Oligoelectrolyte-mediated, pH-triggered release of hydrophobic drugs from non-responsive micelles: Influence of oligo(2-vinyl pyridine)-loading on drug-loading, release and cytotoxicity.

pH-responsive polymeric micelles have been extensively studied for nanomedicine and take advantage of pH differentials in tissues for the delivery of large doses of cytotoxic drugs at specific target sites. Despite significant advances in this area, there is a lack of versatile and adaptable strategies to render micelles pH-responsive that could be widely applied to different payloads and applications. To address this deficiency, we introduce the concept of oligoelectrolyte-mediated, pH-triggered release of hydrophobic drugs from non-responsive polymeric micelles as a highly effective approach with broad scope. Herein, we investigate the influence of the oligoelectrolyte, oligo(2-vinyl pyridine) (OVP), loading and polymer molecular weight on the pH-sensitivity, drug loading/release and cytotoxicity of poly(ethylene glycol-b-ε-caprolactone) (PEG-b-PCL) micelles using copolymers with either short or long hydrophobic blocks (PEG4PCL4 and PEG10PCL10, respectively). The micelles were characterized as a function of pH (7.4 to 3.5). Dynamic light scattering (DLS) revealed narrow particle size distributions (PSDs) for both the blank and OVP-loaded micelles at pH 7.4. While OVP encapsulation resulted in an increase in the hydrodynamic diameter (Dh) (cf. blank micelles), a decrease in the pH below 6.5 led to a decrease in the Dh consistent with the ionization and release of OVP and core collapse, which were further supported by proton nuclear magnetic resonance (1H NMR) spectroscopy and UV-visible (UV-vis) spectrophotometry. The change in zeta potential (ζ) with pH for the OVP-loaded PEG4PCL4 and PEG10PCL10 micelles was different, suggesting that the location/distribution of OVP in the micelles is influenced by the polymer molecular weight. In general, co-encapsulation of drugs (doxorubicin (DOX), gossypol (GP), paclitaxel (PX) or 7-ethyl-10-hydroxycamptothecin (SN38)) and OVP in the micelles proceeded efficiently with high encapsulation efficiency percentages (EE%). In vitro release studies revealed the rapid, pH-triggered release of drugs from OVP-loaded PEG10PCL10 micelles within hours, with higher OVP loadings providing faster and more complete release. In comparison, no triggered release was observed for the OVP-loaded PEG4PCL4 micelles, implying a strong molecular weight dependency. In metabolic assays the drug- and OVP-loaded PEG10PCL10 micelles were found to result in significant enhancement of the cytotoxicity compared to drug-loaded micelles (no OVP) or other controls. Importantly, micelles with low OVP loadings were found to be nearly as effective as those with high OVP loadings. These results provide key insights into the tunability of the oligoelectrolyte-mediated approach for the effective formulation of pH-responsive micelles and pH-triggered drug release.

Teaching an Old Dog New Tricks: A Global Approach to Enhancing the Cytotoxicity of Drug-Loaded, Non-responsive Micelles Using Oligoelectrolytes.

Polymeric micelles have been extensively studied as vectors for the delivery of hydrophobic drugs for the treatment of cancers and other diseases. Despite intensive research, few formulations provide significant benefits, and even fewer have been clinically approved. While many traditional non-responsive micelles have excellent safety profiles, they lack the ability to respond to the intracellular environment and release their cargo in a spatiotemporally defined manner to effectively deliver large doses of cytotoxic drugs into the cytosol of cells that overwhelm efflux pumps. As a novel and adaptable strategy, we hypothesized that well-established non-responsive polymeric micelles could be augmented with a pH-trigger via the co-encapsulation of cytocompatible oligoelectrolytes, which would allow rapid cargo release in the endosome, leading to increased cytotoxicity. Herein, we demonstrate how this strategy can be applied to render non-responsive micelles pH-responsive, resulting in abrupt cargo release at specific and tunable pH values compatible with endosomal delivery, which significantly increased their cytotoxicity up to 3-fold in an ovarian adenocarcinoma (SKOV-3) cell line compared to non-responsive micelles. In comparison, the oligoelectrolyte-loaded micelles were significantly less toxic to healthy 3T3 fibroblasts, indicating a selective cargo release in cancer cell lines. Oligoelectrolytes can be co-encapsulated in the micelles along with drugs at high encapsulation efficiency percentages, which are both ejected from the micelle core upon oligoelectrolyte ionization. Mechanistically, the increase in cytotoxicity appears to also result from the accelerated endosomal escape of the cargo caused by disruption of the endosomal membrane by the simultaneous release of the oligoelectrolytes from the micelles. Furthermore, we show how this approach is broadly applicable to non-responsive micelles regardless of their composition and various classes of hydrophobic chemotherapeutics. The preliminary studies presented here reveal the versatility and wide scope of oligoelectrolyte-mediated, pH-triggered drug release as a compelling and powerful strategy to enhance the cytotoxicity of non-responsive polymeric micelles.

Using GPCRs as Molecular Beacons to Target Ovarian Cancer with Nanomedicines.

The five-year survival rate for women with ovarian cancer is very poor despite radical cytoreductive surgery and chemotherapy. Although most patients initially respond to platinum-based chemotherapy, the majority experience recurrence and ultimately develop chemoresistance, resulting in fatal outcomes. The current administration of cytotoxic compounds is hampered by dose-limiting severe adverse effects. There is an unmet clinical need for targeted drug delivery systems that transport chemotherapeutics selectively to tumor cells while minimizing off-target toxicity. G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, and many are overexpressed in solid tumors, including ovarian cancer. This review summarizes the progress in engineered nanoparticle research for drug delivery for ovarian cancer and discusses the potential use of GPCRs as molecular entry points to deliver anti-cancer compounds into ovarian cancer cells. A newly emerging treatment paradigm could be the personalized design of nanomedicines on a case-by-case basis.