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

Abstract

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-phosphoethanolamine (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, polymeric 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 microenvironment, 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 ultrasound (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) was used as the MMP2-sensitive linker in a PEGylated liposomal nanocarrier that could trigger PEG deshielding and the resultant enhanced cell internalization (3).Although many targeted delivery strategies have shown drug disposition in the tumor, low cellular bioavailability of chemotherapeutics due to insufficient cellular internalization could represent another barrier. To enhance the target cell internalization, cell-penetrating proteins/peptides (CPPs) such as transactivating transcriptional activator peptide (TATp) have been used to modify the nanocarriers/drugs ...

Matrix metalloproteinases in head and neck cancer: current perspectives

“…Liposomes are small vesicles able to conjugate with several compounds, including selective markers or peptides, and transfer them intracellularly. Zhu et al 164 developed such a drug-load nanocarrier containing paclitaxel (PTX) (conjugate/prodrug, PEG 2,000 peptide-PTX) and tested its activity against MMP2. The results were very promising, as the investigators reported high cellular uptake and antitumor efficacy combined with low side toxicity in a non-small-cell lung cancer mouse xenograft model.…”

“…The results were very promising, as the investigators reported high cellular uptake and antitumor efficacy combined with low side toxicity in a non-small-cell lung cancer mouse xenograft model. 164 Similarly, a multifunctional envelope-type mesoporous silica nanoparticle was developed for selective intracellular drug delivery, containing an RGD motif and an MMP-substrate peptide, Pro-Leu-Gly-Val-Arg. 165 Treatment of SCC7, HT29, and 293T cells with this drug-delivery system resulted in increased cell death, with low cytotoxic effects.…”

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

“…These obstacles existing in the body could considerably prevent nanomedicine from reaching its targets in a sufficient drug concentration (7,8). To overcome these barriers, a variety of strategies have been envisioned (9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Despite great advances, these strategies have mainly focused on one or a few biological barriers and led to suboptimal therapeutic effect.…”

Smart nanosystems: Bio-inspired technologies that interact with the host environment

“…Such nanoparticles only unveil a surface of multivalent polyarginine moieties under the PEG brush layer after cleavage by MMPs in the tumor environment, thus leading to an increased interaction and internalization into tumor cells compared with particles that could not be unveiled (42). In the Torchilin lab, the concept of PEG unveiling has also been extended to targeted systems for chemotherapeutic delivery of a liposomal formulation of paclitaxel and leads to significantly decreased tumor growth compared with when liposomes were formulated with uncleavable PEG (43). It is also possible to harness enzymemediated cleavage to cause structural changes in the sensing material.…”