This project builds on prior studies that were designed and conducted by researchers to significantly reduce or remove key limitations to most current cancer treatment processes. A crucial limitation has been that most current therapies cannot effectively restrict drugs to tumor cells. The drug delivery system designed through this work may accomplish a selective targeting and delivery of anticancer drugs to solid tumors. This targeted delivery, achieved via a thermally responsive, biopolymer, elastin-like polypeptide (ELP) of a pre-determined molecular weight, can facilitate drug aggregation in tumors exposed to an externally applied, clinically utilized heat source. The proposed biopolymer carrier can exploit the passive targeting properties of macromolecular carriers and the Enhanced Permeability and Retention effect, along with active targeting properties that make use of heat at the tumor site. Through this cell penetrating peptide?s mediation, an efficient, intracellular delivery of chemotherapeutics to the tumor can be achieved. Researchers have applied this approach in the lab within several experimental cancer models to confirm its potential for clinical use as a human therapeutic.
Cancer, a leading cause of morbidity and mortality worldwide, has been difficult to treat through therapies targeted at specific tumor sites. A tremendous need exist for therapeutic approaches that both increase treatment specificity and efficacy within tumors and reduce cytotoxicity in healthy tissues. This proposed tumor-targeting drug delivery system uses a biopolymer ELP in tandem with hyperthermia techniques to augment standard-of-care by selectively inducing intra-tumoral accumulation of a broad range of anti-cancer therapeutics. This treatment methodology may allow doctors to administer chemotherapeutics at doses sufficient for tumor reduction without also harming healthy tissue, thereby enormously impacting treatment success. Moreover, this therapy, although new, is cost-effective: it can be readily integrated into systemic therapies and harnesses hyperthermia and standard-of-care techniques already common in cancer clinics. Successful completion of this project and its clinical translation may lead to greater health and cost effectiveness in cancer treatment.
Normal 0 false false false EN-US X-NONE X-NONE Intellectual Merit: Surgical removal in tandem with chemo- and/or radiotherapy currently provide the most common therapeutic means of treating solid tumors. However, normal tissue tolerance limitations to chemo- and/or radiotherapy, along with inherent tumor resistance to radiotherapy and/or chemotherapy, combine to yield a narrow therapeutic index for these therapies. To circumvent these limitations, we have developed a targeted therapeutic approach for the treatment of solid tumors that will increase treatment specificity and efficacy while reducing cytotoxicity in normal tissues. This targeted approach at base consists of a three-component drug carrier: (1) a thermally responsive biopolymer Elastin-like Polypeptide (ELP), which forms aggregates when external mild heat is applied, (2) a Cell Penetrating Peptide (CPP), which permits escape of the drug carrier from the tumor vasculature and enhances its entry into tumor cells and (3) a Therapeutic Peptide (TP), or small molecule drug, which has anticancer activity and kills tumor cells. Our application of this approach in our lab within several experimental animal cancer models has confirmed that the intravenously delivered, thermally responsive CPP-ELP-TPdrug is cleared from normal tissues under physiological conditions (T~37°C), but that it accumulates and forms aggregates at tumor sites upon application of a mild, clinically available, external heat (T~41°C). This selective delivery of CPP-ELP-TPdrug to tumor sites produced an efficient reduction of tumor volume and reduced toxicity to normal tissues. Thermal targeting of a TPdrug through our ELP approach can be achieved through an existing, clinically available hyperthermia technology; our approach thus may be both a promising method to selectively induce the tumoral accumulation of a broad range of therapeutic peptides and anti-cancer drugs and feasible for implementation in a clinical setting. Broader Impacts: Cancer is a major public health problem in the United States and throughout the world: one in four deaths in the U.S. is now due to this disease, and worldwide cancer mortality is projected to rise to an estimated 13.1 million deaths by 2030. Current treatment options for cancer are limited, and treatment side-effects are often debilitating. A tremendous need and market thus exist for a therapeutic approach that increases specificity and efficacy of treatment, but reduces cytotoxicity in normal tissues. Application of our tumor-targeting drug delivery system, which uses a thermo responsive biopolymer ELP in combination with hyperthermia, can yield the selective delivery of anti-cancer therapeutics to tumor tissue. It further circumvents many problems now besetting current drug delivery approaches and can provide an effective alternative that can replace or augment current treatments of localized tumors. Our approach can achieve these advantages through four principles that enhance cancer drug accumulation in solid tumors: (1) passive tumor targeting by macromolecular carriers, owing to the EPR effect; (2) enhanced tumor perfusion and vascular permeability due to hyperthermia; (3) active tumor targeting through the thermally triggered phase transition of a genetically engineered carrier ELP; and (4) enhanced tumor blood vessel and tumor cell permeability by TPdrug conjugation to a cell penetrating peptide (CPP). This proposed targeting modality, clinically feasible and accessible through hyperthermia technology now in cancer clinic use, can selectively induce tumoral accumulation of a broad range of anti-cancer drugs, sparing healthy tissues. Through a successful participation in the 2012 NSF I-Corps Cohort and its rigorous customer discovery process, we were able to conduct nearly 80 interviews that allows us to: (1) identify customer segments, associated market sizes, and a preliminary business model for our technology, (2) investigate perceived pharmaceutical company needs for better drug delivery technologies, and (3) determine and discuss potential strategies for product co-development. Our objectives are now to broaden our substantial portfolio of proprietary products and intellectual property and to form agreements for and/or license our products/IP to interested companies that can support these products through clinical trials and marketing. The eventual cancer clinic application of the drug delivery technology we have developed has the potential to increase treatment efficacy, improve drug safety and tolerability, and so significantly broaden treatment possibilities and impact in cancer therapeutics.
