th 2019",datePublished:null,readingETA:"0",abstract:"Brain is well known for its multifarious nature and complicated diseases. Brain consists of natural barriers that pose difficulty for the therapeutic agents to reach the brain tissues. Blood-brain barrier is the major barrier while blood-brain tumor barrier, blood-cerebrospinal (CSF) barrier and efflux pump impart additional hindrance. Therapeutic goal is to achieve a considerable drug concentration in the brain tissues in order to obtain desired therapeutic outcomes. To overcome the barriers, nanotechnology was employed in the field of drug delivery and brain targeting. Nanopharmaceuticals are rapidly emerging sub-branch that deals with the drug-loaded nanocarriers or nanomaterials that have unique physicochemical properties and minute size range for penetrating the CNS. Additionally, nanopharmaceuticals can be tailored with functional modalities to achieve active targeting to the brain tissues. The magic behind their therapeutic success is the reduced amount of dose and lesser toxicity, whereby localizing the therapeutic agent to the specific site. Different types of nanopharmaceuticals like polymeric, lipidic and amphiphilic nanocarriers were administered into the living organisms by exploiting different routes for improved targeted therapy. Therefore, it is essential to throw light on the properties, mechanism and delivery route of the major nanopharmaceuticals that are employed for the brain-specific drug delivery.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67502",risUrl:"/chapter/ris/67502",signatures:"Mahira Zeeshan, Mahwash Mukhtar, Qurat Ul Ain, Salman Khan and Hussain Ali",book:{id:"8331",title:"Pharmaceutical Formulation Design - Recent Practices",subtitle:null,fullTitle:"Pharmaceutical Formulation Design - Recent Practices",slug:null,publishedDate:null,bookSignature:"Dr. Usama Ahmad and Dr. Juber Akhtar",coverURL:"https://cdn.intechopen.com/books/images_new/8331.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1. Barriers in delivering drug to brain",level:"2"},{id:"sec_1_3",title:"1.1.1. The blood-brain barrier (BBB)",level:"3"},{id:"sec_2_3",title:"1.1.2. Other barriers",level:"3"},{id:"sec_5",title:"2. Drug delivery to brain: potential hurdles to overcome",level:"1"},{id:"sec_6",title:"3. Nanopharmaceuticals: an approach to achieve brain targeting",level:"1"},{id:"sec_7",title:"4. Nanopharmaceuticals: brain targeting mechanisms",level:"1"},{id:"sec_8",title:"5. Nanopharmaceuticals classification on the basis of routes of administration",level:"1"},{id:"sec_8_2",title:"5.1. Oral administration",level:"2"},{id:"sec_9_2",title:"5.2. Intraperitoneal administration (IP)",level:"2"},{id:"sec_10_2",title:"5.3. Intravenous administration (IV)",level:"2"},{id:"sec_11_2",title:"5.4. Intranasal administration (IN)",level:"2"},{id:"sec_13",title:"6. Alternate routes and strategies",level:"1"},{id:"sec_13_2",title:"6.1. Conventional enhanced delivery (CED)",level:"2"},{id:"sec_14_2",title:"6.2. Intracarotid delivery",level:"2"},{id:"sec_15_2",title:"6.3. Intratumor delivery",level:"2"},{id:"sec_16_2",title:"6.4. Other parenteral routes",level:"2"},{id:"sec_17_2",title:"6.5. Ultrasound guided drug delivery",level:"2"},{id:"sec_19",title:"7. Future prospects for nanopharmaceuticals delivery",level:"1"},{id:"sec_20",title:"8. Conclusion",level:"1"},{id:"sec_24",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Dong X. Current strategies for brain drug delivery. Theranostics. 2018;8:1481\n'},{id:"B2",body:'Begley DJ. Delivery of therapeutic agents to the central nervous system: The problems and the possibilities. Pharmacology & Therapeutics. 2004;104:29-45\n'},{id:"B3",body:'Sharma U, Badyal PN, Gupta S. Polymeric nanoparticles drug delivery to brain: A review. International Journal of Pharmacology. 2015;2:60-69\n'},{id:"B4",body:'Pehlivan SB. 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Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
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The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 116,000 international scientists and researchers.
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The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
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10,000 GBP Monograph - Long Form
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4,000 GBP Compacts Monograph - Short Form
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\\n\\n
*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\\n\\n
Services included are:
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\\n\\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\\n\\t
Discoverability - electronic citation and linking via DOI
\\n\\t
Permanent and unrestricted online access to your work
What isn't covered by the Open Access Publishing Fee?
\\n\\n
If your manuscript:
\\n\\n
\\n\\t
Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
\\n\\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\\n
\\n\\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\\n\\n
Open Access Funding
\\n\\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
\\n\\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\\n\\n
Added Value of Publishing with IntechOpen
\\n\\n
Choosing to publish with IntechOpen ensures the following benefits:
\\n\\n
\\n\\t
Indexing and listing across major repositories
\\n\\t
Long-term archiving Visibility on the world's strongest OA platform
\\n\\t
Live Performance Metrics to track readership and the impact of your chapter
\\n\\t
Dissemination and Promotion
\\n
\\n\\n
Benefits of Publishing with IntechOpen
\\n\\n
\\n\\t
Proven world leader in Open Access book publishing with over 10 years experience
\\n\\t
+4,400 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes, enabling publication between 8 and 12 months
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Personal support during every step of the publication process
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+84,800 citations in Web of Science databases
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Currently strongest OA platform with over 130 million downloads
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 116,000 international scientists and researchers.
\n\n
The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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OAPF Publishing Options
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\n\t
1,400 GBP Chapter - Edited Volume
\n\t
10,000 GBP Monograph - Long Form
\n\t
4,000 GBP Compacts Monograph - Short Form
\n
\n\n
*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\n\n
Services included are:
\n\n
\n\t
An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\n\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\n\t
Discoverability - electronic citation and linking via DOI
\n\t
Permanent and unrestricted online access to your work
What isn't covered by the Open Access Publishing Fee?
\n\n
If your manuscript:
\n\n
\n\t
Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
\n\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\n
\n\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\n\n
Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
\n\n
Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories
\n\t
Long-term archiving Visibility on the world's strongest OA platform
\n\t
Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
\n
\n\n
Benefits of Publishing with IntechOpen
\n\n
\n\t
Proven world leader in Open Access book publishing with over 10 years experience
\n\t
+4,400 OA books published
\n\t
Most competitive prices in the market
\n\t
Fully compliant with OA funding requirements
\n\t
Optimized processes, enabling publication between 8 and 12 months
\n\t
Personal support during every step of the publication process
\n\t
+84,800 citations in Web of Science databases
\n\t
Currently strongest OA platform with over 130 million downloads
\n
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