pH-Triggered Charge-Reversal Polypeptide Nanoparticles for Cisplatin Delivery: Preparation and In Vitro Evaluation

• Published in: Biomacromolecules 2013-06, Vol.14 (6), p.2023-2032
• Main Authors: Huang, Yue, Tang, Zhaohui, Zhang, Xuefei, Yu, Haiyang, Sun, Hai, Pang, Xuan, Chen, Xuesi
• Format: Article
• Language: English
• Subjects: Aminoacid polymers; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Applied sciences; Biological and medical sciences; Chemotherapy; Cisplatin - administration & dosage; Exact sciences and technology; Hydrogen-Ion Concentration; In Vitro Techniques; Magnetic Resonance Spectroscopy; Medical sciences; Nanoparticles; Peptides - chemistry; Pharmacology. Drug treatments; Physicochemistry of polymers; Synthetic biopolymers
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/bm400358z

A series of pH-responsive random copolymer poly(l-glutamic acid-co-l-lysine) [P(Glu-co-Lys)] were synthesized through the ring-opening polymerization (ROP) of γ-benzyl-l-glutamate N-carboxyanhydride (BLG-NCA) and 3-benzyloxycarbonyl-l-lysine N-carboxyanhydride (ZLys-NCA) and the subsequent deprotection. The chemical structure of the P(Glu-co-Lys)s was confirmed by NMR. Critical aggregation concentration and transmission electron microscopy measurements indicated that the P(Glu-co-Lys)s could self-assemble into aggregates in phosphate buffer. The surface charge of P(Glu-co-Lys) aggregates was greatly affected by the solution’s pH and l-glutamic acid/l-lysine ratio because the carboxyl and amino groups present on the P(Glu-co-Lys) aggregates could be protonated or deprotonated to become charged. The pH value of the solution at which the surface charge of the P(Glu-co-Lys) aggregates reversed could be manipulated by the feed ratio of BLG-NCA and ZLys-NCA. In vitro methyl thiazolyl tetrazolium assays demonstrated that negatively charged P(Glu-co-Lys)s were nontoxic and biocompatible. Positive charged P(Glu-co-Lys)s showed some cytotoxicity to Hela cells. Cisplatin (CDDP) was used as a model anticancer drug to evaluate the charge-reversal drug delivery system. By the manipulation of CDDP loading content, the surface charge of the CDDP/P(Glu-co-Lys) nanoparticles could be reversed to positive from negative at tumor extracellular pH (pHe 6.5–7.2). An enhanced drug uptake and inhibition of cancer cell proliferation were observed for the tumoral pHe triggered charge-reversal CDDP/P(Glu-co-Lys) drug delivery system. These indicated that the CDDP/P(Glu-co-Lys) nanoparticles could be used as intelligent drug delivery systems for cancer therapy.