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.