A tumor acidic microenvironment-responsive nano-drug delivery platform to enhance antitumor effects of the nano-drugs

We have developed a tumor acidic microenvironment (pH ~6.5)-responsive nano-drug delivery system in which the surface potential of the nanoparticles can be reversed based on pH difference between solid tumor and normal tissues. The nanoparticles showed slightly negative charge in normal physiological milieu and blood circulation (pH ~7.4); whereas, when they reached to tumor tissues, their surface potential was able to change from negative to positive charge due to the slightly acidic microenvironment (pH ~6.5) in tumor, which mediated the enhanced interaction of nanoparticles with tumor cells and improved the uptake by tumor cells (Angew Chem Int Ed, 2010, 49, 3621-3626).

We furthered to take the advantage of the slightly acidic microenvironment in tumors and established a new nano-drug delivery system to deliver siRNA drugs in vivo based on charge interactions. A ternary sheddable nanoparticle was generated, and it was shielded by PEGylated polymers to minimize non-specific interactions with serum components during circulation and to significantly improve its accumulation in tumor tissues. Once reaching into the slightly acidic microenvironment in tumors, the nanoparticle unshielded the PEGylated polymer layer and consequentially attenuated the undesirable effects of PEGylation on the reduced uptake of nano-drugs by tumor cells, hence in turn promoted their internalization in tumor cells and enhanced the antitumor effects (ACS Nano, 2012, 6, 771-781，highlighted by Nanomedicine, 2012, 7, 182-183).

A tailor-made dual pH-sensitive polymer drug conjugate nanoparticle system to improve nano-drug cytotoxicity in drug-resistant cancer stem cells

Nanoparticles that respond to both extracellular (environmental) and intracellular (endosomal/lysosomal) pH changes are able to increase drug concentrations in both tumor masses and tumor cells. We have designed a tailor-made dual pH-sensitive polymer drug conjugate nanoparticle system which was capable of extending drug duration in blood circulation (pH ~7.4) to enhance its accumulation in tumors, reversing surface charge from negative to positive at extracellular pH (∼6.8) in tumor to facilitate its internalization in tumor cells, and subsequently promoting encapsulated drugs (e.g., Doxorubicin) release from the endocytosed drug carriers in subcellular compartments (e.g., endosomes, pH ∼5.0). This dual pH-sensitive nanoparticle has demonstrated enhanced cytotoxicity in drug-resistant cancer stem cells, indicating its great potential for cancer therapies (J Am Chem Soc, 2011, 133, 17560-17563). 

A zwitterionic polymer-based charge-switchable nanoparticle for the enhanced therapeutic effects of the nano-drugs

Zwitterionic polymers, containing either zwitterionic groups or a mixture of anionic and cationic terminal groups, can escape from host immune system, exhibit delayed blood clearance in vivo, and enhance nano-drug accumulation in tumors due to EPR effect. Hence we sought to design a charge-switchable nanoparticle based on zwitterionic polymers and harness the intrinsic pH difference between various solid tumors and blood to augment the payload release. This nanoparticle was able to present positive charge by diminishing the anionic component owing to pH change in tumors, facilitate its cellular uptake by tumor cells, and therefore enhance the therapeutic effects (Advanced Materials, 2102, 24, 5476-5480).