Targeting and microenvironment-responsive lipid nanocarrier for the enhancement of tumor cell recognition and therapeutic efficiency.

Poor recognition and penetration of chemotherapeutic agents in solid tumors have been recognized as one of the major challenges limiting the efficacy of cancer therapies. Folic acid and tumor microenvironment-sensitive polypeptide (TMSP) co-modified lipid-nanocarrier (F/TMSP-NLC) are successfully formulated in response to the overexpression of folate receptor (FR) and the upregulation of matrix metalloproteinase-2 (MMP-2) in tumor microenvironment. The F/TMSP-NLC accumulates in tumor via the enhanced permeability and retention (EPR) effect, and folate moiety binds selectively to the FR once it reaches the tumor. In addition, cell-penetrating peptide (CPP)-penetrating activity is initiated by MMP-2 protease-oversecretion tumor. The specificity and efficacy of the co-modified nanocarriers to tumor are investigated in KB, HT-1080 and A549 cells in vitro. Multivalent interactions induce the enhancement of cancer cell recognition and internalization, which subsequently result in cancer cell apoptosis or death. The F/TMSP-NLC shows long-circulation effect, high accumulation in tumor, strong tumor inhibition, increased apoptotic indices, and negligible toxicity in vivo. In conclusion, the present nanocarrier modified with both TMSP and folic acid is a potential drug delivery system for tumor cell recognition and therapy, implying that using more than one target from the pool of tumor-stroma interactions is profoundly beneficial to therapeutic approaches.