Abstract
Nanomedicine and nano delivery systems, although relatively recent but fast-developing technology is one where nanoscale materials are used to function as diagnostic tools or to deliver therapeutic agents to specifically targeted sites in a controlled manner. It also provides many advantages in the management of human diseases. Recently, there has been a range of excellent uses of nanomedicine as chemotherapeutic agents, biological agents, immunotherapeutic agents, etc., for treatment of different diseases. In this chapter we discuss the recent developments and insights obtained in the field of nanomedicine. It provides a review of the numerous nano-based drug delivery systems that enhance the efficacy of new and old drugs. The new opportunities and challenges arising in the area of nanomedicine from therapeutic viewpoint are also addressed.
Keywords
- nanomedicines
- nanoparticles
- drug delivery systems
- drug targeting
- natural products added
1. Introduction
Human beings have been widely utilizing plant-based natural products as medicines against various diseases since ancient times. Many medicines are derived primarily from herbs, based on traditional knowledge and practices. Currently about 25% of the available therapeutic compounds and their derivatives are derived from natural resources [1, 2]. Natural compounds have impressive characteristics, such as exceptional chemical versatility, chemical and biological properties of macromolecular specificities and less toxicity. These thus constitute them as leads in the discovery of novel drugs [3]. In spite of several advantages, pharmaceutical companies are hesitant to commit to more in drug discovery and drug delivery systems based on natural compounds due to concerns associated with biocompatibility, toxicity, large size and targeted delivery, etc., and many natural compounds not even clearing the clinical trial phases [4, 5]. Hence, this presents a greater challenge of using them as medicine. Thus alternatively available libraries of chemical compounds are being explored to discover novel medicines. Various techniques like nanotechnology play substantial role in advancing drug formulations, targeting, efficient release and delivery with immense success. Nanotechnology bridges the barrier between physical and biological sciences by providing nanostructures with potential to fill the lacunae existing in various fields of sciences and in particular in the field of medicine.
The use of nanotechnology in the production of efficient medicines has been recognized as a key enabling technology, capable of delivering fresh and creative therapeutic approaches to address unmet medical demands [6]. The use of nanotechnology for medical purposes is referred to as nanomedicine [7] and nanomaterials are used for prevention, early diagnosis or treatment of a wide range of diseases with high specificity, efficacy, and personalization, to improve quality of life of patients. Owing to their small scale, nanomaterials have novel physicochemical properties, distinct from those of their traditional bulk chemical counterparts. Such properties significantly improve a range of opportunities in drug development. These physicochemical properties of nanoformulations can lead to pharmacokinetics/pharmacodynamics being changed, namely the delivery, absorption, removal and metabolism, the potential for more easily breaching biological barriers and their persistence in the environment and the human body.
The key component of nanomedicines are nanoparticles (NPs) and currently wide range of nanoparticle types exist depending on their structural features such as spheres [8], rods [9], wires [10], stars [11], sheets [12], multipodes [13], cages [14], etc. These particles can efficiently carry and deliver therapeutic agents as well as imaging and sensing agents to targeted sites. Nanoparticle carriers or nanocarriers have many advantages in medicine. First, they allow stable aqueous dispersions of active but poorly water-soluble therapeutic agents for delivery into the biological environment. Second, their structure, scale, shape and surface properties can be finely designed to protect the encapsulated agent when incorporated into the biological world and prevent it from degradation by various endogenous defense mechanisms including, immunodegradation, enzymatic degradation, reticuloendothelial system sequestration (RES) in the bloodstream, acid hydrolysis, lung mucociliary clearance, etc.
2. Delivery system of nanoformulations
Delivery of nanomedicines can be by intracellular transport, epileptic transport and other types. Intercellular transport is facilitated and regulated through intracellularization, transporter mediated endocytosis, and permeation by interactions through particle size and/or cell surface [15, 16]. In addition, a smaller nanomedicine particle size improves intercellular transport which facilitates cell permeation and affects nanomedicine absorption, dissemination, and excretion. In fact, cell internalization by transporter-mediated endocytosis depends on the size of the nanomedicine molecule. Similarly in large particle sized nanomedicine, opsonization occurs quickly and its removal from the blood is facilitated by endothelial macrophages. The susceptibility of nanomedicinal cell surface transporters to nanomedicinal products has been reported to vary depending on the particle size of nanomedicinal products, and this can also impact the effective removal by macrophages of large particles from the blood. Nanomedicines composed of non-charged polymers, surfactants, or polymer coatings that degrade
3. Nanomaterial based delivery system
Nanotechnology in drug delivery has the potential to overturn the treatment of various diseases such as cancer, diabetes, neurodegenerative diseases, vascular diseases, etc. [18]. In the market for sale, nanotechnology based formulations are largely parenteral, with some intended for oral administration [19]. It is hoped that a significant number of preclinical and clinical trials would lead to the production of novel nanotherapeutics intended for non-parenteral delivery routes, such as pulmonary, nasal, vaginal, ocular, and dermal delivery routes. Of special concern to drug delivery systems (European Commission/ETP) [20] is the option of delivery and the obstacles to be addressed. Over time, various formulations based on nanoparticles have been developed to enhance the delivery mechanism of drugs, such as discussed below:
3.1 Polymeric nanoparticles
The most widely used chemical nanoparticles are constructed from synthetic polymers as natural polymers result in low reproducibility and controlled release actions for the trapped products, leading to variability in purity and batch-to-batch quality. At the other side, synthetic polymers with good to batch reproducibility and purity are available which facilitates the modification of the pattern of drug release from polymeric nanoparticles [21]. Nanoparticles formulated with synthetic polymers have been widely studied for drug distribution/delivery. In double emulsion methods hydrophilic moieties will encapsulate onto synthetic polymer-based nanoparticles, as it is not easy to maintain activity in unfavorable environment. Various synthetic polymers reported for drug delivery with biodegradable aliphatic polymers such as polylactide (PLA), poly lactide-co-glycolide, copolymers (PLGA) and poly (ε-carpolactone), as well as non-biodegradable polymers like polyacrylates and poly (methyl methacrylate) are used widely [22]. Polymer nanoparticles can efficiently shield unstable drugs from deterioration/degradation, thus avoiding the side effects of toxic medications. Natural polymeric nanoparticles consist of polymers of natural products like alginate, chitosan, albumin and gelatin [22]. Application of polymeric nanoparticles with therapeutic drugs such as dexamethasone or alpha-tocopheryl succinate can be used to avoid the cisplatin ototoxicity due to treatment with chemotherapy. Nanoparticles, trapping, transporting and ultimately spreading dexamethasone or alpha-tocopheryl succinate are capable of partially preventing large-dose ototoxicity of CDDP [23]. However, when administered systemically for long periods of time, these least soluble drugs have serious side effects. In the hydrophobic cavity of nanoparticles, the integration of such pharmaceutical products provides the requisite results
3.2 Lipid nanoparticles
Lipid nanoparticles that are prepared with a solid matrix are called solid lipid nanoparticles (SLNs). These are constructed from nanoemulsions of oil in water with the utilization of a solid lipid. The first generations of SLNs were formed in the early 1990’s [26]. The benefits associated with SLNs include cheap raw materials, usage of physiological lipids, avoidance of organic solvents, ease of scale-up, strong biocompatibility, enhancement of bioavailability, safety of vulnerable molds from environmental hazards and regulated drug release [27]. Using ultrasonic melt emulsification [28], ciprofloxacin (CIP)-loaded SLNs have recently been formulated with powerful antibacterial action. These were produced with a scale ranging from 165 to 320 nm and a polydispersity index with high trapping efficiency falling between 0.18 and 0.33. A controlled-release pattern of different lipids was shown by CIP release showing the full burst reaction, which contributes to the drug’s rapid release. For 120 days this composition of CIPSTE was found to be stable at room temperature. SLNs for different routes of delivery, such as oral [29], dermal [30], pulmonary [31], ocular [32] and rectal [33], have been extensively tested
3.3 Dendrimers
Dendrimers are special three-dimensional, hyper-branched, globular nano-polymeric structures. Attractive features such as water solubility, nano scaled size, narrow polydispersity index, modifiable molecular structure, internal cavity and several peripheral functional groups separate these from other nano systems. Terminal functionality serves as a platform for the conjugation and targeting of drugs. Such peripheral functional groups also provide them with tailor-made properties which improve their versatility [35]. The most commonly studied dendrimer for drug delivery is polyamidoamine. It’s synthesis starts with the amine group, which interacts with methyl acrylate and contributes to the formation of two new branches of dendrimer terminated by ester. The amine-terminated dendrimer ‘Full-generation’ may be formed by subsequent amidation of the methyl ester with ethylene diamine. PAMAM dendrimers are non-immunogenic, biocompatible and water-soluble, and have functional terminal amine groups that can be altered to targeting drugs [35]. Dendrimers have been widely investigated for biodelivery via transdermal, nasal, ocular, and pulmonary pathways, in addition to improving solubility. Many of the synthetic cationic polymers such as amidised acid-labile allow different cargo delivery [36]. Changing their structure could solve toxicity-related problems [35]. A recent study showed that arginine terminated peptide dendrimers, along with sonophoresis, can significantly increase ketoprofen’s transdermal penetration [37]. The findings revealed that the use of peptide dendrimer and application of ultrasound has worked synergistically.
3.4 Nanoemulsion
Nanoemulsions are a fascinating colloidal drug delivery mechanism, thermodynamically stable and filtration-sterilizable [40, 41]. There are heterogeneous mixtures of oil droplets in aqueous media resulting in nano droplets with a small scale distribution. The resultant nanoemulsions are analyzed as translucent or clear, isotropic and supported by the suitable surfactant [42]. Three types of nanoemulsions can be developed:
water in oil nanoemulsion
oil in water nanoemulsion
bi-continuous nanoemulsion
The most detailed function of nanoemulsions is to mask the unpleasant taste of oily liquids. These also provide long-term drug action and prevention from hydrolysis and oxidation. These nanoformulations can therefore be identified as an efficient and impregnable delivery option with high bioavailability. Nanoemulsions are currently being explored extensively to target different photosensitizers, anticancer drugs, or therapeutic agents. Such nanoformulations propose a number of applications such as drug delivery, biologic diagnostics and chemical agents [43]. In 2016, Simion et al. developed targeted dexamethasone-loaded P-selectin lipid nanoemulsions to minimize vascular inflammation [44]. Prepared formulations have been described for physicochemical assays. In their study, nanoformulation was found to be efficient in both
3.5 Nonstructured lipid carriers (NLC)
Nonstructured lipid carriers comprise the nanosystems of the second generation, consisting of solid lipid embedded into liquid lipids [46]. These nano carriers allow for a strong immobilization of therapeutic agents and avoid particle coalition of particles relative to emulsions [47, 48]. Therefore, because of the liquid oil droplets in a solid matrix, their drug loading potential is increased relative to SLNs. Biodegradability, lower toxicity, controlled release, drug tolerance and avoidance of organic solvents during manufacturing are among the beneficial effects of NLC on polymeric nanoparticles. NLCs have been extensively studied for hydrophobic and hydrophilic drug transport in recent years. The NLCs are developed to satisfy industrial specifications related to certification and registration, basic infrastructure, scale-up and low cost criteria [49]. The presence of multiple consumer goods reflects the carrier’s success story. Numerous other NLC products, including NLC repair cream and NLC restoration cream, are commercially available. For the treatment of different diseases, NLCs were explored through various routes of administration viz. oral, nasal, and parenteral [50]. Fluconazole-loaded NLCs were constructed using probe ultrasonication method and studied for antifungal activity on various
3.6 Nanogel
Nanogels, comprised of flexible hydrophilic polymers, can be prepared as plain gels [52]. Upon swelling, the drug can be randomly inserted into the nanogel. As a result, the gel collapses, resulting in the creation of solid, compact nanoparticles with reduced solvent amount. Nanogels provide novel applications for polymer-based drug carrier systems due to their biocompatibility, high moisture content and suitable mechanical properties. These gels have expanded polyvalent bioconjugation surface area and an internal network for biomolecule trapping. Physical encapsulation of bioactive compounds in the polymeric interlock along with their releasing pattern has been widely explored as a targeted mode of drug delivery [53]. Several approaches for the preparation of nanogels include micro-molding and photolithographic methods, continuous micro fluidics, modification of biopolymers, and heterogeneous living/controlled radical and free radical polymerizations [54]. Several criteria are required for designing and manufacturing of an efficient nanogel drug carrier system for therapeutic application. The consistency of nanogels for long-lasting blood circulation is one significant criterion. Another extraordinary novel feature that can detect receptors on infected cells is the bioconjugation of nanogel surfaces with particular ligands. Eventually, the biodegradability of nanogels should not only control the release of the drug for the required amount of time, but also make it possible to eliminate the empty system after the release of the drug [54]. In a recent study, topical delivery of chitin nanogel loaded with clobetasol is reported. This nanogel demonstrated exceptional toxicity against THP-1 and HaCaT cell lines by MTT assay. Nanoformulation demonstrated significant anti-inflammatory ability with an average inhibition of LOX and COX activities in THP-1 cells of 70 percent and 65 percent. Increased transdermal flux has been obtained from permeation studies of
3.7 Nanocapsule
Nanocapsule consists of either liquid or solid core in which drug is loaded and encapsulated by membrane of synthetic or natural polymers [56, 57, 58]. Lipid core nanocapsules are prepared by the precipitation method. Prepared nanoparticles have been tested for physical, chemical and biological characteristics. The most important characteristics to note during their synthesis are particle size and distribution. This can be calculated through multi-angle laser light scattering in a superconducting quantum interference instrument through X-ray diffraction, X-ray photoelectron spectroscopy, Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM) [57]. Chemically stable, biocompatible and readily reproducible are industrial bioactive nanocapsules. Because of their coating, which protects the encapsulated material from unenviable effects, such as dissolving the liquid and avoiding the release of active components, they have captured the attention of research groups. In biomedical research, agrochemicals, sanitizing materials, cosmetics and water treatment, nanocapsules have a wide range of biomedical applications. In addition, the effectiveness of such medications has also been studied for cancer treatment [59], radiotherapy [60], self-healing, contagion [78] and for use in food and agriculture. New developed nanocapsules will open new avenues of research and development for the delivery of bioactive compounds to target tissues in the future [57, 58]. Due to their ability to destroy colon cancer cells, resveratrol-charged lipid-core-nanocapsules (RSV-LNC) were developed and characterized. Constant and controlled drug release has been confirmed by the RSV-LNC. Increased anticancer activity in HT29 cancer cells compared to free RSV resulted in RSV incorporated in the nanocapsule. RSV-loaded nanocapsules have a promising potential for enhancing therapeutic effectiveness in colon cancer cells based on
3.8 Nanosponges
Nanosponges have drawn the interest of drug delivery scientists in pharmaceutical science as they have the capacity to load both hydrophilic and lipophilic moieties [61, 62]. These are thin, non-toxic, porous colloidal structures of scaffolds that have multiple cavities where drug molecules can be stuck. In the processing of these nanocarriers, α-cyclodextrins are the most commonly used. It is possible to investigate different crosslinkers in their development, such as hexamethylene di-isocyanate, carbonyl di-imidazole, pyromellitic dianhydride, diphenyl carbonate, etc. In water as well as in organic solvents, these structures are insoluble [63], self-sterile [64, 65] and stable up to 300° C and pH range of 2–11. Using ultrasound-assisted synthesis techniques, Trotta and colleagues produced cyclodextrin nanosponges [86] and examined them for anti-tumor drugs [66]. Efavirenz is a class II drug, a non-nucleoside reverse transcriptase inhibitor widely used for HIV [67]. This medicine, however, exhibits less solubility and reduced bioavailability. Beta-cyclodextrin cross linking with carbonates in variable ratios was performed to increase the solubility and dissolution of this compound. Some of the advertised formulations of nanosponge are Glymasason, Prostavastin, Brexin and Mena-gargle [68, 69].
3.9 Inorganic nanoparticles
Silver, gold, iron oxide and silica are included in inorganic nanoparticles. Nevertheless, only a few nanoparticles have been approved for clinical use, while most of them are still in the clinical trial stage. Metal nanoparticles, silver and gold, have different properties such as SPR (surface plasmon resonance) that liposomes, dendrimers, micelles do not exhibit. They show a variety of benefits when it comes to surface durability, such as decent biocompatibility and flexibility. Studies of their delivery-based actions have not been able to establish whether their toxicity is based to the particulate or ionized form; and while two mechanisms, such as paracellular transport and transcytosis, have been suggested, there is inadequate evidence on their
3.10 Quantum dots
Quantum dots (QDs) are regarded as semiconductor nanocrystals with a diameter ranging from 2 to 10 nm with their optical characteristics, such as absorbance and photoluminescence being size-dependent [74]. QDs have received significant interest in the field of nanomedicine, because, unlike traditional organic dyes, QDs pose emissions in the near-infrared region (< 650 nm), a very advantageous phenomenon in the field of biomedical imaging, due to low tissue absorption and decreased light dispersion [75]. Furthermore, the same light source can excite QDs with different sizes and/or compositions resulting in separate emission colors over a wide spectral range [76, 77]. In this way, QDs are quite attractive to multiplex imagery. QDs have been extensively studied in the field of medicine as targeted delivery of drugs, sensoring and imaging agents. A large number of studies on the use of QDs as contrast agents for
4. Natural product based drug delivery system
Natural product-based materials are currently considered to be the key ingredients in the preparation and processing of new nanoformulations as they have interesting features such as biodegradability, biocompatibility, availability, renewability and low toxicity [85, 86, 87]. In addition to the aforementioned properties, biomaterials are largely capable of undergoing chemical modifications, ensuring unique and desirable properties for potential nanomedicine uses [88, 89]. For example, nanoparticles of metals, metal oxide and sulfides have been recorded to be synthesized using different microorganisms, including bacteria, fungi, algae, yeast, etc., [90] or plant extracts. Microorganism that assists the synthesis process is prepared in the adequate growth medium and then mixed with a metal precursor and left for incubation to form the nanoparticles either intracellularly or extracellularly [91, 92, 93]. Similarly, plant extracts are used for synthesis in which the extract is mixed with the metal precursor and incubated further at room temperature or boiling temperature for a definite time or exposed to light as an external stimulus [94]. Currently, natural product-based materials are considered essential ingredients in the preparation and production of nanoformulations as they have fascinating characteristics such as biodegradability, biocompatibility, sustainability, renewable energy and low toxicity [85, 86, 95]. In addition to the above mentioned properties, biomaterials are, for the most part, capable of undergoing chemical modifications, guaranteeing them special and attractive properties for future applications in the field of nanomedicine [89, 96, 97]. Nanoparticles, especially the silver nanoparticles have been prolifically studied
In addition, it can be seen that the sustained release mechanisms of naturally occurring therapeutic agents are a crucial method for increasing the biological efficacy of these agents and addressing their drawbacks by introducing new options for chronic and terminal disease management [107, 108, 109, 110].
The global demand for plant-derived pharmaceuticals will rise from $29.4 billion (as in 2017) to around $39.6 billion in 2022 with a compound annual growth rate (CAGR) of 6.15% in this timeframe (BCC-Data), according to BBC Report. Any of the nanostructure-based materials included in this section have already obtained FDA clearance.
5. Challenges and opportunities
While there have been a large number of nanomedicine-related studies and tests, only a handful have advanced to market-related review and once again a smaller handful have earned final clearance. The conversion of fundamental science into clinical practice was less than 10 percent, based on some reports [111, 112]. Thus, drugs that travel through what is known as the ‘valley of death’ do not seem convenient. This will lead to a time-consuming, lengthy, futile series of reviews, escalating the expense of health care as a whole [113]. Perhaps the reasons for such an undesirable state of affairs lie in multiple fields and procedure facets. One of the key problems involves nanoparticles’
In spite of all the above-mentioned obstacles, the demand for nanopharmaceuticals and nanomedicines will continue to expand over the next few years, primarily thanks to developments in bionanotechnology and nanoengineering, the implementation of explicit guidelines on new nanotechnology-based products, more support from government organizations, more consensus on environmental issues and the creation of collaborations between nanomedicines startups and leading pharmaceutical companies [119]. In other words, in order to convince investors about the value of nanopharmaceuticals and to improve the overall health and well-being of society, intellectual property and regulatory agencies need to change their approach to meeting the specific needs of nanomedicine and shorten their time to regulatory approval. However, in the case of nanodrugs, it is particularly important to consider the risks to health and the environment
6. Conclusion
Initially, the use of nanotechnology was mostly based on improving the solubility, absorption, bioavailability and controlled release of drugs, but now a wide range of nanodimensional tools are included that can be used to diagnose, precisely deliver at target, sense or activate material in the living system. By using nanocarriers formulated with gold, silver, cadmium sulphide, and titanium dioxide polymeric nanoparticles along with solid lipid nanoparticles, nanogels, liposomes, micelles, iron oxide nanoparticles, and dendrimers, the efficacy of the natural products has greatly improved. One of the major interests in the advancement of nanomedicine in recent years is the convergence of therapy and diagnosis (theranostic) as an example of cancer as a disease model. Since the 1990s, there has been a remarkable growth in the number of FDA-approved nanotechnology-based products and clinical trials, including synthetic polymer particles; liposome formulations; micellar nanoparticles; nanocrystals and many others frequently associated with drugs or biologics. Although regulatory frameworks for nanomedicines along with safety/toxicity tests will be the focus of further research in the future, the way we discover and deliver drugs in biological systems has already revolutionized nanomedicine. Thanks to advances in nanomedicine, the ability to deliver, and even targeted delivery, has also become a reality.
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