3 years ago

Enhancing the Efficacy and Safety of Doxorubicin against Hepatocellular Carcinoma through a Modular Assembly Approach: The Combination of Polymeric Prodrug Design, Nanoparticle Encapsulation, and Cancer Cell-Specific Drug Targeting

Enhancing
the Efficacy and Safety of Doxorubicin against
Hepatocellular Carcinoma through a Modular Assembly Approach: The
Combination of Polymeric Prodrug Design, Nanoparticle Encapsulation,
and Cancer Cell-Specific Drug Targeting
Xiao Xu, Shusen Zheng, Jianguo Wang, Linhui Pan, Hangxiang Wang, Jun Zhang, Lin Zhou, Haiyang Xie, Shengjun Xu, Li Xu, Zun Chen, Xuyong Wei
Intervention is urgently required to improve the therapeutic outcome for patients with unresectable hepatocellular carcinomas (HCCs). However, current chemotherapeutics, such as sorafenib and doxorubicin (DOX), provide only limited therapeutic benefits for this devastating disease. In this context, we present a modular assembly approach to the construction of a systemically injectable nanotherapeutic that can efficiently and safely deliver DOX in vivo. To achieve this goal, we covalently attached DOX to a polylactide (PLA) building block (Mw = 2800, n = 36), yielding DOX-PLA conjugate 1. Due to the lipophilicity imparted by PLA, the conjugate 1 coassembled with an amphiphilic lipid, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol) 2000] (DSPE-PEG2000), to form nanoparticles (NPs). To achieve preferential tumor accumulation, we additionally decorated the particle surface with an HCC-specific peptide moiety (i.e., SP94). The resulting HCC-targetable DOX-encapsulating NPs (termed tNP-PLA-DOX) exhibited several unique characteristics, including the feasible fabrication of sub-100 nm NPs, substantially delayed drug release profiles of several weeks, HCC cell-specific uptake and tumor accumulation in an in vivo mouse model, as well as alleviated drug toxicity in animals. Collectively, these results show that the integration of multiple components within a single nanocarrier via modular assembly is cost-effective for the creation of safe anticancer nanotherapeutics. The presented DOX-based nanomedicines have potential for enhancing the therapeutic index in patients.

Publisher URL: http://dx.doi.org/10.1021/acsami.7b14496

DOI: 10.1021/acsami.7b14496

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