期刊
ACS BIOMATERIALS SCIENCE & ENGINEERING
卷 7, 期 7, 页码 3141-3155出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsbiomaterials.1c00582
关键词
siRNA delivery; stimuli-responsive release; highly penetrable capability; charge switchable
资金
- National Natural Science Foundation of China [81872820, 81773668, 81874305, 82073797]
A charge conversional multifunctional nanoplatform was strategically designed to enhance the efficacy of small interfering RNA therapy against nonsmall cell lung cancer. By utilizing a pH-sensitive copolymer to encapsulate siRNA, large-size nanoparticles with a positive charge are generated in the tumor microenvironment, facilitating tumor tissue penetration.
In cancer therapy, it is acknowledged that large-size nanoparticles stay in the circulation system for a long time, but their permeability to tumor tissues is poor. To address the conflicting need for prolonging circulation time and favorable tumor tissue penetration ability, a charge conversional multifunctional nanoplatform was strategically designed to improve the efficacy of small interfering RNA (siRNA) therapy against nonsmall cell lung cancer (NSCLC). The development of nanodrug delivery systems (NDDSs) was constructed by loading siRNA on polyamidoamine (PAMAM) dendrimers to build small-sized PAM/siRNA via electrostatic interaction and then capped with a pH-triggered copolymer poly (ethylene glycol) methyl ether (mPEG)-poly-L-lysine (PLL)-2,3-dimethylmaleic anhydride (DMA) (shorted as PLM) under physiological conditions. While in the tumor microenvironment, the acidic reaction of the PLM copolymer changes from negative charge to positive charge due to the cleavable amide bond between mPEG-PLL and DMA, leading to large-size nanoparticles (NPs) with a negative charge that turns into a positive charge and small NPs with a high tumor-penetrating ability. All of the in vitro and in vivo studies validated that PLM/PAM/siRNA NPs possess desirable features including excellent biocompatibility, a prolonged circulation time, significant pH sensitivity, high tumor tissue penetration ability, and sufficient endo-/lysosomal escape. Taken together, all results suggest tremendous potential of the gene therapy based on the stimuli-sensitive PLM/PAM/siRNA NPs, providing a profound application prospective treatment strategy in cancer gene therapy.
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