POLYSACCHARIDE NANOPARTICLES CROSSING BIOLOGICAL BARRIERS

Biopolymers, the polymers originated from natural sources, offer surplus advantage over conventional polymers and hence emerged as popular candidates for drug delivery carriers. In general, biopolymers are nontoxic, biocompatible, biodegradable, user friendly, and relatively cheap and hence have been found to be very promising for industrial applications in various forms. The main class of biopolymers exploited for drug delivery applications include polysaccharides (cellulose, chitin, chitosan (CS), alginate, etc.) and proteins (albumin, gelatin, collagen, silk, etc.) (Yadav et al, 2015; Raveendran et al., 2017).

Schematic representation comparing the BBB organization in healthy and tumor conditions

FIGURE 9.6 Schematic representation comparing the BBB organization in healthy and tumor conditions.

Polysaccharides, which are ubiquitous such as polyhydroxylated biopolymer containing sugar moieties, serve as a virtuous template for the synthesis of highly biocompatible nanoparticles (NPs) (Liu et al., 2008,2015). Polysaccharide NPs can favor the high rate of solubility, biocompatibility, and prolonged drug delivery at target sites for the theranostic management of cancer. Mucoadhesion properties of polysaccharides enhance the bioavailability of drugs for higher therapeutic effect by binding to the mucus layer of the cell surface in tissues. Certain polysaccharide also tends to bind to cell surface receptors that lead to receptor-mediated endocytosis. For instance, biodegradable hyaluronic acid (HA)-coated CS NPs were developed to encapsulate a chemotherapeutic drug to improve the drug’s antitumor efficiency by achieving targeted drug delivery via CD44 receptor overexpressed in A549 cell lines (Wang et al., 2017).

Polysaccharide NPs offer adaptable characteristics compared to synthetic or semi-synthetic polymeric NPs. First, most of the polysaccharides are biopolymer derived from microbial, plant, and animal sources, which are less expensive and easy to purify. Second, these polymers are highly biocompatible and tend to be retained in the circulating body fluids in the animal body. Third, polysaccharide NPs tend to escape from certain phagocytic cells, which mainly disturbs other polymeric NPs for their effective drug delivery system. Finally, most of the abundantly found polysaccharides possess tunable functional groups for their surface modification as both therapeutic agents as well as imaging agents, which highlights the efficiency of using polysaccharide NPs for biomedical applications (Peptu et al., 2014; Liu et al., 2008, 2015; Saravanakumar et al., 2012).

Polysaccharides used for nanoparticle synthesis can be classified into ionic polyelectrolytes and nonionic polyelectrolytes based on the functional groups (Salatin and Jelvehgari, 2017). Ionic polyelectrolytes classified further into cationic (CS) and anionic (alginate, heparin, HA, pectin) polysaccharides, while neutral polysaccharides include dextran, pullulan, xyloglucan, and galactomannan (Liu et al., 2008; Salatin and Jelvehgari, 2017) List of common polysaccharides used for the preparation of nanoparticles with it structure, charge, and source is tabulated in Table 9.1.

Based on the presence of functional groups and side chain of the polymer, the synthesis of polysaccharide NPs is categorized into self-assembled and cross-linked NPs. Self-assembled polysaccharide NPs are formed by polymer aggregation via their amphiphilic nature of the side chains (Myrick et al., 2014; Raja et al., 2016). The hydrophobic core of the polysaccharides tends to form aggregates within its central core, and the hydrophilic side chains remain in its periphery, offering higher rate of solubility, for example, amphiphilic carboxymethyl dextran with lithocholic acid labeled with Cy5.5 and loaded with the anticancer drug, DOX, for both cancer imaging and therapy (Thambi et al., 2014). These NPs exhibit controlled drug release in response to intracellular glutathione in cancer cells (Thambi et al., 2014). Cross-linked polysaccharide NPs are synthesized based on the ionic interactions between the charged moieties in polymer and the cross-linking agents (Patil and Jadge, 2008). Mostly, peptides and charged molecules tend to form an intermolecular interaction to form nanoaggregates, while certain chemical linkers such as tripolyphosphate (TPP) and calcium salts can produce polymeric NPs via ionic interactions. Previous studies revealed the formation of CS NPs in the presence of TPP due to the interaction of positively charged CS with negatively charged salt (Salatin and Jelvehgari, 2017). The encapsulation of the positively charged small-molecule drug (DOX) into CS (Janes et al., 2001; Soares et al., 2016) and xyloglucan (PST001) (Joseph et al., 2014; Joseph et al., 2014) followed by TPP cross-linking resulted in NPs with higher rate of encapsulation efficiency and successful endocytosis in cancer cells.

TABLE 9.1 List of Common Polysaccharides Used for Synthesizing Nanoparticles for Various Applications

Polysaccharide

Structure

Charge

Source

Chitosan

p-(l-4)-Linked-glucosamine and .V-acetyl-D-glucosamine

Positive

Arthropods

Alginate

(l-4)-Linked p-D-mannuronic acid and a-l-guluronic acid

Negative

Plant

Hyaluronic acid

D-glucuronic acid and iV-acetyl-D-glucosamine

Negative

Microbial

Pectin

D-galactouronic acid

Negative

Plant

Dextran

a-(l-6) glycosidic linkages in its main chain and a variable number of a-(l-2), a-(l-3) and a-(l-4) branched linkages

Neutral

Microbial

Pullulan

a-(l-6)-D-glucopyranose and a-( l-4)-D-glucopyranose

Neutral

Fungi

Xyloglucan

D-Galacto-D-xylo-D-glucans

Neutral

Plant

Various polysaccharide-based NPs were developed so far for the targeted drug delivery system based on the enhanced permeation and retention (EPR) effect of NPs at the tumor sites. CS NPs were developed with various surface modifications for drug encapsulation based on the ionic interactions for the development of successful controlled drug releasing nanovectors. CS NPs have been conjugated with several peptide molecules or ligands, like folic acid (FA), antibodies, and so on, for targeting the cancer cells at the site of action. These ligand-conjugated CS NPs with encapsulated drug were taken up by the cancer cells and released the intracellular drug in a controlled manner. Wang et al. (2017) exhibited the CS NPs decorated with HA encapsulated 5-fluoruracil effectively and were taken up by CD44-overexpressed tumor cells, leading to mitochondrial damage by the production of reactive oxygen species. PTX-loaded CS-coated poly(D, L-lactide-co-glycolide) NPs were found to be effective against lung tumors with increased cytotoxicity in the acidic pH. Multifunctional iron-oxide-loaded BSANPs conjugated with dextran-FA moieties exhibited a suitable system for both tumor diagnosis and therapy in terms of MRI imaging and enhanced tumor reduction in H22 tumor-bearing mice (Hao et al., 2014).

Polysaccharide-based polymersomes are nowadays considered to be a fruitful drug carrier as these particles can encapsulate both hydrophobic and hydrophilic drugs with unproved stability. Lecommandoux et al. have shown the efficient synthesis of block polymer between dextran and poly (y-benzyl L-glutamate) that could deliver the chemotherapeutic drug, DOX. Hollow nanospheres based on polysaccharides also form a full pledged area of research in nanomedicine, as reported based on CS-poly(acrylic acid) nanospheres encapsulated with DOX drug with sustained drug release both in vitro and in vivo. Increased hydrophobicity on the surface of polysaccharides was achieved using liposomal-based polysaccharide NPs for the proficient cellular uptake of NPs. Docetaxel (DTX)-encapsulated N-palmitoyl CS-anchored liposomes exhibited higher in vitro stability with the release of the drug at the site of action. Drug-conjugated pectin NPs with targeting potential to specific cancer cells have been developed with improved drug delivery efficiency. Pectin-methotrexate NPs synthesized via the ionotropic gelation method with a hydrodynamic size of 390 nm provide sustained methotrexate delivery to hepatocellular carcinoma (Chittasupho et al., 2013). Sodium- alginate-based polysaccharide NPs enhance the effectiveness of the drug earner system with controlled and targeted drug release, which is the utmost concern in pharmaceutical and medical allies. Manatunga et al. developed a novel pH-sensitive sodium alginate, hydroxyapatite bilayer-coated iron oxide NP composite (IONP/HAp-NaAlg) via the coprecipitation method that can be recognized as a potential drug delivery system for the purpose of curcurnin and 6-gingerol to treat diseases such as cancer. The study focused on the designing of NPs with pH-triggered drug release with high loading and encapsulation efficiency (Manatunga et al., 2017). Pullulan produced from starch is used nowadays in the development of chemotherapeutic- loaded NPs as well as metal-conjugated NPs for various applications in the biomedical field. A PTX-loaded core-cross-linked nanoplatform was successfully engineered for targeted liver cancer treatment. In this study, reversibly cross-linked pullulan NPs with FA (FA-Pull-LA CLNPs) were fabricated for reduction-responsive liver drug delivery based on the specific affinity of pullulan and FA to overexpress asialoglycoprotein receptors and folate receptors. In vivo therapeutic efficacy studies confirmed that FA-Pull- LAPTX CLNPs achieved an enhanced antitumor effect and reduced systemic toxicity compared to free drugs (Huang et al., 2018). As evident from several studies, polysaccharide NP synthesis is found to be ecofriendly and easy for the development of stable NPs. Similarly, encapsulation of several drugs by rapid entrapment methods favors the advancement in nanosized formulations with high drug payload for the efficient management of cancer.

The development of nanomedicines as fascinating tools for enhancing the transport of drugs across the above-discussed biological barricades and treating cancer remains to be utmost challenge faced by the pharmaceutical companies. The literature shows that the use of NPs dramatically changed the future of therapeutic modalities involved in cancer screening, diagnosis, and treatment. Colloidal carriers based on natural or synthetic origin have been formulated as nanosystems within approximately 1-200 nm size range for carrying different therapeutic payloads for drug delivery. The main factors influencing the transport of NPs across biological barriers include the size (smaller NPs, <100 nm is favored), shape (spherical, cubic, rod, etc.; spherical NPs are most studied and recently rod-shaped NPs were reported to show adhesion propensity compared to their spherical counterparts), and zeta potential (positively charged NPs can cause brain toxicity, so negatively charged stable NPs are preferred for brain delivery). The nanosystems developed for drug delivery can open the TJs and enable the drugs to penetrate the barrier membranes or tissue layers, can be endocytosed by the cells and release the drugs intracellularly, and can also inhibit the transmembrane efflux systems. An ideal nanodrug delivery system designed for cancer management should have the following characteristics: (a) it should be controlled; (b) it should not damage the barrier; (c) the carrier system should be biodegradable and nontoxic; (d) systemic delivery should be targeted to the barrier tissues and the site of intended action; (e) the drug load transported through the barriers should be adequate for reaching therapeutic concentrations in the diseased tissue; and (f) therapeutic concentrations should be maintained for a sufficient duration of time for the desired efficacy.

 
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