Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety

In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting, insufficient tumor cell internalization/bioavailability, and side effects, we developed a unique tumor-targeted micellar drug-delivery platform. Using paclitaxel as a model therapeutic, a nanopreparation composed of a matrix metalloproteinase 2 (MMP2)-sensitive self-assembly PEG 2000-paclitaxel conjugate (as a prodrug and MMP 2-sensitive moiety), transactivating transcriptional activator peptide-PEG1000-phos-phoethanolamine (PE) (a cell-penetrating enhancer), and PEG1000-PE (a nanocarrier building block) was prepared. Several major drug delivery strategies, including self-assembly, PEGylation, the enhanced permeability and retention effect, stimulus sensitivity, a cell-penetrating moiety, and the concept of prodrug, were used in design of this nanoparticle in a collaborative manner. The nanopreparation allowed superior cell internalization, cytotoxicity, tumor targeting, and antitumor efficacy in vitro and in vivo over its nonsensitive counterpart , free paclitaxel and conventional micelles. This uniquely engineered nanoparticle has potential for effective intracellular delivery of drug into cancer cells. nanomedicine | polymer-drug conjugate | polymeric micelles | multifunctional | non-small cell lung cancer D rug-loaded nanocarriers such as liposomes, micelles, poly-meric and inorganic nanoparticles, and drug conjugates have demonstrated various advantages over free therapeutic molecules. These nanopreparations can be further engineered with functional moieties to improve their performance in terms of circulation longevity, targetability, cellular penetration, and stimulus sensitivity. The idea of a stimulus-sensitive drug delivery system is based on the abnormalities in the tumor microenvi-ronment, such as acidic pH (1), altered redox potential (2), and up-regulated proteins (3). These internal conditions and external stimuli such as hyperthermia (4), magnetic field (4), and ultra-sound (5) can be used to change the behavior of nanocarriers, resulting in an enhanced tumor targeting and antitumor effects. Matrix metalloproteinases (MMPs), especially MMP2, are known to be involved and overexpressed in many stages of human cancers (3, 6). Various MMP-sensitive substrates have been designed and showed stimulus responsiveness when used in drug delivery and imaging systems (3, 6). In our previous study, a synthetic octapeptide (GPLGIAGQ)