Peritumorally activatable nanoparticles for delivery of paclitaxel to multidrug resistant ovarian cancer cells.

摘要

Current chemotherapeutics for the treatment of cancer can cause severe systemic toxicity and reduced effectiveness if the cancer has developed multidrug resistance (MDR). Nanoparticles (NPs) have the potential to overcome these challenges by releasing drug only at the tumor site to reduce systemic toxicity and internalizing in the cancerous cells and releasing the drug intracellularly, which may be able to overcome MDR. Thus, we propose a "peritumorally activatable/transformable NP" (PTNP) system that will transform in a tumor-specific manner to increase its distribution at the tumor site as well as uptake by the tumor tissues. The NP is composed of a biodegradable polymer core conjugated to two ligands with distinct functions: first, the NP surface is conjugated via a matrix metalloproteinase (MMP) sensitive peptide linker to a polyethylene glycol (PEG) shell that will protect the NP from the immune system until cleavage by overexpressed MMPs in the tumor microenvironment. Once the PEG shell is removed, the NP will expose its surface conjugated to a second TAT peptide, which will increase the cellular uptake of the NPs into the tumor cells and may be able to bypass MDR mechanisms and increase drug retention at the tumor site.;To test the feasibility of our hypothesis, we first examined the "activated" form of the NPs or PLGA conjugated TAT (PLGA-TAT) NPs to see whether they could be useful in overcoming MDR and increasing cellular retention at the tumor site. Strangely, drug encapsulated PLGA-TAT NPs did not increase cytotoxicity in MDR cells even though efficient cellular uptake was observed with PLGA-TAT NPs and no cellular uptake was observed with PLGA NPs. We attributed the lack of increased cytotoxicity to rapid extracellular drug release from the PLGA NPs. In an attempt to attenuate the extracellular drug release, we tried coating the NPs in polydopamine and calcium phosphate (CaP), but none of our attempts to slow down drug release were successful. On the other hand, polydopamine chemistry allowed simpler and more robust conjugation of TAT to PLGA NP surface than our initial synthesis scheme. We examined whether the TAT-conjugated NPs could help increase the drug retention at the tumor site. TAT-conjugated NPs showed increased retention over PLGA NPs, which may be useful in the dynamic peritoneal environment. From there, we investigated the MMP sensitivity of the fully formed PTNPs. PTNPs were shown to be selectively taken up by ovarian cancer cells in the presence of MMP-2 confirming their MMP sensitivity.;We believe that these NPs have the potential to make a large impact in treating ovarian cancer due to their site-specific sensitivity and increased cellular retention. However, for these NPs to be useful for drug delivery, it is critical to find a way to control drug release from the NPs.