The overall objective of this competing R01 renewal is to exploit a newly discovered, general mechanism of attachment-triggered self-assembly of hydrophobic drugs to create thermally responsive nanoparticles for the treatment of primary and metastatic cancer. In the previous funding cycle, we discovered that the attachment of multiple copies of hydrophobic chemotherapeutics such as doxorubicin (Dox) and paclitaxel (PTX) at the chain end of a recombinant chimeric polypeptide (CP) resulted in the spontaneous self-assembly of the CP- drug conjugate into near monodisperse, highly soluble nanoparticles. CP-Dox nanoparticles showed dramatic efficacy in curing sub-cutaneous (s.c.) murine colon carcinoma (>90%) in mice and some efficacy in treating metastatic breast cancer in an orthotopic model. These results are highly encouraging but suggest that passive targeting alone of a single drug is unlikely to be therapeutically sufficient. We hence propose to build upon the success of this approach to greatly improve the efficacy of CP-drug nanoparticles by exploiting thermal targeting to co-deliver two complementary chemotherapeutics -Dox and paclitaxel (PTX)- by CP-drug nanoparticles to treat primary and metastatic breast cancer in an orthotopic disease model. To impart thermal targeting capabilities to P-Dox nanoparticles, we have re-engineered the composition and chain length of the CPs to undergo selective and reversible aggregation in the vasculature of tumors that are externally heated to 420C. We propose to apply multiple cycles of mild hyperthermia to "pump" the CP-drug nanoparticles out of the tumor vasculature and into the tumor interstitium. The proposed research will test the hypotheses that: (1) combination chemotherapy is superior to monotherapy;(2) thermal targeting will provide increased tissue-level accumulation and better control of primary tumor that will limit dissemination of metastases from the primary tumor. This research is innovative because, to our knowledge, a rationally engineered drug-nanoparticle system that can be thermally targeted to solid tumors has not been demonstrated for a single drug, let alone multiple types of chemotherapeutics. The impact of this research will be the development of a targeted nanoparticle drug delivery platform that will demonstrate therapeutic efficacy in a preclinical orthotopic tumor model for primary and metastatic disease with two different chemotherapeutics, and will position this technology to graduate to a clinical trial at the end of this funding period.
This research will develop a new and simple method to make nanoparticles of a safe and biodegradable protein-like polymer that contains one or two cancer drugs. This project will demonstrate the superior efficacy of these nanoparticle drug formulations as compared to free drug and will seek to understand the basis for their better performance.
|Liu, Jinyao; Liu, Wenge; Weitzhandler, Isaac et al. (2015) Ring-opening polymerization of prodrugs: a versatile approach to prepare well-defined drug-loaded nanoparticles. Angew Chem Int Ed Engl 54:1002-6|
|McDaniel, Jonathan R; MacEwan, Sarah R; Li, Xinghai et al. (2014) Rational design of "heat seeking" drug loaded polypeptide nanoparticles that thermally target solid tumors. Nano Lett 14:2890-5|
|Yousefpour, Parisa; Chilkoti, Ashutosh (2014) Co-opting biology to deliver drugs. Biotechnol Bioeng 111:1699-716|
|Sinclair, S Michael; Bhattacharyya, Jayanta; McDaniel, Jonathan R et al. (2013) A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation. J Control Release 171:38-47|
|McDaniel, Jonathan R; Bhattacharyya, Jayanta; Vargo, Kevin B et al. (2013) Self-assembly of thermally responsive nanoparticles of a genetically encoded peptide polymer by drug conjugation. Angew Chem Int Ed Engl 52:1683-7|
|McDaniel, Jonathan R; Radford, D Christopher; Chilkoti, Ashutosh (2013) A unified model for de novo design of elastin-like polypeptides with tunable inverse transition temperatures. Biomacromolecules 14:2866-72|
|Asai, Daisuke; Xu, Donghua; Liu, Wenge et al. (2012) Protein polymer hydrogels by in situ, rapid and reversible self-gelation. Biomaterials 33:5451-8|
|McDaniel, Jonathan R; Macewan, Sarah R; Dewhirst, Mark et al. (2012) Doxorubicin-conjugated chimeric polypeptide nanoparticles that respond to mild hyperthermia. J Control Release 159:362-7|
|Liu, Wenge; MacKay, J Andrew; Dreher, Matthew R et al. (2010) Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model. J Control Release 144:2-9|
|McDaniel, Jonathan R; Callahan, Daniel J; Chilkoti, Ashutosh (2010) Drug delivery to solid tumors by elastin-like polypeptides. Adv Drug Deliv Rev 62:1456-67|
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