MMP-9 Responsive PEG Cleavable Nanovesicles for Efficient Delivery of Chemotherapeutics to Pancreatic Cancer

Abstract

Significant differences in biochemical parameters between normal and tumor tissues offer an opportunity to chemically design drug carriers which respond to these changes and deliver the drugs at the desired site. For example, overexpression of the matrix metalloproteinase-9 (MMP-9) enzyme in the extracellular matrix of tumor tissues can act as a trigger to chemically modulate the drug delivery from the carriers. In this study, we have synthesized an MMP-9-cleavable, collagen mimetic lipopeptide which forms nanosized vesicles with the POPC, POPE-SS-PEG, and cholesteryl-hemisuccinate lipids. The lipopeptide retains the triple-helical conformation when incorporated into these nanovesicles. The PEG groups shield the substrate lipopeptides from hydrolysis by MMP-9. However, in the presence of elevated glutathione levels, the PEG groups are reductively removed, exposing the lipopeptides to MMP-9. The resultant peptide-bond cleavage disturbs the vesicles’ lipid bilayer, leading to the release of encapsulated contents. These PEGylated nanovesicles are capable of encapsulating the anticancer drug gemcitabine with 50% efficiency. They were stable in physiological conditions and in human serum. Effective drug release was demonstrated using the pancreatic ductal carcinoma cells (PANC-1 and MIAPaCa-2) in two-dimensional and three-dimensional “tumor-like” spheroid cultures. A reduction in tumor growth was observed after intravenous administration of the gemcitabine-encapsulated nanovesicles in the xenograft model of athymic, female nude mice.

High-yield clicking and dissociation of doxorubicin nanoclusters exhibiting differential cellular uptakes and imaging

“…Furthermore, the amounts of the internalized Au gradually increased in proportion to the increase in amount of nanoclusters in the culture medium. Thus, these results strongly demonstrate that the internalization of the nanoclusters depends on the concentration of MMP-2, which suggests that the endocytotic behaviors of the nanoclusters depend on the overexpression of MMP-2 in tumor tissues [41][42][43].…”

Polymersome-Based Drug-Delivery Strategies for Cancer Therapeutics

“…The number and location of the incorporated disulfide bonds allow fine-tuning of the release property from the vesicles. A typical composition that has been used widely for preparing redox-sensitive micelles [66] and liposomes [67] has been successfully implemented with polymersomes [8]. These copolymers contain a disulfide bond to connect the hydrophobic and hydrophilic polymers.…”

“…At the tumor tissue, peptide cleavage destabilizes the drug carrier’s structure and releases the encapsulated contents. Overexpressions of matrix metalloproteinases [77,78] (MMP-9 and MMP-2), serine proteases and cysteine protease [79] (Cathepsin B) in tumor tissues have been utilized for designing enzyme-responsive polymersomes [26] and liposomes [67]. …”

Recent Advances in Endogenous and Exogenous Stimuli-Responsive Nanocarriers for Drug Delivery and Therapeutics

“…Hashida et al, and other groups have also reported on MMP based delivery systems. [44][45][46][47] Other proteases and enzymes, such as phospholipases 48) and glucose-oxidase, 49) have been utilized as stimulus triggers in drug delivery systems, too.…”