Intracellular delivery of reactive oxygen species generating polypeptide-drug conjugates for cancer therapy

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  • March 20, 2019
Creator
  • Wadhwa, Saurabh
    • Affiliation: Eshelman School of Pharmacy
Abstract
  • Auto-oxidation of D-penicillamine (D-pen), FDA registered for the treatment of Wilson's disease and rheumatoid arthritis, generates reactive oxygen species (ROS), a reaction catalyzed by transition metal ions (TMIs). D-pen has anti-proliferative and anti-angiogenic effects and is known to modulate several signaling pathways. However, an exact mechanism of action is not known. A reactive thiol group, strong plasma protein binding, rapid clearance, higher effective concentrations and cell impermeability challenge the development of D-pen as an anticancer agent. This dissertation work investigates poly([alpha])-L-glutamic acid (PGA) conjugates of D-pen for enhanced delivery to cancer cells and overcome the challenges mentioned above. Complete biodegradability, ability to carry large payloads of D-pen, reversible conjugation, biocompatibility, longer circulation and passive tumor accumulation make PGA an ideal drug carrier. Evidence is presented that PGA-D-pen conjugates enhance the intracellular uptake of D-pen. Upon release from the conjugate, D-pen causes significant elevation in ROS levels leading to apoptotic cell death in murine and human leukemia, and breast cancer cells. Treatment with PGA-D-pen improves the survival of CD2F1 mice bearing intra-peritoneal (i.p.) leukemia with no apparent adverse events. Idarubicin (Ida), an anthracycline chemotherapeutic, has shown efficacy as first-line treatment in acute leukemia and other cancers. ROS elevation that plays a major role in mediating its cytotoxicity is dependent on and augmented in the presence of low molecular weight thiols (LMWTs) like D-pen. We hypothesized that a combination of Ida and D-pen formulated as dual drug conjugates (DDCs) will provide co-delivery leading to enhanced anticancer effects while increasing the therapeutic index of Ida. Targeting to sigma-1 receptors, known to be over-expressed in many different cancers, to further enhance the efficacy and specificity was also examined. It was shown that stable DDCs could be synthesized with programmed drug release properties. The conjugates were successfully targeted in-vitro to sigma-1 receptor over-expressing non-small cell lung cancer (NSCLC) cells with a novel benzamide derivative, trivalent anisamide, as the ligand. DDCs showed prolonged circulation, enhanced tumor accumulation, reduced cardiac exposure of Ida, and improved tumor efficacy and survival in athymic nu/nu mice bearing NSCLC tumor xenografts.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the UNC Eshelman School of Pharmacy."
Advisor
  • Mumper, Russell J.
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  • Chapel Hill, NC
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  • Open access

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