Tao Li,Xiufen Chen,Yajun Liu,Lulu Fan,Liqing Lin,Yu Xu,Sijia Chen,Jingwei Shao
Ursolic acid (UA) as a nature product exhibits good anti-cancer activity, low toxicity, and good liver protection features. However, the low-solubility and poor bioavailability restrict its further clinical application. To overcome this problem, a pH-sensitive prodrug delivery system (UA@MSN-UA) that incorporated acid-sensitive linkage between drug and silica-based mesoporous nanosphere (MSN) was successfully designed and synthesized. The physicochemical properties of the UA@MSN-UA nanoparticles were investigated for shape, particle size, zeta potential , nitrogen adsorption-desorption and infrared (IR) spectroscopy. The nanoparticles were further evaluated for in vitro cytotoxicity, including proliferation inhibition, cell cycle distribution and apoptotic effects against human hepatocellular carcinoma HepG2 cells. The TEM image showed that the size of synthesized MSN nanoparticle was a near-spherical shape with ~ 100 nm diameter. In vitro cytotoxicity testing demonstrated that UA@MSN-UA nanoparticles prodrug exhibited higher proliferation inhibition, cell cycle arrest at the G2/M phase and significantly caused the early and late apoptosis in HepG2 cells, which would be contributed to high loading capacity, high cellular uptake and sustained release of UA. Overall, the UA-modified MSN prodrug delivery system can be a promising drug carrier for improving the bioavailability of UA, and further enhance its anti-cancer efficacy.
Jean Felix Mukerabigwi,Wei Yin,Zengshi Zha,Wendong Ke,Yuheng Wang,Weijian Chen,Abd Al-Wali Mohammed Mohammed Japir,Yi Wang,Zhishen Ge
Therapeutic nanoreactors are currently emerging as promising nanoplatforms to in situ transform inert prodrugs into active drugs. Nevertheless, it is still challenging to engineer a nanoreactor with balanced key features of tunable selective membrane permeability and structural stability for prodrug delivery and activation in diseased tissues. Herein, we present a facile strategy to engineer a polymersome nanoreactor with tumor-specific tunable membrane permeability to load both hydrophobic phenylboronic ester-caged anticancer prodrugs ( e.g. , camptothecin or paclitaxel prodrug) and hydrophilic glucose oxidase (GOD) in the membranes and cavities, respectively. The nanoreactors maintain inactive during blood circulation and in normal tissues. Upon accumulation in tumors, the mild acidic microenvironment triggers selective membrane permeability to allow small molecules (glucose and O 2 ) to diffuse across the membrane and react under the catalysis of GOD. The massively generated H 2 O 2 triggers in situ transformation of innocuous prodrugs into toxic parental drugs through cleavage of the self-immolative degradable caging groups. The developed system showed significantly enhanced antitumor efficacy by H 2 O 2 production and prodrug activation via combined oxidation-chemotherapy. The well-devised polymersome nanoreactors with tumor-pH-tunable membrane permeability to coload H 2 O 2 -responsive prodrug and GOD represent a novel strategy to realize prodrug delivery and activation for enhanced therapeutic efficacy with low side toxicity.
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