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Polymeric vehicles for the optimal delivery of synergistic chemotherapeutics

  • Author(s): Vogus, Douglas
  • Advisor(s): Mitragotri, Samir
  • et al.
Abstract

Combination chemotherapy is the current gold standard for treating advanced malignancies, but treatment is often limited by systemic toxicity. Polymeric delivery vehicles have emerged as a useful tool to deliver chemotherapeutics with greater tumor selectivity and reduced healthy tissue toxicity than standard chemotherapy. As a result, many nano-sized polymeric systems containing a single drug have recently entered clinical trials for the treatment of advanced cancers; however, few have been approved due to lack of improvements in tumor regression. This thesis focuses on engineering more therapeutically active polymeric vehicles by optimally delivering combinations of synergistic chemotherapy drugs. Polymer drug conjugates and bi-phasic nanoparticles are engineered to precisely deliver synergistic drugs, and I show that relative drug release rates govern the therapeutic activity of a given combination delivery vehicle. I further show that combination polymer drug conjugates can effectively inhibit the growth of an aggressive, orthothopic tumor model in vivo more effectively than single drug conjugates and the free drug combination. The conjugates are capable of preventing tumor growth through various parenteral administration routes, motivating future development for clinical translation.

In addition to new vehicle development, continued improvements in therapeutic activity rely on fundamentally understanding the mechanisms by which vehicles interact with biological systems and release their therapeutic payloads. In the latter part of this thesis, I develop a microfluidic technique capable of measuring concentration profiles with high spatio-temporal resolution. The technique is used to measure the transport of a model drug in hydrogels. I show that interactions between the polymeric mesh and the solute significantly impact solute transport and resulting drug release properties. Understanding the physical mechanisms in which drugs interact with their carrier can govern drug release kinetics and is critical for the future development of effective polymeric delivery vehicles.

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