Our research focuses on advancing macromolecule drug delivery technology by developing new materials. We are actively working in the following application areas:
1. Cancer Therapy
Over 12 million people in the United States are currently battling cancer. Cytotoxic chemotherapy remains the preferred frontline strategy used against most types of cancer. While effective, treatment-related side effects such as major organ damage, infertility, immunosuppression and nausea/vomiting severely compromise patient quality of life. We are developing technologies for improved detection and treatment of cancer.
Ongoing projects in this area include:
- Immunomodulation to potentiate chemotherapy. We are developing constructs for targeting tumor-associated macrophages (TAMs). The prevalence of these cells in tumor microenvironment has been shown to correlate with poor prognosis in patients. Using library selection, we have identified a peptide for targeting TAMs. We are using this peptide in targeted nano-formulations for targeted depletion of anti-inflammatory macrophage as a means to improve outcome from standard treatments (in collaboration with Elaine Raines, UW Pathology, and Andre Lieber, UW Medical Genetics).
- Synthetic materials for T-cell engineering. T-cell immunotherapy is demonstrating remarking anti-cancer activity in several early clinical trials. We are working with Michael Jensen’s group (Seattle Children’s Research Institute) to develop materials that improve the process for T-cell manufacturing.
- Polymeric coatings for oncolytic adenovirus. We are synthesizing self-assembling materials for reversible shielding of oncolytic adenoviruses to reduce their immunogenicity and hepatotoxicity (in collaboration with Andre Lieber and Dmitry Shayakhmetov, UW Medical Genetics).
- Early detection of esophageal cancer. We are developing targeted nanoparticles for fluorescent endoscopy applications (in collaboration with Joo Ha Hwang, UW Gastroenterology; William Grady, UW Gastroenterology and FHCRC; and Lih Lin, UW Electrical Engineering).
- Polymers for drug delivery. Current chemotherapies generally have a narrow therapeutic range. We are synthesizing polymeric drug carriers to change the biodistribution of small molecule drugs, thereby reducing toxicity.
- Ngambenjawong C, Gustafson HH, Pineda JM, Cieslewicz ME, and Pun SH. Serum stability and affinity optimization of an M2 macrophage-targeting peptide (M2pep). Theranostics 2015, 6, 1403-1414.
- Wei H*, Wang CE*, Tan N, Boydston AJ, and Pun SH. ATRP Synthesis of Sunflower Polymers using Cyclic Multimacroinitiators. ACS Macro Letters 2015, 4, 938-941.
- Cieslewicz M, Tang J, Yu JL, Cao H, Zavaljevski M, Motoyama K, Lieber A, Raines EW, and Pun SH. Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival. PNAS 2013, 110, 15919-15924.
- Chan LW, Wang Y-N, Lin LY, Upton MP, Hwang JH, and Pun SH. Synthesis and characterization of anti-EGFR fluorescent nanoparticles for optical molecular imaging. Bioconjugate Chem. 2013, 24, 167-175.
- Kim TH, Mount CW, Dulken BW, Ramos J, Fu CJ, Khant HA, Chiu W, Gombotz W, and Pun SH. Filamentous, mixed micelles of triblock copolymers enhance tumor localization of indocyanine green in a murine xenograft model. Mol. Pharm. 2012, 9, 135-143.
We are grateful to the following current and past funding sources: NIH NCI, NIH NIBIB, NSF DMR, Alliance for Cancer Gene Therapy, and Washington Research Foundation.
2. Delivery to the Central Nervous System
The delivery of exogenous agents to cells in the central nervous system is a powerful technique with applications in treatment of neurological disease.
Ongoing projects in this area include:
- Gene delivery to the brain. We are synthesizing multifunctional polymers for targeted nucleic acid delivery to neural progenitor cells in the subventricular zone of the brain (in collaboration with Philip Horner, UW Neurosurgery).
- Targeted drug delivery to glioma cells. We are developing targeted polymers to deliver peptides and siRNA to glioma and glioblastoma cells for brain cancer treatment (in collaboration with Bob Rostomily, UW Neurosurgery).
- Drug delivery for spinal cord injury. We are developing injectable materials for localizeddrug delivery after spinal cord injury (in collaboration with Philip Horner, UW Neurosurgery).
- Sellers DL, Bergen JM, Johnson RN, Ravits J, Horner PH, and Pun SH. Targeted Axonal Import (TAxI) peptide delivers functional proteins into the spinal cord after peripheral administration. PNAS 2016, 113, 2514-2519.
- Chu DSH, Sellers DL, Bocek MJ, Fishedick AE, Horner PJ, and Pun SH. MMP-sensitive polymers mediate environmentally-responsive bivalirudin release and thrombin inhibition. Biomaterials Science 2015, 3, 41-45.
- Sellers DL, Kim TH, Mount CW, Pun SH, and Horner PJ. Prolonged hirudin delivery from poly(lactic-co-glycolic) acid microspheres encapsulated in Pluronic F-127 and functional recovery from a demyelination lesion. Biomaterials 2014, 35, 8895-8902.
- Wei H, Volpatti LR, Sellers DL, Maris DO, Andrews IW, Hemphill AS, Chan LW, Chu DS, Horner PJ, and Pun SH. Dual-responsive, stabilized nanoparticles for efficient in vivo plasmid delivery. Angew. Chem. Int. Ed. Engl. 2013, 52, 5377-5381.
- Wei H, Schellinger JG, Chu DSH, and Pun SH. Neuron-targeted copolymers with sheddable shielding blocks synthesized using a reducible, RAFT-ATRP double-head agent. J. Am. Chem. Soc. 2012, 134, 16554-16557.
- Shi J, Choi JL, Chou B, Johnson RN, Schellinger JG, and Pun SH. Effect of polyplex morphology on cellular uptake, intracellular trafficking, and transgene expression. ACS Nano 2013, 7, 10612-10620.
We are grateful to NIH NINDS and DOD SCIRP for funding support.
3. Materials for Hemostasis
Image by William Walker
Bleeding management is a critical part of care for trauma patients and those with bleeding disorders. Hemorrhage due to uncontrolled bleeding is responsible for 30-40% of deaths associated with traumatic injuries. With Dr. Nathan White (UW Emergency Medicine), we are developing new injectable hemostatic materials. This work has been featured on the AAAS Science Update podcast and UWTV.Selected recent publications:
- Lamm RJ, Lim EB, Weigandt KM, Pozzo LD, White NJ, and Pun SH. Peptide valency plays an important role in the activity of a synthetic fibrin-crosslinking polymer. Biomaterials 2017, accepted.
- Chan LWG, Kim CH, Wang X, Pun SH, White NJ, and Kim TH. PolySTAT-modified chitosan gauzes for improved hemostasis in external hemorrhage. Acta Biomaterialia 2016, 31, 178-185.
- Chan LWG, Wang X, Wei H, Pozzo LD, White NJ, and Pun SH. Fibrin-crosslinking polymers for modulating clot properties and inducing hemostasis. Sci. Transl. Med. 2015, 7, 277ra29.
We are grateful to NIH NHLBI for funding support.
4. Kidney Disease Treatment
Chronic kidney disease is a major health problem worldwide. Due to limited therapies to arrest disease advancement to kidney failure, many patients suffer high morbidity and poor five-year survival rates. In many kidney diseases, injury and loss of kidney podocytes directly underlies declining kidney function. With Dr. Stuart Shankland (UW Nephrology), we are developing polymer- and cell-based therapies to protect and regenerate podocytes.
We are grateful to the DOD PRMRP for support.