Tumor Microenvironment Stimuli-responsive Nanoparticles for Programmed Anticancer Drug Delivery.

It is well known that large size nanoparticles stay long in the circulation system, but show poor tissue penetration and low cellular uptake. In order to reconcile the conflicting needs for extended circulation time, extensive tumor tissue penetration and enhanced cellular uptake for nano-drug delivery systems, we designed DOX-containing hypersensitive nanoparticles that responded to the tumor microenvironment for programmed DOX delivery. A super-sensitive polymer material, poly (2-ethyl-2-oxazoline)-poly (methacryloyl sulfadimethoxine), was synthesized (PEOz-b-PSD, pKa=6.96). At the physiological environment, PEOz-b-PSD and polyamidoamine/DOX (PAMAM/DOX) can form nanoparticles PEOz-b-PSD/PAMAM/DOX (PEPSD/PAM/DOX) via electrostatic adsorption. The PEPSD/PAM/DOX has an intact structure, which can prolong circulation time. While in the tumor environment, the PEOz-b-PSD was rapidly protonated and showed charge reversal, leading PEOz-b-PSD to get detached from the nanoparticles, then the large size nanoparticles with a negative charge (PEPSD/PAM/DOX) instantaneously turn into positively charged ultrafine nanoparticles. The sudden inversion of size and charge can effectively improve tumor accumulation and internal penetration. After entering tumor cells, nanoparticles can release drugs quickly through the action of PAMAM proton sponge, resulting in enhanced tumor inhibition. Our results proved that the programmed nanoparticles could remarkable enhance the in vivo antitumor efficacy and reduce cardiotoxicity of DOX. This study designed ultra-sensitive nanoparticles in the tumor microenvironment, which appear to be beneficial for enhancing the treatment efficacy of DOX in solid tumors.