Abstract
In this study, the biocompatible and biodegradable polymers, poly(lactic acid-co-glycolic acid)-modified hyaluronic acid (HA-g-PLGA) and PEG-b-poly(histamine methacrylamide) (PEG-b-PHMA) were employed to develop a smart midway-pickup drug delivery system for improving therapeutic efficacy of tumor hypoxia. The SN38-loaded polymer micelles were first attained by the self-assembly of HA-g-PLGA and SN38 in aqueous solution. To further functionalize these artificial micelles with superior in vivo colloidal stability and pH-responsive detachment of PEG chain segments, PEG-b-PHMA was deposited in sequence onto the assembly outer surfaces. Taking advantage of nano-sized particles for drug delivery, this drug-loaded nanoparticles can largely accumulate within tumors via the enhanced permeability and retention (EPR) effect. Once they arrive at tumor sites, the HMA residues of the PEG-b-PHMA copolymer prefer to protonate under the acidic tumor microenvironment. These hydrophilic PEG-b-PHMA copolymers are prone to disassociate from the shell of polymeric micelles. As the same time, the CD44 targeting ligand, HA, becomes exposed on the surface of polymer micelle. These HA-covered polymer micelles show excellent effective internalization behavior by tumor-associated macrophages (TAMs) within the solid tumor via CD44 receptor-mediated endocytosis. The internalized polymer micelles could be further transported to tumor hypoxia due to the inherent TAM tropism toward hypoxia. The drug liberation was achieved via degradation of PLGA segments under acidic environment such as tumor microenvironment or intracellular endosome and lysosome. The SN38 released from the TAMs could be further internalized by cancer cells, with thus efficiently inhibiting the cell proliferation. Our results strongly indicate that this “midway pickup” drug delivery strategy could enhance the antitumor efficacy of chemotherapy in tumor hypoxia, which may create a new opportunity for the current anti-cancer research.