title: Targeting and microenvironment-responsive lipid nanocarrier for the enhancement of tumor cell recognition and therapeutic efficiency.
abstract: 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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P. R China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Tingting
authors.initials: T
authors.lastname: Meng
authors.forename: Nianqiu
authors.initials: N
authors.lastname: Shi
authors.forename: Hongmeng
authors.initials: H
authors.lastname: Zhuang
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Xianrong
authors.initials: X
authors.lastname: Qi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D005492:Folic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008055:Lipids / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D049329:Nanostructures / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D008055:Lipids; D005492:Folic Acid
keywords: cancer cell recognition; cell-penetrating peptide; lipid nanocarriers; microenvironment responsive; target