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.
