POLYSACCHARIDE NANOPARTICLES FOR ORAL DRUG DELIVERY

Based on the above-discussed ambit, natural and biodegradable polysaccharides could be a preferred option for oral drug delivery due to then biocompatibility, nontoxicity, and adjustable controlled release properties. In 2014, Feng et al. designed coacervate microcapsules immobilized with multilayer sodium alginate beads (CMs-M-ALG beads) for oral drug delivery. The CMs-M-ALG beads were prepared by immobilization of doxorubicin hydrochloride-loaded CS/carboxymethyl coacervate microcapsules (DOX:CS/CMCS-CMs) in the core and layers of sodium alginate beads. The obtained CMs-M-ALG beads exhibited a layer-by-layer structure and a rough surface with many nanoscale particles. These earner systems showed good gastric tolerance, and the ex vivo studies demonstrated that CMs-M-ALG beads were able to enhance the absorption of DOX by controlled release and prolong the contact tune between the DOX:CS/CMCS-CMs and small intestinal mucosa (Feng et al., 2014). Later, the same group constructed sodium alginate beads with a porous core (internal cross-linking) and without a porous core (external cross- linking) based on CS and carboxymethyl chitosan (CMC) NPs immobilized in multilayer of sodium alginate beads (Li et al., 2016). The study showed that the internally cross-linked beads could efficiently pass through acidic gastric fluid and provide sustained release of a potent anticancer agent, doxorubicin hydrochloride, and hence presumed to have excellent potentials as earners for the sustained release of oral drugs (Li et al., 2016). In these earner systems, the prolonged contact time of these nanosystems with the intestinal mucosa could be due to the slow and sustained release of DOX-loaded CS NPs from the alginate beads and the hydrogen bonding between the carboxylate ions in the earner systems and mucin; the high binding capacity to Ca²⁺ of deprotonated carboxyl groups on ALG could further enhance the absorption of DOX (Feng et al., 2014; Li et al., 2016). CS-coated polycaprolactone (PCL) NPs loaded with curcumin demonstrated their strong ability to electrostatically interact with the mucin glycoprotein and hence found to be mucoadhesive. These NPs showed in vitro anticancer profile on oral cancer cell line SCC-9 and hence were observed to be used as a formulation that could deliver curcumin directly to the oral cavity and reduce oral cancer (Mazzarino et al., 2015). Thiolated chitosan (TCS)-coated poly(methyl methacrylate) core was reported to be useful for the oral delivery of hydrophobic drug, DTX. In vitro drug release studies showed an initial burst release, but after that, a sustained release for 10 days was seen. When formulated as NPs, the transportation of DTX from the intestinal membrane showed a significant increase in ex vivo studies (Shahrooz et al., 2011). TCS-modified PCL NPs were studied for the oral delivery of taxol for lung cancer. Preliminary studies reported that TCS increased the mucoadhesiveness and permeation properties, resulting in enhanced NP uptake by the GI mucosa and improving drug absoiption. These mucoadhesive NPs increased PTX transpoit by opening TJs and bypassing the efflux pump of P-gp of lung cancer cell lines (A549). Further in vivo evaluation could make these NPs eligible for applications in oral chemotherapy (Jiang et al., 2013). An oral delivery system was devised for entrapping PTX into 7V-((2-hydroxy- 3-tmnethylammonium)propyl)chitosan chloride (HTCC) NPs of about 130 mn. In vitro and in vivo transport investigations had proved that the presence of positive charges on the surface enhanced the intestinal permeability of these NPs. Additional exploration into side effects revealed that HTCC-NP:PTX caused lower Cremophor EL-associated toxicities compared with taxol. These results strongly suggested that HTCC NPs could be exploited as an oral earner of PTX for cancer therapy (Lv et al, 2011). CS was also exploited as a coating for improving the stability, controlled delivery, mucoadhesion, and eventually cellular uptake by cancer cell lines. CS capping was shown to further improve the stability of solid lipid NPs (SLNPs) in simulated gastric condition by forming a distinct and thick layer around the SLNPs against their aggregation, as a result of which they can be developed as the oral drug delivery system for hydrophobic drugs (Luo et al., 2014). A blend of phospholipid (lecithin) and CS was used for the nanoformulation of tamoxifen citrate (TAM) (Barbieri et al., 2015), where CS played the role of bridging the negative polar heads in the phosphatidyl choline-based liposomes and strengthened the vesicle structure. Ex vivo studies showed that the penetration of TAM drug solution across the rat intestinal walls was enhanced by the lecitihin/CS NPs. The effect of enzymes on intestinal permeation of tamoxifen was shown only when tamoxifen-loaded NPs were in intimate contact with the mucosal surface. The encapsulation of tamoxifen in lecithin/CS NPs improved the nonmetabolized drug passage through the rat intestinal tissues via paracellular transport (Barbieri et al., 2015). Oxaliplatin-loaded HA-coupled CS NPs encapsulated in Eudragit pellets were reported to be effective for colonic tumors. In tumor-bearing Balb/C mice, orally administered formulations showed significant accumulation in the colon and tumors post 12 h of administration. These DDS show relatively high drug concentration in the colonic milieu and colonic tumors with prolonged exposure time, which indicates enhanced antitumor efficacy with low systemic toxicity for the treatment of colon cancer (Jain et al., 2010). In another study, Tsai et al. designed cisplatin-HA nanoconjugate (HCNPs), which were further coated with Eudragit for colon-targeted anticancer effect toward colon cancers (Tsai et al., 2013). HCNPs were entrapped in Eudragit SlOO-coated pectinate/alginate microbeads (PAMs) by using an electrospray method and a polyelectrolyte multilayer-coating technique in aqueous solution. Orally administered microbeads in rats facilitated colon-specific delivery of cisplatin ligand-receptor relationships and pH-dependent degradation, which limited the release in acidic conditions and only under simulated colonic conditions. Eudragit-coated HCNP-PAMs also reduced cisplatin-affiliated nephrotoxicity in vivo (Tsai et al., 2013). Similarly prelhninary studies on 5-fluorouracil (5-FU)-loaded CS NPs with enteric coating (Eudragit) reported them to be effective against colon cancers (Tummala et al., 2014). Gemcitabine-loaded CS NPs formed by the ionic gelation using pluronic F-127 resulted in less than 200-nm-sized NPs. The mucoadhesion study indicated that the positively charged amino groups of CS interact ionocially and forms hydrogen bonding with the mucin chains, thereby enhancing the mucoadhesivity. These CS NPs could be further exploited as a potential candidate for the oral delivery of Gemcitabine (Hosseinzadeh et al., 2012). pH-sensitive CS/Fucoidan NPs were formed at pH 1.2 with a size distribution of 200-300 mil. These NPs became larger at higher pH and release the loaded drug (Curcumin). This property will help in developing these NPs as an efficient oral delivery system (Huang and Lam, 2011).

Natural gums play a dual role in protecting the drug in the gastric as well as intestinal conditions. An improved delivery system was developed for

5-FU using polysaccharides such as guar gum (GG) and xanthan gum (XG) NPs. These NPs reported to show dual advantage of targeted release of 5-FU specifically in colon and replenishing the colonic microflora, which was damaged by the chemical attack of the dmg. Accordingly, the study focused on overcoming the issue of toxicity toward the natural microbial flora and offered a solution to the problem in terms of concomitant administration of probiotics along with colon-targeted 5-FU (Singh et al., 2015).

Dextran sulfate-PLGANPs were studied as a earner system for vincristine sulfate (VCR). In vivo pharmacokinetics in rats after oral administration of vincristine solution (VCR-Sol) and vincristine sulfate-loaded dextran sulfate- PLGA hybrid NPs (VCR-DPNPs) indicated that the apparent bioavailability of VCR-DPNPs was increased to approximately 3.3-fold compared to that of VCR-Sol. The relative cellular uptake of VCR-DPNPs was 12.4-fold higher than that of VCR-Sol in MCF-7/Adr cells, implying that P-gp-mediated dmg efflux was diminished by the introduction of DPNs. Observations from this study indicated that it could be an effective strategy for oral delivery ofVCR with improved encapsulation efficiency and oral bioavailability (Ling et al., 2010). The role of polysaccharides in GI residence of the NPs and bioenhancement of loaded therapeutic agents was studied by Anisha et al. using curcumin as a model drug (Souza and Devarajan, 2016). They extensively analyzed the NPs adsorbed with polysaccharides: arabinogalactan (AG) and kappa carrageenan (КС); galactose-based polysaccharides and pullulan (Pul); and glucose-based polysaccharides. Following oral administration of these nanoformulations, it was observed that AG- and КС-based formulation enhanced the gastroretention and improved the oral bioavailability of curcumin. The study pointed toward the advantage of using galactose-based polysaccharide nanoformulations, which enhance the drug absorption through galectin-mediated absoiption. Bioenhancement could therefore be manifold for drugs that exhibit good stability throughout the GI tract (Souza and Devarajan, 2016).

Among various polysaccharides, pectin, which is enzyme-resistant (protease and amylase, which are active in the upper GI tract), has been shown to be a better matrix for the delivery of orally administered diugs and for colon-specific drug delivery with controlled release properties. Pectin/ethyl cellulose film- coated 5-FU tablets given orally to rats exhibited an accumulation specifically in the cecum and colon, whereas uncoated pellets remained distributed in the upper GI tract (Wei et al., 2008). Eudragit S-100-coated citius pectin NPs were developed by Subudhi et al. for 5-FU (Subudhi et al., 2015). In vivo data clearly depicted that Eudragit S100 successfully guarded NPs to reach the colon region, where NPs were taken up and showed drug release for a prolonged period. Citrus pectin also acts as a ligand for galectin-3 receptors that are overexpressed on colorectal cancer cells and was found to enhance the targeting potential of E-CPNs to cancer cells (Subudhi et al., 2015). In 2016, Izadi et al. reported p-lacto globulin pectin NPs as a carrier for anticancer platinum complex to colon. The drug release profile in simulated GI conditions demonstrated that p-lacto globulin with a secondaiy coating is stable in acidic conditions and able to release its cargo at pH 7, which could seive as an effective vehicle for oral drug delivery preparations (Izadi et al., 2016). Earlier study from our laboratory reported that a natural polysaccharide PST001, isolated from Tamarindus indica, was conjugated with Imatinib mesylate, a tyrosine kinase inhibitor and an antitumor drug that inhibits the BCR-ABL kinase caused by chromosomal rearrangements in chronic myeloid leukemia and acute lymphoblastic leukemia, and found to be effective against K562-resistant cell lines in vitro and showed no toxicity to mice when administered orally (James et al., 2017).