Matrix Metalloproteinase-2-Responsive Surface-Changeable Liposomes Decorated by Multifunctional Peptides to Overcome the Drug Resistance of Triple-Negative Breast Cancer through Enhanced Targeting and Penetrability

Abstract

Although nanomedicine has demonstrated great potential for combating drug resistance, its suboptimal recognition of malignant cells and limited transport across multiple biological obstacles seriously impede the efficacious accumulation of drugs in tumor lesions, which strikingly limits its application in the clinical therapy of drug-resistant triple-negative breast cancer (TNBC). Hence, a surface-variable drug delivery vehicle based on the modification of liposomes with a multifunctional peptide (named EMC) was fabricated in this work and used for encapsulating doxorubicin and the p-glycoprotein inhibitor tariquidar. This EMC peptide contains an EGFR-targeting bullet that was screened from a "one-bead one-compound" combinatorial library, an MMP-2cleaved substrate, and a cell-penetrating segment. The EGFR-targeting sequence has been validated to possess excellent specificity and affinity for EGFR at both the cellular and molecular levels and could be unloaded from the EMC peptide by MMP-2 in the tumor microenvironment. This doxorubicin/tariquidar-coloaded and peptide-functionalized liposome (DT-pLip) exhibited superior efficacy in tumor growth inhibition to drug-resistant TNBC both in vitro and in vivo through EGFR targeting, osmotic enhancement in response to MMP-2, controllable release, and inhibited efflux. Consequently, our systematic studies indicated the potential of this liposome-based nanoplatform in the therapy of drug-resistant TNBC through targeting effects and tumor microenvironmenttriggered penetration enhancement.

Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple‐negative breast cancer

“…Under the EPR effect, the nanoplatform triggered the release of the PD-1 blocker AUNP-12 in the TME via MMP-2, activated T cells, and released the oxygenase inhibitor NLG919 to achieve dual targeting. In another study about MMP-2-responsive liposome, DOX and EGFR were loaded to relieve TNBC drug resistance through drug efflux reduction (Liu et al, 2022). The highly expressed MMP-2 enzyme catalyzes the cleavage of the EGFR-targeted bullet from the carrier, and DOX was released under the action of the lysosome.…”

Recent Advances in Targeted Nanocarriers for the Management of Triple Negative Breast Cancer

“…This targeted nanocarrier provided potential therapeutics to control tumor growth in drug-resistant TNBC via EGFR targeting and also exhibited controlled release, and prevent transporter efflux which helps the drug to be bioavailable at the tumor site. This study suggested that enzyme stimuli based targeted nanoplatform has the potential to treat drug-resistant TNBC and also enhanced the penetration of drug into the TME [ 226 ].…”

Peptide therapeutics in the management of metastatic cancers

“…The liposome specically targeted cancer cells and showed high therapeutic potential. 101 The bombesin/gastrin-releasing peptides (BN/GRP) stimulate cancer progression through interaction with GPCRs. Peptide antagonists binding the GRP receptors inhibit cancer growth in various cancers 98 (Fig.…”