Advances in Natural Polymeric Nanoparticles for the Drug Delivery

Abstract

Natural and biodegradable polymers have been the key area for utilizing their advantages which make them a possible option for development of various drug delivery systems. The complexity of diseases and the intrinsic drug toxicity and side effects has led to an interest for development and optimization of drug delivery systems. The advancements in nanotechnology have favored the development of novel formulations which can modulate the biopharmaceutical properties of bioactives and thus improves the pharmacological and therapeutic action. The shape, size, and charge nanoscale delivery system, such as nanoparticles (NPs) are required to be investigated and changed in order to promote and optimize the formulations. The various natural polymeric NPs (PNPs) have been found to be key tool to enhance bioavailability or specific delivery to certain site of action. In this chapter, the uses of various polymeric materials for the development of NPs as drug delivery systems for various ailments have been described. The entrapment of bioactive compounds in PNPs systems is a hopeful move toward improvement of efficacy of drug toward the treatments of various diseases.

1. Introduction

The research for natural polymeric material for the advancement in the drug delivery has been a prime focused for the researchers in the last two decades. The concept of natural polymeric material is one of the frontier research areas and is being focused for the enhancing the bioavailability along with the specific/targeted drug delivery and therapeutic index for the treatment of some life threatening diseases, like cancer [1]. Polymeric drug delivery system has been used to enable the delivery of drug molecule into the body for the therapeutic action. Various polymers biodegradable and non-biodegradable origin has been widely identified and used which are accompanying various advantageous features with them. For different novel drug delivery systems development, biodegradable and bio-reducible polymers are used which make a possible choice helping delivery of bioactives.

Nanotechnology is the branch which deals in the system, structures and devices in the range of nanometer. Nanotechnology has been a keen interest area in today’s novel growing world associated with the significant development in controlled delivery of genes and drugs. NPs in the field of nanotechnology found to be very advantageous proving their efficiency for drug delivery, biodegradable nature, better bioavailability, versatility, less toxicity and high encapsulation efficiency. NPs carriers play a competent role for the controlled delivery of drug molecules for cancer therapy and site specific delivery of bioactive molecules as target site [2, 3].

The present chapter has complied the various natural polymeric material extensively used in the delivery of drugs and genes acting as the backbone for the development and delivery of bioactive agents in various cases.

2. Natural polymers for drug delivery

Natural polymers for the development of drug delivery and delivery of bioactive molecules have been extensively investigated producing better encapsulation of drugs, thus have attracted tremendous attention. These natural polymers do have the inherent advantages, such as biocompatibility, specific interactions with some biomolecules, controlled enzyme degradation, and easy surface modification furnish them with greater versatility in drug delivery. Different types of natural polymers and derivatives have been chemically and physically modified which are focusing the efficiently therapy through the use of various bioactive for smart stimuli-triggered or targeted delivery [4].

2.1 Animal-based biopolymers

2.1.1 Gelatin

Gelatin being a fibrous protein is identified as a natural, biocompatible, biodegradable, non-antigenic, low cost and multipurpose biopolymer and due to its unique mechanical and technological properties since timely memorial is commonly used in pharmaceutical (drug and vaccine delivery) cosmetic, food, and medical applications [5]. Gelatin is obtained from its parent molecule collagen in various thermo-reversible forms and the major commercial sources of gelatin are porcine or bovine skin, bones, aquatic and poultry sources [6]. But it has been observed that gelatin obtained from mammalian source is preferred over that produced from aquatic animal sources due to its strong gel strength, ideal gelling and melting temperatures, acceptable viscosity, and lack of fishy odor or allergens [7]. When gelatin is considered structurally it has triplets of the amino acids’ alanine, proline, and glycine in repeating sequences that give gelatin its triple helical shape and both cationic and anionic groups chemically. It is this chemical composition of gelatin which is responsible for its stability and is exploited for chemical modification and covalent drug attachment in preparation of drug delivery systems [8]. These wide ranges of opportunities for chemical alterations and drug attachment of drug via covalent bond can be carried out either within the particle matrix or on the particle surface. In the former scenario, the gelatin macromolecules must undergo chemical alterations prior to the formation of NPs, whereas in the latter scenario, the particle surface is utilized [9].

Depending on its so easy to handle and play with availability of structure, it has been adapted for non viral gene delivery in various forms like alendronate gelatin, PEGylated gelatin, cationic gelatin, thiolated gelatin, and EGFR gelatin NPs [10]. In context with these [11] designed MMP-2-triggered gelatin NPs loaded with doxorubicin (DOX) and 5-Aminolevulinic acid (5-ALA) providing combined chemotherapeutic and photodynamic therapy for breast cancer. The system employed the naturally occurring MMP-2 enzyme in tumor tissue, which via its high expression level was employed for gelatin degradation and targeted drug release was achieved [11]. Kirar et al. [12] found that a singlet oxygen was produced by biodegradable gelatin NPs damaging the microbial cell membrane, leading to cell death. The therapy regimen was adorned by Rose Bengal (RB) conjugated and entrapped in gelatin nanoparticle-based biodegradable nanophototheranostic. According to the study, gelatin NPs can be used in place of substances like potassium iodide, calcium chloride, ethylenediaminetetraacetic acid (EDTA), and polymyxin nonapeptide to allow drugs to penetrate cell membranes and exert antibacterial action [12].

2.1.2 Albumin

Albumin has been identified as most common protein in blood. Due to its function in the maintenance of intravascular colloid osmotic pressure, neutralization of toxins, high availability, non-immunogenic, strong binding capabilities for both hydrophobic and hydrophilic medicines, a lengthy half-life, the ability to target specific regions of inflammation, and almost little toxicity they have been readily accepted since the early twentieth century and welcomed for transport of therapeutic agents [13]. There are three forms of their existence and mainly utility is seen as bovine serum albumin, Human serum albumin, and Ovalbumin, [14]. The versatility of albumin-based NPs lies in their specificity been explored not only for deliverance of drugs but at the same time for navigating the possibilities of various drug delivery routes [15], multifunctional bioimaging [16], delivery of albumin functionalized aptamers [17, 18, 19, 20] allowing its use as modified versions enhancing their interactions with enzymes like myeloperoxidases at inflamed site [21] achieving site specific drug delivery. In addition to these they are also utilized for conjugation with antibodies increasing their half life in circulation and was reported by [22] that engineered human albumin maintained FcRn-binding characteristics after conjugation and drop in glycemia was observed as a function of receptor targeting when given orally to human FcRn-expressing mice that had been given diabetes-inducing drugs, with a reduction up to 40% occurrence 1 h after delivery [22]. Albumin has also been explored for conjugation with nanobodies which are derived from different region of immunoglobulin’s heavy chain single domain antibody [23]. Henaki et al. reported that a genetic fusion between the irrelevant nanobody R2 and the HER2-targeted nanobody 11A4 to increase binding with albumin-binding domain (ABD) leading to extended serum half-life noticeably, and uniform tumor formation [24].

2.1.3 Hyaluronic acid (HA) and its derivatives

HA is a natural polysaccharide discovered in 1934 from bovine eyes found in abundance as extracellular matrix’s primary component, crucial to the human body’s physiological processes. It is chemically composed of 1,3 and 1,4 glycosidic connections that frequently connect N-acetylglucosamine and glucuronic acid [25]. Since its discovery and further derivatization according to advances in drug delivery target potentials, improvisation of stability and shelf life is achieved. With these advancements, utility of HA and its derivatives in surgery, medication development, treatment of arthritis, targeting, formation of nanoparticulate/gel/microsphere/gene vectors based drug delivery systems has also enhanced over the past few years [26]. Bai et al. reported the construction of supramolecular self-assemblies of β-cyclodextrin and HA which were further drug–drug conjugates self-assembled into NPs for achieving active targeting. This multifunctional delivery system demonstrated co-drug delivery and release patterns that were responsive to pH and esterase, achieving improved synergistic therapeutic efficacy, and active targeting capability [27]. Hyaluronic acid mediated treatment possibility was checked by Lu et al., were by linking an o-phenylenediamine group, levofloxacin was conjugated with hyaluronic acid to create a CD44 mediated cellular targeting via NO-sensitive nano-micelles which provided with their ability to fight against bacteria leading to reduction in the inflammatory levels [28]. Duan et al., worked on coping up with thrombosis considered as one of the major complications of cancer by incorporating anticoagulant heparin (Hep) as an adjuvant to the therapy with carbon dots as drug delivery system loaded with doxorubicin hydrochloride. He found that this dual drug and adjuvant therapy enhanced the blood compatibility of the system and in vitro MTT and scratch tests showed that this drug delivery method could specifically suppress cancer cell growth and migration [29]. Hyaluronate mediated targeting of cancerous cell was also seen in breast cancer where Batool et al., create a papain grafted S-protected HA-lithocholic acid co-block (PAP-HA-ss-LCA) polymeric excipient that functions as an amphiphilic muco penetrating stabilizer for breast cancer epithelial cells. These cells are overexpressed with CD44 receptors. By creating a tamoxifen (TMX) loaded self-nanoemulsifying drug delivery system, the mucopermeating, stabilizing, and targeting capabilities of the PAP-HA-ss-LCA polymeric excipient were studied [30].

2.1.4 Silk fibroin

Polymer-based delivery systems that are effective must be biocompatible, biodegradable, low toxic, have the right mechanical properties, call for ambient production conditions, and offer sustained release. Due to its distinct structural characteristics of self-assembling capacity, high strength, processing flexibility, biodegradability, and biocompatibility, silk a natural polymeric biomaterial meet these needs [31]. A fibrous fundamental protein called Silk Fibroin (SF) and a stick-like coating made of sericin make up silk as it is well known. Commercially silk has been obtained from silk cocoons from silkworms of Bombyx mori mainly. Although Eight subspecies of Bombycoidea family, have been exploited but only the Bombycidae (mulberry) and Saturniidae (non-mulberry) are significant commercially [32]. According to descriptions of SF, it is a naturally occurring amphiphilic block co-polymer made up of hydro-phobic (highly conserved, arranged) and hydrophilic (less conserved, more complicated, less organized) blocks that combine to give SF its flexibility and strength. From a morphological perspective, SF consists of recurring chains made up of small side chain amino acids, such as glycine and alanine, and hydrophilic blocks having H-bonding and hydrophobic interactions, which are the basis of SF’s tensile strength. Together with the less organized hydrophilic blocks, these effective hydrophobic blocks produce the flexibility [33, 34].

Cao et al., utilized FDA-approved SF, to utilize the advantages of the features as carrier polymer, demonstrating a single-step electrospraying procedure without an emulsion process uses the blends SF and polyvinyl alcohol (PVA) with drug. A distinct core-shell structure was obtained with doxorubicin encapsulated in the core. By changing the PVA/SF ratio, the controlled drug release profiles were possible to achieve. The SF coating reduced the drug’s first burst release, but a lot of drug molecules were still retained by the carrier polymers and portrayed a pH dependent drug release [35]. Chouhan et al., critically presented the use of SF in wound healing premises and showed the efficacy of silk based matrices for healing efficiency [36]. To overcome the problem of intravenous administration Gangrade et al., utilized two silk proteins and created a nano hybrid silk hydrogel-based delivery of anticancer medications locally, precisely, and instantly. The β-sheet structure helped to form the hydrogel network and payload efficiency was enhanced using the carbon nano tubes [37]. Air spun nanofibers for drug delivery [38], temperature-responsive poly (N-isopropylacrylamide) (PNIPAM) hydrogel and SF scaffold microcarriers for controlled and sustained drug release [39], silk based embolic material a potential next-generation multifunctional embolic agent including nivolumab labeled with albumin was delivered to treat vascular disorders, including malignancies, as well as achieve embolization [40]. Its utilization has been explored nevertheless in all possible directions for drug delivery.

2.2 Plant-based biopolymers

2.2.1 Cellulose

Cellulose is a high-molecular-weight natural homopolysaccharide, materialized as multifunctional drug delivery polymer because of their inbuilt porosity, which can aid in the liquid uptake. Water and cellulose can interact significantly, causing cellulose to swell easily in water. This swelling property is correlated with the cellulosic polymer network’s capillarity. It is common knowledge that a medicine with a speedy swelling effect will also dissolve quickly and thus enhances the dissolution process [41]. Structurally cellulose connected to acetal molecule between the C-4 of hydroxyl group and C-1 of the carbon by covalent bond. One primary and two secondary hydroxyl groups can be found in anhydro glucose molecules. Because of the extremely strong inter- and intramolecular hydrogen bonds created by this hydroxyl group, cellulose is insoluble in aqueous or organic solvents. Cellobiose units are composed of two glucose moieties joined by a 1–4 bond having high molecular weight. D-hydroxyl glucose’s is a good candidate for modification and the formation of various derivatives. Various derivatives of cellulose have been in use for various purposes depending on their physical properties like ethyl cellulose, methyl cellulose, carboy methyl cellulose, carboxy ethyl cellulose, hydroxy propyl methyl cellulose (HPMC), hydroxy ethyl cellulose, etc. [42]. Because of their properties they are used in ocular, rectal, vaginal, anti-tumor deliveries.

Recently, Long et al., recreated the efficacy of cellulose nanocrystals (CNCs) by utilizing the numerous hydroxyl active functional groups on the surface of CNCs allowing for easy chemical modification to improve targeting via manifesting weakly acidic tumor environment with a hydrazone bond along with anti-cancer drug. Owing to its properties Sheng et al., came up with CaCO₃ microspheres with methotrexate and aspirin co-entrapped in hydrogels, achieving significant pH dependent drug release on sites [43]. Pooresmaeil et al. [44], made use of Green chemistry to prepare layered double hydroxides LDHs known for their high ion exchangeability to deliver controlled and sustained drug release at acidic medium of stomach through loading of this LDH Zn/Al 5-Fluro uracil in CMC on site.

2.2.2 Starch

Starch, a readily available material, is most abundant and affordable biopolymer after cellulose and chitin that has been employed in a variety of biomedical applications, drug delivery systems, and tissue engineering platforms. Starch is a composition of two, amylose and amylopectin, which combine to generate these granules in chloroplast of plant cells. Amylose, a straight or slightly branched polysaccharide, is made up of glucose units connected by 1–4 glycosidic linkages while amylopectin is a branching biopolymer with extra -1-6 glycosidic linkages [45]. Shehabeldine et al. synthesized eco-friendly ciprofloxacin hydrochloride (CIP) loaded green-based nanocomposite to improve its activity and regulate the antibiotic’s release and bioavailability. Microbiological glycoside hydrolases assist in the enzymatic hydrolysis of starch. Using an environmentally friendly process, hydrolyzed starch/chitosan loaded with CIP (HS/Ch-NC) was created. And optimal release of CIP was achieved [46]. A water soluble polysaccharide called as Pullulan is composed of maltotriose units and is produce by the fungus Aureobasidium pullulans, was reviewed by Grigoras for producing drug delivery systems enhancing therapeutic efficacy of hydrophobic drugs, increasing their water solubility [47]. Promoting the use of natural constituents for treatment purpose Nallasamy et al., designed a polyherbal nano-formulation incorporating Triphala churna in starch NPs exhibiting high loading efficiency, sustained release and its antibacterial, antibiofilm, and neuroprotective properties were equally retained [48].

2.2.3 Soy protein

After getting approved by UDFDA in 1999 as protective for coronary heart diseases its incorporation and utilization for various health treatments as adjuvants drastically increased. A globular protein extracted from soy beans, soy protein is relatively stable and has a long shelf life. Soy proteins when considered chemically have albumins and globulins as their primary components, which can be further segregated on the basis of sedimentation coefficients into 2S, 7S, 11S and even 15S fractions where 7S (SC), 11S (SG), or 15S fractions often correlate to the globulins, while the albumins in soy proteins are reported in the 2S form [49]. Mainly extracted from soy beans, they exist as soy flour, soy protein concentrate, and soy protein isolate available in quantities ranging from 50–90% after removal of carbohydrates, fats, oils, moisture and other components [50]. Its most commonly existing form is 11S (SG) consisting of 6 subunits. A disulfide bond connects the basic polypeptide (B) with the acidic polypeptide (A) that makes up each subunit. These subunits with functional groups like -NH₂, -OH, and -SH in soy protein make it easy to modify the protein chemically or physically or mix it with other biopolymers, which is equally reflected in the changes that the protein undergoes on heating, pH and other environmental exposures which are exploited for preparation of pH responsive gels, nano-formulations [51]. Being a good source of plant-based protein, it adds on formulations benefit in a way of being less immunogenic, more stable. They have a strong propensity to aggregate and gel, act as good emulsifiers, and are frequently employed as functional additives in food compositions. Its physical propensity has been identified with other plant-based ingredients like cellulose and pine needle extract for development of packaging material as well. Xu et al., by breaking the hydrogen bonds that existed between the N—H groups of soy proteins and water molecules added cellulose nanocrystals CNCs which reduced the moisture content, elongation at break of the film samples and increased the tensile strength as a result of the filling action of CNCs. Addition of pine extract not only added to antioxidant properties to the film but at the same time decreased its water permeability enhancing its water vapor barrier capacity [52]. Cheng et al. further advanced the drug release pattern and accumulation in cancer lines by grafting soya protein with D-α-Tocopheryl polyethylene glycol succinate which acted as an adjuvant to the Cisplatin delivery system by itself being a good stabilizer, wetting agent and solubilizer and provided acid responsive delivery [53]. Soy protein has been incorporated as 2D surfactant to enhance the electrical conduction of nanocomposites [54], as an excellent promoter of enzymatic hydrolysis extracted from inexpensive defatted soy powder (DSP) in liquid hot water pretreated lignocellulosic substrates making the process inexpensive and biocompatible [25, 55], as a 4D printing food material along with carrageenan, and vanilla as flavor enhancer [56].

2.2.4 Zein

First identified in nineteenth century, zein is a plant based prolamins extracted majorly from corn existing as α, β, γ, and δ zein. α zein ia considered the most common and abundant among existing varieties. It is a hydrophobic protein that dissolves better in aqueous acetone, aqueous ethanol, and various organic solvents other than in plain water. Being a hydrophobic protein, it is found to be suitable for drug delivery system designing due to its certain important features, like biocompatible, and biodegradable nature [57]. Its utility has been reported in multi-domains of pharmaceutical industry like food coating, packaging, tissue engineering as well. Various zein based delivery systems such as nanocarriers, microspheres, tablets, capsules electro-spun fibers, etc. for delivery of drugs in spatiotemporal manner has been used widely [58]. Manifesting its natural non immunogenic existence Ruberedo et al., reported preparation of PEG-coated zein NPs made by a simple and repeatable process without the use of reactive chemicals suitable for increasing the oral bioavailability of bioactives and other physiologically active substances with limited permeability [59]. The poor stability and re-dispersibility of zein NPs was mitigated by preparation of loading of anti-inflammatory drug imidazole into zeolitic imidazole framework-8 frame and further coating this with succinylated zein, these modifications were able to provide pH responsive oral delivery which was tested due to the stable under neutral conditions and rapidly degradation phenomenon in an acid environment due to protonation of zeolitic imidazole framework-8.

2.3 Biopolymers from marine organisms

2.3.1 Alginate

Alginates are polysaccharide polymers made up of sequence of two (1Ñ4)- linked α-L-guluronate (G) and β-D- (M) derived from brown seaweed (Phaeophyceae). They are biocompatible, show low toxicity and possess carboxyl groups which shows charge at pH values more than 3–4, making them soluble in alkaline and neutral environments. This pH dependent solubility portrayed by alginates and it’s salts is promotive for some medications, for whom additional safeguards are required for preferential absorption in the lower gastrointestinal tract and thus are used to design various modified release dosage forms [60]. Santinon et al., reported delivery of Valsartan through sericin and alginate matrix, where addition of alginate during particle formation stage due to the gelation capacity on contacting with multivalent cations, such as Ca²⁺, which helped in evaluating the efficacy of cross-linking agents like proanthocyanin, PVA, PEG, citric acid in formulations drug loading and drug release [61]. Properties of alginate to form pH sensitive gels was further extrapolated by Esfahlan et al., reported gelatin (Gel) and alginate (Alg) based a magnetic natural hydrogel, where after partly oxidizing alginate (OAlg), the Alg-Gel chemical hydrogel was created via a “Shift-Base” condensation process and then Fe₃O₄ magnetic NPs (MNPs) were entrapped into this gel via in situ chemical co-precipitation method. This resulted an efficient and “smart” drug delivery system for cancer chemotherapy as it out-performed free doxorubicin in terms of pH-dependent and delayed drug release profile, magnetic property for diagnosis by MRI approach, and isolation at targeted region [62]. They are utilized handsomely in pharmaceutical industry as thickening, gel-forming, and stabilizing properties whose action changes with concentration, environment/medium of dissolution involved [63].

2.3.2 Carrageenan

Carageenans discovered first in Ireland, are marine sourced linear polysachharides of red algae’s that are sulphated [64]. Since 1973, the Food and Drug Administration (FDA) has deemed carageenans to be “Generally Recognized As Safe” (GRAS) (FDA SCOGS) (Select Committee on GRAS Substances). The European Food Safety Authority has certified carrageenan (E-407) and semi-refined carrageenan (E-407a) as food additives [65]. After receive of such approvals their inclusion in foods, pharmaceutical drug delivery systems increased. With time its efficiency has been seen in tissue engineering and regenerative medicines as well. Khan et al., designed porous polymeric nanocomposites and made use of sulphonic groups in carrageenan’s structure which due to the self-assembly of their helical structures exhibit several biological properties along with acrylic-acid/graphene/hydroxyapatite. These nanocomposite scaffolds were able to enhance bone regeneration efficiently [66]. Vijaykumar et al., prepared zinc oxide NPs enveloped in kappa-carrageenan for anti-inflammatory effects on Methicillin resistant Staphylococcus aureus (MRSA) culture, where this MRSA causes human skin and nosocomial infections. The formulation acted as super bug for MRSA growth at a minimal concentration, reducing bacterial cell surface hydrophobicity with no evidence of hemolytic or morphological changes in human RBC [67]. It has been reported that sulphated algae polysaccharides showed anti-viral activity for which carrageenan and fucoidan where considered the norms for viral crisis of which kappa carrageenan with higher sulphated content proved to be really effective [68].

2.3.3 Chitosan

Chitosan is a linear naturally occurring amino polysaccharide, Rouget made the initial discovery and discussion of it in 1859 revealing its generation from chitin. After celluloe, chitosan is considered to be the second most prevalent amino polysaccharide after cellulose. Significant research has been conducted on pharmaceutical and biomedical and applications, such as drug delivery, tissue engineering, wound-healing dressing, etc. because of its nontoxic, biocompatible, antibacterial, and biodegradable qualities. It is structurally made up of repeated glycosidic units made of N-acetyl-d-glucosamine and d-glucosamine units, each of which has two hydroxyl groups and one amino group. The amino group which carve out for the cationic versatility of chitosan to provide rate and time specific drug release, bio-adhesion, in situ gelation, antibacterial, permeation enhancement, etc. [69]. Chitosan can be classified according to its inherent features, such as purity, molar mass, viscosity, acetylation level, quality, and physical shape. Chitosan’s performance, synthesis, characterization, and applications are all influenced by its degree of acetylation characteristics as well as its molar mass [70]. Baghaei et al., prepared a polyelectrolyte complex of trimethyl chitosan, hyaluronate/dextran/alginate NPs using D optimal design and checked their efficacy for gene delivery and for further translational work in industries. He found that chitosan and hyaluronate showed desired size, entrapment efficiency and in-vitro killing [71]. Ziminska et al., in line of promoting the patient compliance, a thermo responsive gel was designed for minimal invasive delivery utilizing free radical polymerization to create a stable, hydrogel network at body temperature, with low molecular weight chitosan of 75–85% deacetylation and N-isopropylacrylamide with unique physical characteristics were used. The fact that NCTC-929 cells could be transfected by the released RALA/pEGFP-N1 indicates that the hydrogel had no effect on the stability of the supplied nucleic acid [72].

2.3.4 Fucoidan

Enormous marine supply of ingredients showing biocompatibility, non-immunogenicity, and bioavailability has increased their demand in numerous fields, including biology, food science, pharmacology and cosmetics, empowering the value of this resource. Three major categories of marine biomaterials are as follows: lipids, polysaccharides, and proteins [73]. Out of these three biomaterials, marine polysaccharides are most stable, with fundamental or covalent structure which shows the arrangement of monomeric units throughout the chain which are used to categorize them. By restricting the orientations of the monomers, these repeating units are joined by covalent chemical bonds. This property limits the forms that a polysaccharide chain may take on, known as “secondary structures”. Depending on these fundamental sequences marine polysaccharides possess inherent qualities that are extremely important in the field of medication delivery. Biomaterials utilizing enzymatic and chemical processes, developing stimuli-responsive delivery vehicles, modified as gels, and produce interpenetrated polymeric networks [74]. These may further get conjugated, and complexes with bioactive molecules or proteins [75]. Fucoidan is one such marine sulfated polysaccharide obtained from brown algae and invertebrates from marine origin. A top-notch candidate for pharmaceutical uses is fucoidan. Because of its many biological features, including antiviral, anticoagulant, antiangiogenic, anticancer, antioxidant, antiproliferative, anti-inflammatory, and immunomodulating activities, fucoidan has recently received attention [76]. For instance, fucoidan’s anticancer action is mostly associated with its lower molecular weight [77]. Shanmugapriya et al., designed fucoidan-based nanomaterials for the precise medicine administration to the cancer cells in the gastrointestinal tract loaded with nanohydroxyapatite/collagen. The formulation showed effective results with potent administration of drug at target site [78].

3. Natural PNPs for cancer nanomedicine

As cancer is becoming the main cause of mortality in wealthy nations. In fact, according to specialists, there will be a 70% increase in the occurrence of this disease during the next 20 years [79, 80]. Surgery, chemotherapy, and radiation make up the standard treatment regimen for treating cancer. The most general form of cancer treatment is chemotherapy, but it has a high level of toxicity since it affects both healthy and malignant cells [81]. An option that is more focused is known as “nanomedicine,” which is the use of materials at the nanometric scale in medicine. Its primary goal in oncology is to deliver the medication solely to cancer cells in order to increase its efficacy and lessen its toxicity. Additionally, early cancer detection technologies and combination medicines that improve treatment effectiveness and prognosis are both possible applications of nanomedicine [80]. Many PNPs have been employed up to this point to transport anticancer medications like paclitaxel, doxorubicin, or camptothecin in various cancers. By experimenting with new drug delivery methods, mixing active ingredients to enhance their effects, or combining with other therapies like gene therapy, the usage of PNPs can lead to advancements in cancer treatment. As an alternative to intravenous delivery, Ahmad et al. [82] suggested improving the oral bioavailability of doxorubicin by surface-modified biodegradable PNPs. They investigated the pharmacokinetics of doxorubicin and drug-loaded PEGylated PLGA NPs in Wistar rats. Results indicated that when compared to oral medications, NPs had superior activity and higher bioavailability. Soma et al. [83] investigated the synergistic impact of doxorubicin and cyclosporin A nanoparticulate formulations in comparison to NPs alone is successful in slowing the growth rate of P388/ADR cells, according to the results. The FDA has authorized albumin-bound (nab)-paclitaxel NPs (Abraxane^®) for the treatment of cancer in 2012. Since then, a wide range of cancers, including pancreatic cancer, metastatic breast cancer, and lung carcinoma have been treated with it. These NPs were created to help with paclitaxel’s pharmacokinetics and pharmacodynamics as well as to prevent the toxicities of the polyoxyethylated castor oil solvent (Cremophor), which was previously employed since paclitaxel had a difficult time dissolving in water. Additionally, these NPs plus gentamicin together had a somewhat higher survival probability for advanced and metastatic pancreatic cancer. A new paclitaxel liposome-albumin composite that was recently developed at the nanoscale had a remarkable encapsulation effectiveness of 99.8% [84].

Brain Targeted PNPs were also investigated by researchers and to be found affective drug delivery. Crpanl et al. [85] investigated camptothecin-loaded cyclodextrin NPs for brain cancer. The effectiveness of these NPs demonstrated an increase in the survival time and was studies in a rat glioma model for brain cancers. Pandey et al., reported the improved delivery of anticancerous agent doxorubicin via surface modified silk fibroin NPs through Tween-80 coating. The hydrophobic nature of these NPs assists make then susceptible for macrophageal and reticulo-endothelial system (RES) uptake which was overcome by surface coating of NPs with Tween-80 which is a hydrophilic stabilizers, thus making them long circulating and helping to cross blood brain barrier (BBB) by low density lipoprotein (LDL) [34].

Breast cancer, most common kind of cancer in women, is accounting for a staggering 30% of all instances that have been officially diagnosed. In order to better understand the effects of pH-sensitive PEG-PLGA-PGlu (polyglutamic acid) NPs implanted with doxorubicin and curcumin on breast tumor cells and drug-resistant cancer stem cells, Yuan et al. used mouse models [86]. Hu et al. looked at the usage of photodynamic therapy and nanoparticulate systems together in the treatment of breast cancer. They created oxygen-producing theranostic poly(caprolactone-co-lactide)-b-PEG-b-poly(caprolactone-co-lactide) NPs of doxorubicin, chlorin e6, and colloidal MnO₂ to create oxygen in tumor environment, relieve tumor hypoxia, and enhance photodynamic therapy. The NPs also improves the action of doxorubicin [87]. Breast cancer has also been studied in relation to MDR.

As the third cause of death brought on by oncologic diseases, liver cancer is the most common malignancies with high mortality rate. The majorities of anti-cancer medications have considerable liver toxicity and can result in serious adverse effects. With the aim of to increase the efficiency of anticancer medications and to lessen the emergence of adverse effects, PNPs are used as potential carriers. Zhu et al. reported a novel galactosamine-conjugated polydopamine-modified copolymer (Gal-pD-TPGS-PLA) NPs to create a nanosystem [88]. Gal-pD-TPGS-PLA NPs was used to target HepG2 cells by ASGP receptor-mediated recognition, and dramatically decrease cell growth, according to an in vitro cellular uptake and cytotoxicity study. Furthermore, docetaxel-loaded Gal-pD-TPGS-PLA NPs decreased tumor growth more as compared to docetaxel-loaded TPGS-PLA NPs, pD-TPGS-PLA NPs, or saline, in vivo. An overview of the nanoparticulate systems used as drug delivery system for cancer therapy are summarized in Table 1.

Biactive	Polymer	Type of cancer	Experimental model	References
Camptothecin	PCL–PEG	Glioma	4 T1 cells in BALB/c mice	[85]
Docetaxel	Gal–pD–TPGS–PLA	Liver Cancer	MCF-7 cells in BALB/c mice	[88]
Docetaxel and salinomycin	TPGS–PLGA	Breast Cancer	MCF-7/DOX cell line	[89]
Doxorubicin	PEGylated PLGA	Various	Bioavailability assay in Wistar rat	[82]
Doxorubicin and Chlorin e6 MnO2	PCLLA–PEG–PCLLA	Breast Cancer	MCF-7/ADR cells xenograft in female BALB/c nude mice	[87]
Doxorubicin and metformin	TPGS–PLGA	Breast Cancer	MCF-7 cells in nude mice	[90]
Doxorubicin–curcumin	mPEG–PLGA–PGlu	Breast Cancer	LM2 cells in BALB/c homozygous nude mice	[86]
Doxorubicin–cyclosporin A.	PACA	Various	P388/ADR cells line	[83]
Paclitaxel	Lip–BSA	Various	4T1 cells in BALB/c mice	[84]
Paclitaxel	PLGA–PEG	Glioma	Gliosarcoma 9L cells in Fischer F344 rats	[89]
Paclitaxel	PLA–PEG–maleimide	Breast Cancer (TNB)	MDA-MB-231 cells BALB/c homozygous nude mice	[86]
Paclitaxel	PCL–PEGPEG–PCL	Lung Cancer	MCF-7/ADR cells in BALB/c nude mice	[87]
Paclitaxel	PEI–PLA	Lung Cancer	A549 cells in BALB/c mice	[91]

Table 1.

Polymeric NPs bearing anticancer drug for cancer treatment.

4. Methods of preparations for PNPs

Methods of preparations for PNPs are classified as general methods and modern methods which are discussed in details as follow.

4.1 General methods

Recently, various biodegradable polymers and their co-polymers have been used to create NPs, being the most frequently used to create PNPs and encapsulate bioactive. Micelles, platelets, dendrimers, fibers, spheroids colloids, core-shells, and polymer matrixes with embedded NPs are just a few examples of multi-functionalized polymeric nanocarrier systems (Figure 1).

Figure 1.

General methods of preparation of PNPs.

Depending on the specific application, PNPs must have their characteristics tuned. The method of preparation is crucial in achieving the desired qualities. Consequently, it is very beneficial to have preparation methods on hand in order to create PNPs with the appropriate characteristics for a certain application. Various methods are employed, including polymerization, premade polymers, ionic gelation, etc. These can be completed using the many techniques listed below.

• Solvent evaporation

• Nanoprecipitation

• Emulsification/solvent diffusion

• Salting out

• Dialysis

• Supercritical fluid technology (SCF).

Methods for preparation of NPs from polymerization of monomers

• Emulsion

• Mini emulsion

• Micro emulsion

• Interfacial polymerization

• Controlled/Living radical polymerization (C/LRP)

• Ionic gelation or coacervation of hydrophilic polymers

4.1.1 Solvent evaporation

The first technique created to make PNPs was solvent evaporation. This method involves development of polymer solutions in volatile solvents and creating emulsions. Ethyl acetate, which has a superior toxicity profile, has replaced dichloromethane and chloroform premade polymer [92], which were once frequently utilized. As the solvent evaporates and allowed to pass into the continuous phase of the emulsion, the emulsion is transformed into a suspension of NPs. The manufacture of single-emulsions, such as oil-in-water (o/w) or double-emulsions, such as w/o/w, are the two major techniques utilized in the conventional procedures for creating emulsions. These techniques involve ultrasonication or high-speed homogenization, followed by the solvent evaporation either by continuous magnetic stirring at ambient temperature or under decreased pressure. NPs can be recovered by ultracentrifugation and rinsed with distilled water to get rid of additives (Figure 2). The product is lyophilized at the end [92, 93].

Figure 2.

Solvent-evaporation technique for NPs formation.

4.1.2 Nanoprecipitation

Solvent displacement technique is another name for nanoprecipitation. A polymer from organic solution gets precipitated, and the organic solvent diffuses across the aqueous medium whether a surfactant is present or not [94, 95]. The nanospheres precipitation occurs for the polymer, typically PLA, which get dissolved in a water-miscible solvent (medium polarity). This phase is added to an aqueous solution with agitation and contains a stabilizer as a surfactant. Instantaneous production of a colloidal suspension results from polymer deposition on the water-organic solvent interface brought on by the solvent’s rapid diffusion [96]. Phase separation is carried out using a fully miscible solvent that is also a non-solvent of the polymer to help the production of colloidal polymer particles during the first step of the operation [97]. Although acetone and dichloromethane (ICH, class 2) are employed to dissolve and enhance drug entrapment, the dichloromethane increases mean particle size [98], and it is therefore hazardous. Due to the solvent’s miscibility with the aqueous phase, this approach can only be used to encapsulate lipophilic pharmaceuticals and is ineffective for water-soluble medications. Numerous polymeric polymers, including PLGA, PLA, PCL, and poly (methyl vinyl ether-comaleic anhydride) (PVM/MA), have been subjected to this technique [99, 100]. Entrapment efficiencies of up to 98% showed that this method was well suited for the inclusion of cyclosporin A [101]. The antifungal medications Bifonazole and Clotrimazole were loaded into nanoparticulate systems using the solvent displacement approach (Figure 3) [102].

Figure 3.

Nanoprecipitation technique (surfactant is optional) for NPs formation.

4.1.3 Emulsification/solvent diffusion (ESD)

A modified form of the solvent evaporation technique is used here [103]. To attain the initial thermodynamic equilibrium of liquids phase, the polymer gets dissolved in a slightly water soluble solvent, like propylene carbonate. It is necessary to encourage the diffusion of the dispersed phase’s solvent by dilution with an excess of water which results in the formation of precipitate of the polymer and the subsequent NPs formation. Then, depending on the ratio of oil to polymer, the polymer-water solvent phase is emulsified in an aqueous solution with stabilizer, resulting solvent diffusion to exterior phase leading to the formation of nanocapsules or nanospheres (Figure 4). Depending on its boiling point, the solvent is finally removed via evaporation or filtering. Figure 4 shows the process in action. The mesotetra(hydroxyphenyl)porphyrin- and doxorubicin-loaded PLGA (p-THPP) NPs, the plasmid DNA- and coumarin-loaded PLA NPs, the indocyanine- and the cyclosporine (Cy-A)-loaded gelatin- and sodium glycolate-loaded NPs were NPs developed by the ESD technique (Figure 4) [104].

Figure 4.

Emulsification/ solvent diffusion technique for NPs formation.

4.1.4 Salting out

The principle behind salting out is the use of the salting out phenomenon to separate a water miscible solvent from aqueous solution. A variant of the emulsification/solvent diffusion process is the salting out process. The salting-out agent such as electrolytes (calcium chloride, magnesium chloride, etc) or non-electrolytes (sucrose) and a colloidal stabilizer (PVP or hydroxyethyl cellulose) are added to the initially dissolved polymer and drug is dissolved in a solvent, like acetone. This o/w emulsion is thinned out with enough aqueous solution to speed up acetone’s diffusion into the liquid phase, which causes the production of nanospheres [93]. Salting out agent selection is crucial since it can have a significant impact on how effectively the medicine is encapsulated (Figure 5). To remove both the solvent and salting out agent, cross-flow filtration is used. This method is very effective and simple to scale up. Salting out has the principal benefit of reducing stress on protein encapsulants [105]. When heat-sensitive materials need to be treated, salting out may be helpful because it does not need a rise in temperature [106].

Figure 5.

Salting out technique for NPs formation.

4.1.5 Dialysis

Small, narrow-distributed NPs can be produced using a quick and efficient procedure called dialysis [107, 108, 109]. A dialysis tube is filled with a polymer dissolved in an organic solvent and has had the appropriate molecular weight cut off. Another non-solvent miscible with the solvent is used for dialysis. The polymer gradually gets aggregates as a result of decrease in solubility leading to development of homogenous NPs suspensions. The shape and size of NPs are influenced by type of solvent evolve to make the polymer solution. For the manufacture of different natural and synthetic PNPs, Chronopoulou et al. [110] developed a unique osmosis-based technique (Figure 6). This method is based on physical barrier (dialysis membrane or semi-permeable membranes) which enable the passive transit of solvents resulting decelerate the mixing process of non-solvent with polymer. The polymer solution presents in the dialysis membrane.

Figure 6.

Osmosis-based method for polymer NPs formation.

4.1.6 Supercritical fluid technology

The use of supercritical fluids technology is more environmentally friendly having the power to produce the highly pure PNPs without any traces of organic solvent [111]. With the majority of the limitations of conventional approaches avoided, supercritical fluid technology and dense gas technology are predicted to offer an intriguing and efficient method of particles creation.

For the synthesis of NPs with supercritical fluids, two concepts have been developed:

1. Rapid expansion of supercritical solution (RESS).

2. Rapid expansion of supercritical solution into liquid solvent (RESOLV).

4.1.6.1 Rapid expansion of supercritical solution

RESS involves dissolving the solute in a supercritical fluid to create a solution, which is then rapidly expanded over an aperture or a capillary nozzle into the surrounding air. The creation of well-dispersed particles is caused by homogeneous nucleation. For homogeneous nucleation, the high degree of super saturation and quick pressure reduction in the expansion are the requirements. Both nanometer and micrometer sized particles are able to get produced through expansion jet. Three main components of the RESS experimental equipment are (a) high pressure stainless steel mixing cell, (b) a syringe pump, and (c) a preexpansion unit. At room temperature, a polymer solution in CO₂ is created. Syringe pumps are used to pump the solution to the pre-expansion unit where it is isobarically heated to the pre-expansion temperature before it leaves the nozzle. Now, at atmospheric pressure, the supercritical solution is left to expand through the nozzle (Figure 7). For RESS, the particle size and shape are significantly influenced by the polymer’s concentration and saturation level [112, 113].

Figure 7.

RESS method for polymer NPs formation.

4.1.6.2 Rapid expansion of supercritical solution into liquid solvent

Expansion of the supercritical solution into solvent rather than ambient air is a straightforward but important adjustment to the RESS process [106]. Poly (heptadecafluorodecyl acrylate) NPs having size less than 50 nm were created. Although, there is no organic solvents involvement in the RESS process for the formation of PNPs, still the fundamental disadvantage of RESS is that the primary products created using this technique are microscaled rather than nanoscaled. A new supercritical fluid technique called RESOLV has been created to get over this limitation. The liquid solvent in RESOLV inhibits particle development in the expansion jet, allowing the formation of mostly nanosized particles (Figure 8) [114].

Figure 8.

RESOLV process.

4.1.7 NPs formation by polymerization of a monomer

Designing appropriate polymer NPs can be done during the polymerization of monomers in order to get the needed characteristics for a specific application. The procedures for creating PNPs by polymerizing monomers are explained below.

4.1.7.1 Emulsion polymerization

The quickest and most scalable process for producing NPs is emulsion polymerization. Depending on whether an organic or an aqueous continuous phase is used, the approach is grouped into two groups. In order to use the continuous organic phase approach, a monomer must be dispersed into an emulsion, an inverse microemulsion, or a substance in which it is not soluble (nonsolvent). Using this technique, polyacrylamide nanospheres were created [115]. Later, via dispersion of surfactants into solvents including cyclohexane, n-pentane, and toluene as the organic phase, poly(ethylcyanoacrylate) (PECA), poly(methylmethacrylate) (PMMA), and poly(butylcyanoacrylate) (PBCA) NPs were generated. Surfactants or emulsifiers are not required in the dissolving continuous aqueous phase. When a monomer molecule get dispersed in continuous phase, it strikes an initiator molecule (may be ion or a free radical) initiation starts. As an alternative, powerful ultraviolet or visible light, high-energy radiation can convert the monomer molecule to act as an initiating radical. According to an anionic polymerization process, chain development begins when starting monomer ions or radicals strike additional monomer molecules. Before or after the polymerization process has finished, phase separation and the production of solid particles may occur [116].

4.1.7.2 Mini-emulsion polymerization

Water, a monomer combination, a costabilizer, a surfactant, and an initiator make up a typical formulation for miniemulsion polymerization. Differences between mini-emulsion polymerization and emulsion polymerization is the use of a high-shear device and a low molecular mass molecule which act as co-stabilizer (ultrasound, etc.).

4.1.7.3 Micro-emulsion polymerization

A novel and successful method for producing PNPs has gained a lot of attention: micro-emulsion polymerization. The emulsion and micro-emulsion polymerization techniques are involved in the formation of colloidal polymeric particles via using completely different kinetic. Micro-emulsion polymerization technique results in much lower particle sizes. A thermodynamically stable micro-emulsion with swollen micelles is introduced to the aqueous phase of micro-emulsion polymerization together with water-soluble initiator. The polymerization starts from this spontaneously point which help in production of thermodynamically stable state which depends on large amounts of surfactant complexes having almost zero interfacial tension at the o/w contact. Additionally, due to the application of surfactant in high amount, the particles are totally covered by surfactant. The delicate micro-emulsions are later destabilized by the elastic and osmotic impact of the chains, which generally result in a rise in particle size, the generation of empty micelles, and subsequent nucleation. In the finished product, the bulk of empty micelles coexist with very tiny latexes, with size of about 5–50 nm. Some of the key variables influencing the kinetics and characteristics of PNP in microemulsion polymerization techniques are the type and concentrations of the initiators, surfactant, monomer, and reaction temperature [117].

4.1.7.4 Interfacial polymerization

It is one of the tried-and-true techniques for creating polymer NPs. The reaction for the process occurs at the interface of the two liquids. It utilizes the polymerization as step by step process of two reactive monomers that are distributed in two phases, respectively. By using interfacial cross-linking processes (polyaddition, polycondensation, radical polymerization) nanometer-sized hollow polymeric particles were formed [118]. By polymerizing monomers at the o/w interface of o/w micro-emulsion, oil-containing nanocapsules were created. It was thought that the interfacial polymerization of the monomer took place at the surface of the oil droplets which was formed during emulsification and organic solvent (miscible with water) functioned as a monomer carrier. Aprotic solvents like acetone and acetonitrile should be used to encourage the development of nanocapsules [119].

4.1.8 Controlled/living radical polymerization

Future commercial success of controlled/living radical polymerization depends on its application in the industrially significant aqueous dispersion systems, which produces PNPs having control over particle size and size distribution. Atom transfer radical polymerization (ATRP), reversible addition and fragmentation transfer chain polymerization (RAFT), and Nitroxide-mediated polymerization (NMP) are some of the successful in-depth approaches for controlled/living radical polymerization that are now accessible [120]. Hydrophilic polymers may gel or accelerate ionically. Some biodegradable hydrophilic polymers like gelatin, sodium alginate, and chitosan are generally used for the development of PNPs. By using ionic gelation, a technique for producing hydrophilic chitosan NPs was developed. Ionic gelation was used to create chitosan NPs that were loaded with dexamethasone sodium phosphate [121]. Chitosan is a di-block co-polymer of ethylene oxide or propylene oxide (PEO-PPO), and poly anion sodium tripolyphosphate are the two aqueous phases that are mixed together in the procedure. Through the interaction with the negatively charged tripolyphosphate, positively charged amino groups of chitosan forms coacervates of size range in nanometer. In contrast to ionic gelation, which occurs when a substance changes from a liquid to a gel as a consequence of ionic interaction conditions at ambient temperature, coacervates are created via electrostatic contact between two aqueous phases. Ionic gelation method for formation of PNPs is shown in Figure 9.

Figure 9.

Ionic gelation method for formation of PNPs.

4.2 Modern methods

The recognition of the multi-functional, environment-responsive, targeted, and controlled drug delivery system has recently made PNPs as one of the most promising and practical technological platforms. In a rapidly developing new technical field called “polymer in smart medication delivery”, many therapeutic uses of nanotechnology are anticipated to address patient concerns in the medical field.

The use of several contemporary techniques, including microelectromechanical systems [122], microfluidic systems [123], electrodropping system [77], advanced high pressure homogenization, microneedle based system, interfacial emulsion polymerization, etc. are helpful to synthesize a variety of novel biocompatible polymers with well-defined nanometers to a few micrometers structures. The few contemporary methods for creating PNPs are shown in Figure 10. Based on the particular application, the physiochemical properties of PNPs must be tuned. To create different nano-particulate systems with different polymers, several techniques can be applied. The creation of multifunctional PNPs for single/dual or multiple drug release, including nano hydrogel, environment-responsive micelles, core-shell NPs, colloids, nano-spheres, and core-shell nano-spheres, has already been produced. The mechanism of the formulation approach is crucial in obtaining the required qualities. Therefore, having a synthesis technique available is crucial for approaching multifunctional PNPs with precise physiochemical characteristics for a given application.

Figure 10.

Schematic diagrams representation of the advanced techniques for preparation of PNPs via sonication based system and csore- shell particulate system.

Recent studies have focused on developing smart delivery methods for target biomolecules for a variety of therapies. The design of multi-functional PNPs for delivery of bioactives are closely related to the regulation of multiple cellular events. In particular, various peptides, proteins, growth factors, and cytokine therapy for different ailments are helpful in plying an important role in cellular responses [124]. In the sonication techniques, prob. sonication was used to generate the self-assembled NPs, and process involved cavitation, nucleation, and reversible locking concept, giving the formed nanostructure greater flexibility in its nature [125]. Self-assembled and core-shell particulate delivery systems, such as water-soluble polymeric drug compound conjugates, block polymeric micelles [126], long-circulating nano encapsulations, polymeric micelles, and core-shell nano-spheres were developed by using an in situ two-step semi-batch emulsion polymerization technique as a means of accurately and consistently delivering the right dose of drugs. Additionally, pH-responsive controlled release of hydrophobic anticancer drugs and its transport to tumor tissues/cells with acidic pH have been accomplished by core-shell nanospheres. Recently, an electrodropping system was designed and developed to create uniform, biocompatible core and shell capsules for angiogenesis in dual delivery systems [127], with an emphasis on regenerative medicine. The particle aggregation and drug encapsulation efficiency can be overcome by this electro-dropping technique.

In terms of micro-fluidics, the many applications have been significantly impacted by the cutting-edge science and technology used to manipulate micro/nano-scale volumes in micro-fluidic channels. Most micro-fluidic systems for synthesis, PNPs are still under development and they have the widest possible to develop because they are easily modifiable, highly reproducible, and can be combined with other techniques. Some advancement in micro-fluidics are anticipated to improve the preparation of PNPs and shift to clinical evaluation. Numerous microfluidic devices have recently been developed to allow quick mixing without the need of stimuli like electric force or stirring. The flow-focusing, droplet mixers, and other technologies are often used and enable micro-mixing inside the micro channel [128]. A fast solvent exchange through diffusion occurs as a result of the flow concentrating, which squeezes the solvent stream between two anti-solvent streams.

5. Future perspectives

The developments of the natural based PNPs have made the treatments to be more efficient and safe, utilizing the enormous variety of NPs design along with various functionalization. PNPs have to be biodegradable in nature and must possess a high capacity of circulation to avoid their removal from the systemic circulation. They developed systems should be nontoxic and non-immunogenic and should be able to produce the required effects as aimed. The role of copolymers could not be avoided in considering the tuning of the NPs system with the body components like blood proteins or mucosa which help in controlling their in vivo fate and the stabilizing of NPs. Stimuli responding polymers are gaining interest for the coming future and research will be focused while considering their tuning properties for the development of NPs. The development of NPs with numerous potential, such as image contrast enhancement and targeting (as multifunctional NPs) has to be considered to match the various objectives required for the preparation and reaching hope of better scenario.

6. Conclusions

Natural polymers have been now taken into consideration for the development of NPs and are gaining sky-scraping consideration due to the biodegradability, biocompatibility, and flexibility ability of these materials using varieties of natural materials to obtain the required characteristics for a precise function. The continue demand for natural biomaterials has always been their due various advantages associated with these natural materials, like polysaccharides and proteins leading to the development of more stable formulation under industrial processing environment and biological matrix, through techniques such as cross-linking is among the most advanced research area nowadays while using different techniques.

Disclosures

There is no conflict of interest and disclosures associated with the manuscript.

Abbreviations

5-ALA	5-Aminolevulinic acid
BBB	Blood brain barrier.
CNCs	Cellulose nanocrystals.
DOX	Doxorubicin.
EDTA	ethylenediaminetetraacetic acid.
ESD	Emulsification/solvent diffusion.
HA	Hyaluronic acid.
HPMC	Hydroxy propyl methyl cellulose.
LDL	Low density lipoprotein.
MRSA	Methicillin resistant S. aureus.
NPs	Nanoparticles.
PNPs	Polymeric NPs.
PVA	Polyvinyl alcohol.
RES	Reticulo-endothelial system.
SF	Silk Fibroin.