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Dual-responsive nanoparticles with transformable shape and reversible charge for amplified chemo-photodynamic therapy of breast cancer

引用

Acta Pharmaceutica Sinica B 2022年第8期12卷 3354-3366页

作者： Wenfeng Jia Rui Liu Yushan Wang Chuan Hu Wenqi Yu Yang Zhou Ling Wang Mengjiao Zhang Huile Gao Xiang Gao Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610064China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of BiotherapyWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China

Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6(Ce6), hydrophilic chemotherapeutic drug berberrubine(BBR) and matrix metalloproteinase-2(MMP-2) response peptide(PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6(BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine(PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively,we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.

关键词： Shape transformation Charge reversal Chemo-photodynamic therapy Self-delivery MMP-2 response p H response carrier-free nanoparticles Breast cancer

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