Multifunctional Nanocarriers for Combination Cancer TherapyXu, Jieni (2019) Multifunctional Nanocarriers for Combination Cancer Therapy. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractCombination therapy of multiple drugs with different mechanisms can overcome drug resistance, improve safety and efficacy, and thus becomes a promising strategy in cancer treatment. However, the difference of physiochemical and pharmacokinetic properties of the combined drugs might lead to suboptimal uptake and biodistribution of two drugs at the tumor sites. Multifunctional nanocarriers merge as an ideal strategy to circumvent these limitations and improve the therapeutic effect of anticancer agents. A dual-functional nanocarrier was first developed based on the PEG-conjugated S-trans, trans-farnesylthiosalicylic acid (FTS) for delivery of paclitaxel (PTX). FTS is a potent nontoxic RAS antagonist. To facilitate the release of FTS from the carrier and improve the drug loading capacity and formulation stability, both disulfide linkage and Fluorenylmethyloxycarbonyl (Fmoc) group were incorporated to PEG5k-FTS2 to form a PEG5k-Fmoc-S-S-FTS2 micellar system. PTX-loaded PEG5k-Fmoc-S-S-FTS2 micelles exhibited a superior synergistic therapeutic effect in vitro and in vivo. Despite the potent therapeutic effect, the drug content from PEG-conjugated prodrug nanocarriers is relatively low. In order to solve this problem, drug-based monomer was polymerized to increase the number of drug units in each polymer molecule. Here a PPMP-based prodrug copolymer micelle (POEG15-b-PPPMP7), in which each carrier molecule contains 7 units of PPMP, was developed. PPMP is a potent inhibitor of glucosylceramide synthase (GCS), the major catabolic enzyme of ceramide. Doxorubicin (DOX)/POEG-b-PPPMP micellar system exhibited significantly improved antitumor response in vitro and in vivo. The polymeric prodrug-based carrier strategy was also applied to another drug, suberoylanilide hydroxamic acid (SAHA), and developed a well-characterized POEG15-b-PSAHA12 nanocarrier. SAHA is a histone deacetylase inhibitor (HDACI) approved by FDA. In vivo delivery of DOX via POEG-b-PSAHA led to significant inhibition of 4T1.2 tumor growth. However, not all targets have small molecule drugs. Better synergism would be achieved through the combination of small molecule drugs (for known targets) and gene therapeutics for “undruggable” targets. This inspired us to develop a creatine-based polymer (POEG-PCre) for the co-delivery of nucleic acids and chemodrugs. POEG-PCre carrier is effective in co-delivery of DOX and bioengineered miR-34a to tumor cells and specific accumulation to lung tissue for the treatment of breast cancer lung metastasis. Share
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