Self-assembled nanocomplex between polymerized phenylboronic acid and doxorubicin for efficient tumor-targeted chemotherapy

• Published in: Acta pharmacologica Sinica Vol. 38; no. 6; pp. 848 - 858
• Main Authors: Lee, Junseok, Kim, Jinhwan, Lee, Yeong Mi, Park, Dongsik, Im, Sooseok, Song, Eun Ho, Park, Hansoo, Kim, Won Jong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2017; Nature Publishing Group
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Boronic Acids - chemistry; Boronic Acids - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug Screening Assays, Antitumor; Female; Humans; Hydrogen-Ion Concentration; Immunology; Internal Medicine; Medical Microbiology; Mice; Mice, Inbred BALB C; Molecular Structure; Nanostructures - chemistry; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Original; original-article; Pharmacology/Toxicology; Polymerization; Structure-Activity Relationship; Vaccine; 纳米复合物; 纳米结构; 纳米颗粒; 聚合物; 肿瘤; 自组装; 苯基硼酸; 阿霉素; self-assembly; boronic ester; doxorubicin; nano-sized complex; anticancer drugs; pH-responsive
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2017.16

Since the discovery that nano-scaled particulates can easily be incorporated into tumors via the enhanced permeability and retention （EPR） effect, such nanostructures have been exploited as therapeutic small molecule delivery systems. However, the convoluted synthetic process of conventional nanostructures has impeded their feasibility and reproducibility in clinical applications. Herein, we report an easily prepared formulation of self-assembled nanostructures for systemic delivery of the anti-cancer drug doxorubicin （DOX）. Phenylboronic acid （PBA） was grafted onto the polymeric backbone of poly（maleic anhydride）, pPBA-DOX nanocomplexes were prepared by simple mixing, on the basis of the strong interaction between the 1,3-diol of DOX and the PBA moiety on pPBA. Three nanocomplexes （1, 2, 4） were designed on the basis of [PBA]：[DOX] molar ratios of 1：1, 2：1, and 4：1, respectively, to investigate the function of the residual PBA moiety as a targeting ligand. An acid-labile drug release profile was observed, owing to the intrinsic properties of the phenylboronic ester. Moreover, the tumor-targeting ability of the nanocomplexes was demonstrated, both in vitro by confocal microscopy and in vivo by fluorescence imaging, to be driven by an inherent property of the residual PBA. Ligand competition assays with free PBA pre-treatment demonstrated the targeting effect of the residual PBA from the nanocomplexes 2 and 4. Finally, the nanocomplexes 2 and 4, compared with the free DOX, exhibited significantly greater anti-cancer effects in vitro and even in vivo. Our pPBA-DOX nanocomplex enables a new paradigm for self-assembled nanostructures with potential biomedical applications.