Preparation, characterization and in vitro release of chitosan-stavudine conjugate nano-prodrug

Abstract

Chitosan-stavudine (d4T) conjugate with a succinic spacer was synthesized via carbodiimide coupling reaction and structurally characterized. In order to nanosize it for improving its therapeutic properties, the chitosan-5′-O-succinyl-d4T conjugate was crosslinked with sodium tripolyphosphate (TPP) to obtain the chitosan-d4T conjugate nano-prodrug. The morphologies of chitosan-d4T conjugate nanoparticles were observed by transmission electron microscopy (TEM), and their zeta potential, particle size, and polydispersity (size distribution) were measured by the dynamic light scattering (DLS) techniques. In vitro drug release studies at pH 1.1 and pH 7.4 indicate that the crosslinked chitosan-d4T conjugate nano-prodrug can prevent the coupled d4T from leaking out before entering the target viral reservoirs and provide a mild sustained release without the burst release. The results reveal that constructing conjugated chitosan nano-prodrugs may be a promising approach for improving the therapy efficacy of drugs in antiviral treatment.

Keywords

chitosan / stavudine / nano-prodrug / polymeric conjugate

References

[1] Hoste K, Winne K D, Schacht E Polymeric Prodrugs[J]. Int. J. Pharm., 2004, 277(1–2): 119-131.

[2] Pasut G, Veronese F M Polymer-drug Conjugation, Recent Achievements and General Strategies[J]. Prog. Polym. Sci., 2007, 32(8-9): 933-961.

[3] Zou M, Okamoto H, Cheng G, . Synthesis and Properties of Polysaccharide Prodrugs of 5-aminosalicylic Acid as Potential Colonspecific Delivery Systems[J]. Eur. J. Pharm. Biopharm., 2005, 59(1): 155-160.

[4] Lee E, Lee J, Lee I H, . Conjugated Chitosan as a Novel Platform for Oral Delivery of Paclitaxel[J]. J. Med. Chem., 2008, 51(20): 6 442-6 449.

[5] Vicent M J, Duncan R Polymer Conjugates: Nanosized Medicines for Treating Cancer[J]. Trends Biotechnol., 2006, 24(1): 39-47.

[6] Daus S, Heinze T Xylan-Based Nanoparticles: Prodrugs for Ibuprofen Release[J]. Macromol. Biosci., 2010, 10(2): 211-220.

[7] Sengupta S, Eavarone D, Capila I, . Temporal Targeting of Tumour Cells and Neovasculature with a Nanoscale Delivery System[J]. Nature, 2005, 436(28): 568-572.

[8] Tan X L, Chu C K, Boudinot F D Development and Optimization of Anti-HIV Nucleoside Analogs and Prodrugs: A Review of Their Cellular Pharmacology, Structure-activity Relationships and Pharmacokinetics[J]. Adv. Drug Delivery Rev., 1999, 39(1–3): 117-151.

[9] Clercq E D Acyclic Nucleoside Phosphonates: Past, Present and Future Bridging Chemistry to HIV, HBV, HCV, HPV, adeno-, herpes-, and Poxvirus Infections: The Phosphonate Bridge[J]. Biochem. Pharmacol., 2007, 73(7): 911-922.

[10] Giammona G, Cavallaro G, Fontana G, . Coupling of the Antiviral Agent Aidovudine to Polyaspartamide and in vitro Drug Release Studies[J]. J. Control. Release, 1998, 54(3): 321-331.

[11] Gunaseelan S, Gunaseelan K, Deshmukh M, . Surface Modifications of Nanocarriers for Effective Intracellular Delivery of Anti-HIV Drugs[J]. Adv. Drug Delivery Rev., 2010, 62(4–5): 518-531.

[12] Kumar M N V R, Muzzarelli R A A, Muzzarelli C, . Chitosan Chemistry and Pharmaceutical Perspectives[J]. Chem. Rev., 2004, 104(12): 6 017-6 084.

[13] Calvo P, Remunan-Lopez C, Vila-Jato J L, . Novel Hydrophilic Chitosan-Polyethylene Oxide Nanoparticles as Protein Carriers[J]. J. Appl. Polym. Sci., 1997, 63(1): 125-132.