Although targeting the ubiquitin-proteasome pathway by proteasome inhibitors, e.g. bortezomib (BTZ), is considered a targeted anticancer approach, its applications are hampered by poor drug solubility, low tumor specificity, drug resistance, side effects, and unsatisfying efficacy toward solid tumors. The current attempts, including the design of new proteasome inhibitors and drug delivery systems, focused mainly on improving drug bioavailability, but failed to address other important issues. Folate receptors (FRs) are overexpressed on many cancer cells as the major mechanism supportive of rapid cell growth, providing the rationale for the development of FR-targeted therapeutics. Unfortunately, some normal cells also express FRs, increasing the risk of off-tumor toxicity. The cancer targetability of these therapeutics has to be further improved. The matrix metalloproteinase 2 (MMP2) upregulation is highly associated with cancer growth, invasion and metastasis and emerged recently as a stimulus for the tumor-targeted drug delivery. To deal with the aforementioned issues of BTZ, in this application, a novel micellar nanopreparation is proposed, which contains a FR-targeted small-molecule drug conjugate (FA-Cat-BTZ) and an MMP2-sensitive self-assembling polymer (PEG2k-pp-PE). In the design, the MMP2-sensitive FR-targeting will improve the BTZ?s tumor specificity. In the tumor, the upregulated MMP2 will deshield the PEG layer and collapse the micellar nanoparticles, leading to the rapid release of FA-Cat-BTZ. Then, the released FA-Cat-BTZ will bind to the FRs on cancer cells for endocytosis. Therefore, this system undergoes the ?two-stage? transition from a nanoparticle to a small molecule, which will satisfy the nanoparticles? tumor accumulation, small molecules? tissue penetration, and cancer cell-specific drug uptake. Additionally, PEG2k-pp-PE possesses the capability of overcoming the efflux-mediated drug resistance. As a result, the novel strategy will maximize BTZ?s anticancer activity, overcome drug resistance, and minimize side effects. The major goals of this proposal are to preclinically evaluate the strategy and gather the essential information/data for future clinical translation.
Three specific aims are proposed: (i) Prepare and optimize the micelles; (ii) Evaluate the combinatorial effects of PEG2k-pp-PE and FA-Cat-BTZ; and (iii) Evaluate the in vivo tumor targeting and anticancer activity. The proposal is driven by the need to broaden the anticancer spectrum and improve the efficacy of proteasome inhibitors, and to develop a strategy that can be a stepping stone towards attaining the ultimate goal of cancer-specific drug delivery. This study will be the first exploration of the dual (MMP2 and FR) targeted delivery of targeted therapeutics to the solid tumor and the novel combination regimen (proteasome inhibitor and efflux inhibitor) for treating drug-resistant cancers. The positive findings from this study are expected to be translated into potential clinical progress. This AREA grant will also strengthen the research environment in the College of Pharmacy at TAMHSC and provide more research opportunities for PharmD, graduate, and undergraduate students.
The goal of this study is to develop and evaluate a novel dual-targeted platform for cancer-specific drug delivery and cancer sensitization. The platform will improve the tumor specificity and inhibit the drug resistance of proteasome inhibitors, resulting in the enhanced anticancer activity and decreased off-target toxicity. The facile preparation methods, simple structure, and multiple functions will make the proposed drug delivery system feasible for further clinical translation and drug development.
