Anisamide-functionalized pH-responsive amphiphilic chitosan-based paclitaxel micelles for sigma-1 receptor targeted prostate cancer treatment

• Published in: Carbohydrate polymers Vol. 229; p. 115498
• Main Authors: Qu, Ding, Jiao, Mengying, Lin, Haijiao, Tian, Chunli, Qu, Guowei, Xue, Jingwei, Xue, Lingjing, Ju, Caoyun, Zhang, Can
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2020
• Subjects: Amphiphilic chitosan derivate; Animals; Chitosan - chemistry; Chitosan - toxicity; Delayed-Action Preparations; Drug Carriers - chemistry; Drug Carriers - toxicity; Gene Expression Regulation, Neoplastic; Hemolysis - drug effects; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Male; Materials Testing; Mice; Micelles; Molecular Targeted Therapy; Paclitaxel; Paclitaxel - chemistry; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; PC-3 Cells; pH-responsive release; Prostate tumor targeting; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, sigma - metabolism; Sigma-1 Receptor; Xenograft Model Antitumor Assays; Amphiphilic chitosan derivate; Prostate tumor targeting; pH-responsive release; Micelles; Paclitaxel
• ISSN: 0144-8617; 1879-1344
• DOI: 10.1016/j.carbpol.2019.115498

[Display omitted] •Anisamide-conjugated N-octyl-N,O-maleoyl-O-phosphoryl chitosan (a-OPMPC) features with targeting ability and pH sensitivity.•a-OPMPC can self-assembled into micelles for solubilization of paclitaxel (PTX).•PTX loaded a-OPMPC micelles (PTX-aM) can effectively deliver PTX to prostate cancer cells via sigma-1&anisamide affinity.•PTX-aM can rapidly release PTX in endo/lysosomes with acidic environment.•PTX-aM exhibited improved antitumor efficacy against prostate cancer. Controlled release and tumor-selective distribution are highly desirable for anticancer nanomedicines. Here, we design and synthesize an anisamide-conjugated N-octyl-N,O-maleoyl-O-phosphoryl chitosan (a-OMPC) which can form amphiphilic micelles featuring pH-responsive release and high affinity to sigma-1 receptor-overexpressed tumors for paclitaxel (PTX) delivery. Thereinto, maleoyl and phosphoryl groups cooperatively contribute to pH-responsive drug release due to a conversion from hydrophile to hydrophobe in the acidic microenvironment of endo/lysosomes. We demonstrated that PTX-loaded a-OMPC micelles (PTX-aM) enhanced the cellular internalization via the affinity between anisamide and sigma-1 receptor, rapidly released drug in endo/lysosomes and elevated the cytotoxicity against PC-3 cells. The in vivo studies further verified that PTX-aM could largely accumulate at the tumor site even after 24 h of administration, resulting in obvious inhibition effect and prolonged survival period in PC-3 tumor xenograft-bearing mice. Moreover, OMPC showed no obvious hemolytic and acute toxicity. Collectively, this chitosan derivate holds a promising potential in application of prostate cancer-targeted drug delivery system.