To improve
tumor targetability and drug efficacy and decrease drug resistance of
dasatinib (
DSB), the multifunctional micellar nanoparticles that combined the
matrix metalloproteinase 2 (MMP2)-sensitive
tumor (site) targeting with
folate receptor-mediated
tumor (cell) targeting were developed. Two major functional
polymers,
polyethylene glycol (5000 Da)-MMP2-sensitive
peptide-
phosphoethanolamine (PEG5k-pp-PE) and
folic acid-
polyethylene glycol (2000 Da)-phosphoethanolamine (FA-PEG2k-PE), were synthesized to construct the dual-targeted micellar nanoparticles (
MMP/FR
micelles). In the absence of MMP2, the FA was shielded by PEG5k and the
MMP/FR
micelles showed low bioactivity. In the presence of MMP2, the nanoparticulate structure, stability, and cargo release profile of the
MMP/FR
micelles were not significantly affected, however, the MMP2-mediated PEG5k deshielding and FA exposure remarkably increased the cellular uptake and anticancer activity of the
micelles in the MMP2 and FR expressing (MMP2+/FR+) cells, including multidrug resistant (MDR)
cancer cells, rather than the MMP2- and FR- cells. In the 3D MDR
tumor spheroids, the significant MMP2-dependent tissue penetration, uptake and cytotoxicity of the
MMP/FR
micelles were also observed. Furthermore, in the in vivo biodistribution study, the MMP2 and FR dual targeting strategy could significantly prolong the systemic circulation, decrease the nonspecific distribution in nontumor tissues, and increase the
tumor accumulation of the polymeric
micelles in a
melanoma xenograft mouse model. The MMP2-sensitive FR-targeted
micelles might have great potential as a
tumor-targeted platform for delivery of molecular targeted
therapeutics.