MMP9-Sensitive PEG-Shedding Nanoliposomes for Targeted Codelivery of Erlotinib and Doxorubicin to MDA-MB-231 Cells

Tumor microenvironment-sensitive nanoliposomes (TMS-NLs) were prepared as triple negative breast cancer (TNBC)-specific carriers for synergistic therapeutics. The NLs shed polyethylene glycol (PEG) by matrix metalloproteinase 9 (MMP9) secreted from the cancer cells, expose a cell-penetrating peptide, the X peptide, and are consequently internalized into syndecan-4 overexpressed by the cancer cells. TMS-NLs containing an unprecedented conjugate, palmitoyl-X-MMP9-cleavable peptide (M)-methoxy PEG2000, were prepared and coencapsulated with erlotinib (ERL) and doxorubicin (DOX). Treatment of DOX after ERL represented synergistic cytotoxicity against MDA-MB-231 cells. The X peptide generated from the XMX peptide by MMP9 was internalized into the cancer cells. The ERL and DOX-coencapsulated TMS-NL labeled with Cy5.5 demonstrated internalization of the NL into the cancer cells. ED-TMS-NLs were cytotoxic against MDA-MB-231 cells, not MCF-7 cells. Compared with other ED-NL formulations, the PEG-shedding ED-TMS-NL showed higher cellular uptake and cytotoxicity against MDA-MB-231 cells, as well as DOX transport to the nucleus. In the MDA-MB-231 tumor-xenografted mouse model, the tumor growth inhibition of the ED-TMS-NL was superior to that of the ED-PEGylated-NL. The MMP9-sensitive PEG-shedding and syndecan-4-targeting TMS-NL can be a platform for a TNBC cell microenvironment-sensitive transport system of synergistic therapeutics.