NANOPARTICLES-BASED DELIVERY SYSTEMS: TYPES AND PROPERTIES

Delivery technologies represent an important broader part of science, which engages multidisciplinary methodical improvement. Usually, delivery systems are associated with a carrier. In nanoparticle based delivery systems, the active compound is dissolved or entrapped or encapsulated in the carrier; in addition, the active compound could be adsorbed or attached to the nanoparticle (11). Often the drug is attached with the nanosphere and encapsulated in nanocapsule (Figure 1). There are several advantages of nanoparticles as delivery
systems. First, the particle size, particle morphology and surface charge of nanoparticles can be easily controlled (12). Second, controlled and sustained discharge of the active molecule in the time of the delivery and at the location of localization. Third, particle degradation properties can change with a modified carrier. Lastly, the site-specific delivery can be carried out in nanoparticle based delivery systems that can be used for various routes of drug deliveries like oral, nasal, parenteral, etc. Based on the importance, the development of nanoparticle based delivery systems is rapidly growing using proteins, natural polymers, synthetic polymers, and fullerenes.

3.1. Protein based delivery systems

Several nano-sized protein based delivery systems are available (Figure 2A). Albumin, gelatin, gliadin and legumin are the protein based nanoparticles which play a vital role in drug delivery. Among these proteins, albumin, gelatin are animal based; gliadin and legumin are plant based.

3.1.1. Albumin

                Albumin is a versatile protein carrier, and extensively used to construct nanospheres and nanocapsules (13).  Albumin is a plasma protein which is well accepted due to its harmless in nature such as non-hazardous, non-immunogenic, biocompatible and biodegradable nature (14). Several nanotechnological methodologies such as desolvation, emulsification, thermal gelation, nano-spray drying and self-assembly are used quite often for fabrication of albumin nanoparticles especially from bovine serum albumin (BSA)  as well as human serum albumin (HSA) (15,16). Albumin carries different reactive groups such as thiol, amino, and carboxylic groups. These groups can be applied for ligand binding or other surface alterations. Albumin has a tendency to accumulate on solid tumors (17) and therefore, this property has been explored for site-specific delivery of anti-tumor drugs. For example, noscapine, a benzylisoquinoline alkaloid from plants of the papaveraceae family has been recently delivered to tumor cells to see its efficacy as anticancer agent using HSA nanoparticle carrier. Here, optimal ranges (150-300 nm) of HSA nanoparticle size and drug-loading effectiveness (85%-96%) have been achieved (18). Therefore, albumin nanoparticle is particularly useful for efficient delivery of chemical and pharmaceutical active ingredients.

3.1.2. Gelatin

Gelatin comes from collagen which is a fundamental component of animal skin, bones or connective tissue and used in the production of nanoparticle delivery systems. Stringy collagen, an insoluble protein, is hydrolyzed to prepare gelatin (19). It is a biodegradable and non-toxic nanoparticle that is easy to crosslink (20). As such, there is an enormous scope for the research of colloidal drug delivery using gelatin (21, 22). Gelatin molecule contains amino acids such as glycine, proline and alanine; and these amino acids are accountable for the helical arrangement especially triple helical structure of this molecule (23). Sometimes, chemical modifications can be performed in the process of preparing the nanoparticles for the development of a drug delivery system (24).

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Recently, a study by Lee et al. (25) loaded three dissimilar drugs (tizanidine hydrochloride, gatifloxacin and fluconazole) in gelatin nanoparticles. This group reported that gelatin nanoparticle filled with tizanidine hydrochloride, blank nanoparticles and gatifloxacin- filled nanoparticles, under crosslinked situation, 59.3, 23.1 and 10.6% yield of drug loaded gelatin. In another study by Zhao et al. (26), they used gelatin nanoparticles with insulin used for diabetes treatment through pulmonary administration. These findings reflect the better bioavailability, speedy and stable hypoglycemic outcome. Several reports on the applications of gelatin nanoparticle based drug delivery systems include ocular delivery (27), anticancer drug delivery (28), etc. In gelatin drug delivery system, the outer of layer gelatin capsule (hard and soft ) has a tendency to form  inter or intra-molecular cross-link that is dependent on time, temperature and humidity; because of this trend, the use of gelatin in pharmaceutical formulations is debated (29).

3.1.3. Gliadin

Gliadin, a plant based protein, is suitable for the construction of mucoadhesive nanoparticles. It can be extracted from wheat and vicillin (30). Based on the natural origin, biodegradability, and biocompatibility, this nanoparticle is used in various drug deliveries. This drug delivery is used for controlled release of pharmaceutical ingredients (31). To evaluate its bioadhesive properties, gliadin nanoparticle was added to carbazole in two forms i.e. non-hardened gliadin nanoparticles (NPs) as well as cross-linked gliadin nanoparticles (CL-NP). Both of these nanoparticles showed a good absorption at the upper gastrointestinal regions, especially in the stomach mucosa (32). When gliadin nanoparticles were used for the oral delivery of tetanus toxoid, the results showed 50% w/w antigen stability over 3 weeks of testing (33). Thus, it has greater potential for the delivery of active molecules in targeted therapy of upper gastrointestinal tract and possibly for other targeted delivery systems.

3.1.4. Legumin

Legumin is a protein from pea and a source of sulfur-containing amino acids. Legumin-based nanoparticle delivery systems can be made following aggregation and chemical cross-linkage with glutaraldehyde (34). Irache et al. (35) prepared legumin nanoparticles of approximately 250 nm diameter using the pH-coacervation method and chemical cross-linking with glutaraldehyde. However, one study with legumin immunized rats robustly expressed antibodies against this protein. This may be due to the reduction of antigenic epitopes of is protein bring on the glutaraldehyde employed throughout the cross-linking (34).

3.2. Natural polymers and their derivates

Nanoparticle based delivery systems can be prepared from different natural materials. Chitosan, dextran, starch, liposome  etc. are such nanoparticle based drug delivery systems.

3.2.1. Chitosan

Chitosan, is a structural part within exoskeleton of subphylum crustaceans, can be formed commercially by deacetylation (36). It is biodegradable, safe, biocompatible, easily modified, no difficulty for DNA or protein composite formation, widespread accessibility, and low-priced which makes the chitosan a promising delivery system. It is of natural origin making it well accepted for the biological applications. Chitosan, a mucoadhesive polymer increases the cellular permeability, improves the bioavailability of orally delivered protein based drugs (37) and boosts the protein uptake (38-41). Oral delivery of chitosan DNA nanoparticles was examined for vaccine delivery and seems to be useful for inducing immune system against Toxoplasma gondii (42).

3.2.2. Dextran

Dextran is a complex, polysaccharide of D-glucose monomers linked by glycosidic bonds (43). Magnetite dextran nanoparticles can be developed from dextran. These particles have null zeta potential which contributes to high safety margin and efficacy (44). Presently, this polysaccharide nanoparticle is used as drug carrier system (45) in tumor targeted delivery (46), oral delivery of insulin (47), reticuloendothelial delivery (48) etc. It has been reported that chitosan-carboxymethyl dextran nanoparticles regulate cell proliferation and serum cytokine (49).

2.2.3. Starch

Starch is a natural polymer found in grains of plants like rice, corn, wheat, tapioca, potato etc.  It is biodegradable and abundant biomass material in nature (50, 51).  Nanocrystal (52), nanoparticles (53) and nanocolloids (54) were prepared from the starch. Several researchers have used starch as a drug delivery system. Cross-linked starch nanoparticles with hydrophobic end were used for drug delivery of indomethacin (55). Starch has been used as drug delivery system for tumor-targeted drug delivery (56), trans-dermal drug delivery (57) and brain tumor-targeted drug delivery (58). A starch microsphere is utilized as drug delivery for tissue engineering. This starch microsphere further loaded with definite growth factors and immobilized, and can be employed for delivery of encapsulate living cells (59). 

3.2.4. Liposome

 Liposome, made of lipid bilayer, is an extensively explored drug delivery system. Its diameter varies from 20 nm to more than a few hundreds of nanometers and width of the phospholipid bilayer is about 4–7 nm (60). Liposomes can be classified into three forms such as multilamellar vesicles (MLV), small unilamellar vesicles (SUV) and large unilamellar vesicles (LUV). MLV consists of a number of concentric bilayers in a particle and the diameter of this liposome may differ from hundred to thousands of nanometers. MLVs can be processed to produce unilamellar vesicles. According to size, unilamellar vesicles can be classified into two types such as small unilamellar vesicles (SUV) and large unilamellar vesicles (LUV). SUVs show a diameter lower than 100 nm, while LUVs have diameter bigger than 100 nm (61-63). In addition, there were several reports indicating the application of liposomes as dyes in textiles (64), pesticides for plants (65), food ingredients (66) and cosmetics to the skin (67) in areas other than drug delivery systems. Several drugs are in clinical trials, which use liposomal delivery systems (68). However, for targeted cancer drug and therapeutic protein delivery, liposome constructed with PEG (Polyethylene Glycol) is one of the sought after preferences for the delivery. It can increase the plasma stability and solubility property of the drug. Conversely, this increase properties help to decrease its immunogenicity and now PEGylated drugs in clinical practice.  One example of PEGylated drug is Oncaspar (PEG–L-asparaginase) which familiar to treat acute lymphoblastic leukemia (68).

3.3. Polymeric carriers

Several polymer based carriers are available (Figure 2C) such as polylactic acid, block copolymers, polyethyleinemine, etc. These polymer carriers are significant in drug delivery systems.

3.3.1. Polylactic acid

 Polylactic acid (PLA), thermoplastic aliphatic polyester, is promising biodegradable polyester (79). PLA is a member of the family of aliphatic polyesters. This family usually composed of α -hydroxy acids. Polylactic acid nanoparticles are used as colloidal drug delivery system for lipophilic drugs (70). This type of delivery system is regularly used for the cancer related drug delivery (71, 72). For example, PEG-coated polylactic acid nanoparticle was used for the delivery of Hexadecafluoro zinc phthalocyanine (ZnPcF16) for the mammary tumor therapy (71). Another example, cucurbitacin, was delivered using polylactic acid nanoparticles to oral cancer (72). Recently, PLA is used for the Plasmid DNA delivery. These results showed lower cytotoxicity compare to Lipofectamine 2000. PLA can transfer gene into HELA cells. From this we conclude that PLA can be a promising non-viral nano-device for cancer gene therapy (73).

3.3.2. Block copolymers

Block copolymers, a type of copolymer, is made up of different polymerized monomers (74). Amphiphilic block copolymers encompass the capacity to bring together into multiple morphologies in solution (75).  However, vesicle configuration of amphiphilic block copolymers depends on raise in total molecular weight and increasing bending modulus (K). A vesicular morphology is applicable in the fields of drug delivery (76). Amphiphilic linear-dendritic block copolymers (LDBC) have been developed for drug delivery (77). Further, synthesized LDBC was established to be a candidate for drug delivery due to some important characteristics such as relative stability, drug encapsulation and release property (78). In vitro release behavior of LDBC can be controlled by light which is a potential carrier for controlled drug delivery (79). Recently, biodegradable amphiphilic copolymer was used for cancer drug delivery (80, 81). Eg. Block copolymer COPY-DOX showed high anticancer efficacy in the course of some biochemical test such as MTT assays against cancer cells (80).

3.3.3. Polyethyleinemine

 Polyethyleneimine, containing secondary amines, is a biodegradable polymer and widely used in the cell culture for the attachment of weakly anchoring cells (82). It is insoluble in cold water, benzene, etc. This polymer includes primary, secondary, and tertiary amino groups. Polyethyleneimine is also used in gene delivery (83, 84) and  gene therapy (85).  It is also used for drug delivery (86) especially to cross the blood-brain barrier (87). Extreme cytotoxic effect prevents its use from drug delivery (88).

3.4. Dendrimers

Dendrimers are branched polymers, presently used a significant drug carrier system (Figure 2D). Poly (amidoamine) spherical dendrimers, poly (Propylene Imine) dendrimers are similar type of nanoparticle.

3.4.1. Poly (amidoamine) spherical dendrimers (PAMAM)

Poly (amidoamine), is one of the well known dendrimers which conatin a diamine. This is commonly used in analytical chemistry in the separation science (89-91). These molecules are used in gene delivery (92). Gamma-Glutamyl PAMAM dendrimers are used as versatile precursor for dendrimer-based delivery of active pharmaceuticals (93).

3.4.1. Poly (propylene imine) dendrimers (PPI)

During the last few years, poly (propylene imine) dendrimers (regularly branched molecules) is popular due to their unique physical properties. Poly (propylene imine) dendrimers are the preeminent surveyed dendrimer systems (94-97). Numerous hybrid dendrimers have been prepared with different end groups with distinctive characters (97-100). Multifunctional dendrimeric systems derived from poly (propylene imine) dendrimers are used as targeted drug delivery systems to encapsulate the drug (101). In a study, antimicrobial activity was analyzed using this delivery system against Bacillus subtilis, Staphylococcus aureus and Escheriachia coli where exceptional inhibition capacity was reported against these bacteria. They used with silver nanoparticles as antimicrobial drug (102). Dendrimer is toxic due to its positively charged exterior part. However, this toxicity can be reduced by putting an outside layer these peripheral cationic groups with carbohydrate residues (103).

3.5. Fullerene

Fullerene, a hollow sphere or tube composed of carbon, can be used as a drug delivery system (Figure 2E). Buckyball clusters are examples of fullerene which have been studied for drug delivery.

3.5.1. Buckyball clusters

Buckyball clusters have hexagons and pentagons linked jointly in a coordinated manner and can develop a hollow ground with bonding strains composed entirely of carbon. All these molecules are used in delivery systems particularly for drugs (104,105).

3.6. Carbon nanotubes (CNTs)

Carbon nanotubes, covalently bonded fullerenes, are used as molecular anchors (106). These fullerenes have bigger inner volume which can be used as the active molecule container. Therefore, several molecules can be attached with this carrier which is readily taken up by the cell (107). CNTs are used in the drug delivery of several molecules, especially for cancer drugs (108,109). These can be applied as biological transporters as well an agent for some cancer cell destruction (108). In vivo distribution and tumor targeting of CNTs have been studied (109). Concerns about CNTs that prevents advancement in its drug delivery applications include lack of solubility, clumping and aggregation and 6.8h half-life (110). However, studies have demonstrated that functionalized CNTs are non-cytotoxic (111). CNT has fibrous contour which is needle-like and toxic property has been related with asbestos. One of the major concerns is that extensive application of CNT may lead to cancer especially lung cancer (253). However, to avoid excessive surface interactions, CNT can be used as nanocapsules shown its biocompatibility for intravenous drug delivery (254).