NSF Award
1640519
This PFI: AIR Technology Translation project, Thermally Targeted Biopolymers for the Delivery of Anticancer Drugs, focuses on translating a thermally responsive biopolymer technology into a new cancer treatment drug delivery system. This system has the potential to improve outcomes and reduce drawbacks now experienced by patients during cancer treatment. Currently, only a small fraction of chemotherapeutic drugs reach tumor sites. The rest of these drugs, systemically administered at dosages strong enough to eradicate cancer cells, are distributed throughout the body, causing extensive damage to normal tissue. The developed drug delivery system attaches a powerful chemo-drug, Doxorubicin, to a thermally responsive, biopolymer, elastin-like polypeptide (ELP). At physiological temperatures (37ºC), this ELP exists in a more liquid state (soluble). However, the ELP can be prompted by an externally applied, clinically available, mild hyperthermia (40-41°C) to undergo a phase transition (into being more solid) and aggregate at the tumor site. To help these aggregated ELPs and their attached Doxorubicin enter the tumor cells at this site, a cell-penetrating peptide (CPP), is also conjugated to the ELP. This drug delivery system thus makes an innovative use of conjugated drug delivery biopolymers, an external, localizing heat, and a peptide able to mediate entry into cancer cells, where it can release the Doxorubicin for a more targeted and efficient tumor cell uptake and action.<br/><br/>The project will yield an externally triggered drug delivery system that can greatly improve the selective delivery of anti-cancer drugs to breast tumors by its unique exploitation of three key features: (1) the passive targeting properties of macromolecular carriers deriving from the enhanced permeability and retention effect, (2) active drug targeting to tumor sites by a clinically available external trigger, and (3) efficient, intracellular tumor drug delivery mediated by a cell penetrating peptide to reduce tumor growth, improve treatment outcomes, and retain better patient quality of life. The developed drug delivery system confers important advantages over competing systems based on drug-polymer conjugates, drug antibody conjugates, liposomes, and nano- and microparticles: (1) this drug delivery system enhances drug half-life and improves drug pharmacokinetic profile; (2) ELP modification by a CPP dramatically (15-20 fold) enhances cellular uptake, yielding more efficient tumor vasculature penetration and greatly enhancing efficacy in both tumor cell entry and the targeting of specific cellular compartments; (3) the water-solubility of lipophilic or water-insoluble drugs can be attained/much improved by their coupling to ELP biopolymers; (4) ELP biopolymers, based on simple genetic code, are simple and inexpensive to manufacture, can be easily modified to add therapeutic peptides for intracellular targeting, and can contain more than one drug, permitting their use in combination therapy. With this targeted drug delivery system, therapeutic drugs can be administered at maximum tolerated dose, but with substantially reduced side effects, resulting in greatly increased cancer treatment efficacy. The system thus addresses current drug delivery technology limitations and yields a competitive advantage over existing approaches for treating localized tumors, one better targeting tumor cells and sparing healthy tissue. <br/><br/>In addition, through a structured program of seminars and workshops, graduate students and post-docs will be guided in recognizing and implementing key steps for advancing the commercial potential of research. They will be introduced to case-based business research and collaboration, as well as regulatory and market research skills, crucial to creating viable business plans that permit the translation of vital research discoveries to the marketplace where their potential benefits can be maximized. The project engages CytRx Inc., a biopharmaceutical research and development company specializing in oncology, to provide guidance on technological aspects of the project and its technology translation from research discovery to commercial reality.
