Biomaterials
Nanomedicine
Our lab has pioneered an unconventional, targeted nanomaterial delivery system called “Enzyme-Directly Assembly of Particle Therapeutics” (EDAPT). The approach relies on disease associated inflammatory signals in the form of enzymes, as endogenous stimuli for accumulation of material in a targeted fashion for subsequent, sustained drug release. This concept has been demonstrated in multiple disease models including cancer, myocardial infarction, and ischemic skeletal muscle.
Peptide Therapeutics
With an interest in peptide therapeutics, and the tremendous translational potential of universal peptide delivery technologies, we have developed the “Protein-Like Polymer” (PLP) platform. This unique approach results in increased half-life and efficacy of peptides. This proteomimetic, rather than peptidomimetic strategy provides multifunctionality, multivalency and rapid design build test cycles for drug development.
New Approach to Lipidation
In 2019 we introduced a new direction in our research with the development of an 18 carbon α,ω-dicarboxylic acid monoconjugated via an ester linkage to paclitaxel (PTX). This octadecanedioic acid-PTX (ODDA-PTX) prodrug forms a non-covalent complex with human serum albumin (HSA). Preservation of the terminal carboxylic acid moiety on ODDA-PTX enables binding to HSA in the same manner as native long chain fatty acids (LCFAs), wherein LCFAs bind HSA within hydrophobic pockets and make favorable contacts between carboxylates and positively charged amino acid residues. Therefore, this carrier strategy for small molecule drugs is based on naturally evolved interactions between LCFAs and HSA, demonstrated first for PTX. ODDA-PTX shows differentiated pharmacokinetics, higher maximum tolerated doses and increased efficacy in vivo in several subcutaneous human tumor xenograft models in mice compared to FDA-approved clinical formulations. This platform is currently under development for the delivery of multiple classes of therapeutics.
Cancer
In the context of cancer therapy and diagnostics, three biomolecule-polymer based drug delivery platforms are being developed and pioneered by our laboratory: protein-like polymers (PLPs) (top), enzyme-directed assembly of particle therapeutics (EDAPT) (bottom), and a novel fatty acid facilitated drug delivery system (right). See below for recent, representative papers on these topics.
1) Enzyme-directed assembly of particle therapeutics
Delivery of Immunotherapeutic Nanoparticles to Tumors via Enzyme‐Directed Assembly
Claudia Battistella, Cassandra E. Callmann, Matthew P. Thompson, Shiyin Yao, Anjana V. Yeldandi, Tomoko Hayashi, Dennis A. Carson, and Nathan C. Gianneschi* Adv. Healthcare Mater. 2019, 8, 1901105, DOI: 10.1002/adhm.201901105
Tumor Retention of Enzyme-Responsive Pt(II) Drug-Loaded Nanoparticles
Maria T. Proetto, Cassandra E. Callmann, John Cliff, Craig J. Szymanski, Dehong Hu, Stephen B. Howell, James E. Evans, Galya Orr, and Nathan C. Gianneschi* ACS Central Science, 2018, ASAP, DOI: 10.1021/acscentsci.8b00444
2) 1,18-Octadecanedioic Acid (ODDA) facilitated drug delivery
Antitumor Activity of 1,18-Octadecanedioic Acid-Paclitaxel Complexed with Human Serum Albumin
Cassandra E. Callmann, Clare L. M. LeGuyader, Spencer T. Burton, Matthew P. Thompson, Robert Hennis, Christopher Barback, Niel M. Henriksen, Warren C. Chan, Matt J. Jaremko, Jin Yang, Arnold Garcia, Michael D. Burkart, Michael K. Gilson, Jeremiah D. Momper, Paul A. Bertin, and Nathan C. Gianneschi* J. Am. Chem. Soc. 2019, 141, 30, 11765–11769, DOI: 10.1021/jacs.9b04272
3) Protein like polymer to enhance drug efficacy, safety and circulation half-life
Paclitaxel-terminated peptide brush polymers
Jialei Zhu, Hao Sun, Cassandra E. Callmann, Matthew P. Thompson, Claudia Battistella, Maria T. Proetto, Andrea S. Carlini, and Nathan C. Gianneschi* Chem. Commun., 2020, 56, 6778, DOI: 10.1039/c9cc10023g
Biomolecular Densely Grafted Brush Polymers: Oligonucleotides, Oligosaccharides and Oligopeptides
Wonmin Choi, Hao Sun, Claudia Battistella, Or Berger, Maria Vratsanos, Max Wang, and Nathan C. Gianneschi* Angew. Chem. Int. Ed., 2020, Accepted DOI: 10.1002/anie.202005379
Myocardial Infarction
Myocardial infarction (MI) and associated heart failure is a leading cause of death worldwide. Following MI, ischemia results in the death of cardiomyocytes, triggering a massive inflammatory response. Excessive extracellular matrix degradation by overexpressed matrix metalloproteinase leads to significant heart tissue remodeling and ultimately deterioration of cardiac function. Early intervention via minimal invasive methods may offer a promising approach to preserve cardiac function. However, nanoparticles relying on passive delivery suffer from fast clearance and conventional hydrogels usually require local injection locally which is too invasive for clinical translation. Hence, our group in collaboration with the Christman Group (UCSD) has employed the EDAPT concept for the development of injectable nanoparticles (left) and progelators (right) that can target and accumulate in the diseased heart. Ongoing work involves EDAPT based drug delivery to the heart. See below for recent, representative papers.
1) Enzyme directed assembly of particle therapeutics (EDAPT)
Mary M. Nguyen†, Andrea S. Carlini†, Miao-Ping Chien, Sonya Sonnenberg, Colin Luo, Rebecca L. Braden, Kent G. Osborn, Yiwen Li, Nathan C. Gianneschi*, and Karen L. Christman* Advanced Materials, 2015, 27 (37), 5547–5552, DOI: 10.1002/adma.201502003
2) Enzyme responsive hydrogels
Andrea S. Carlini, Roberto Gaetani, Rebecca L. Braden, Colin Luo, Karen L. Christman* and Nathan C. Gianneschi* Nature Communications, 2019, 10, 1735 DOI: 10.1038/s41467-019-09587-y
Developing Injectable Nanoparticles to Repair the Heart
Mary M. Nguyen, Nathan C. Gianneschi, and Karen L. Christman. Current Opinion in Biotechnology, 2015, 34, 225-231, DOI: 10.1016/j.copbio.2015.03.016/ma502163j