@article{fix_koppolu_novell_hopkins_kierski_zaharoff_dayton_papadopoulou_2019, title={ULTRASOUND-STIMULATED PHASE-CHANGE CONTRAST AGENTS FOR TRANSEPITHELIAL DELIVERY OF MACROMOLECULES, TOWARD GASTROINTESTINAL DRUG DELIVERY}, volume={45}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2019.02.004}, abstractNote={The gastrointestinal (GI) tract presents a notoriously difficult barrier for macromolecular drug delivery, especially for biologics. Herein, we demonstrate that ultrasound-stimulated phase change contrast agents (PCCAs) can transiently disrupt confluent colorectal adenocarcinoma monolayers and improve the transepithelial transport of a macromolecular model drug. With ultrasound treatment in the presence of PCCAs, we achieved a maximum of 44 ± 15% transepithelial delivery of 70-kDa fluorescein isothiocyanate-dextran, compared with negligible delivery through sham control monolayers. Among all tested rarefactional pressures (300–600 kPa), dextran delivery efficiency was consistently greatest at 300 kPa. To explore this unexpected finding, we quantified stable and inertial cavitation energy generated by various ultrasound exposure conditions. In general, lower pressures resulted in more persistent cavitation activity during the 30-s ultrasound exposures, which may explain the enhanced dextran delivery efficiency. Thus, a unique advantage of using low boiling point PCCAs for this application is that the same low-pressure pulses can be used to induce vaporization and provide maximal delivery.}, number={7}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Fix, Samantha M. and Koppolu, Bhanu P. and Novell, Anthony and Hopkins, Jared and Kierski, Thomas M. and Zaharoff, David A. and Dayton, Paul A. and Papadopoulou, Virginie}, year={2019}, month={Jul}, pages={1762–1776} }
 @article{smith_baltz_koppolu_ravindranathan_nguyen_zaharoff_2017, title={Immunological mechanisms of intravesical chitosan/interleukin-12 immunotherapy against murine bladder cancer}, volume={6}, ISSN={["2162-402X"]}, DOI={10.1080/2162402x.2016.1259050}, abstractNote={ABSTRACT There is a critical unmet clinical need for bladder cancer immunotherapies capable of inducing durable antitumor immunity. We have shown that four intravesical treatments with a simple co-formulation of interleukin-12 and the biopolymer chitosan not only destroy orthotopic bladder tumors, but also promote a potent long-lasting systemic immune response as evidenced through tumor-specific in vitro killing assays, complete protection from rechallenge, and abscopal antitumor responses at distant non-treated tumors. This study investigates the immunological kinetics underlying these results. We show through depletion studies that CD8+ T cells are required for initial tumor rejection, but CD4+ T cells protect against rechallenge. We also show that even a single intravesical treatment can eliminate tumors in 50% of mice with 6/9 and 7/8 mice eliminating tumors after three or four treatments respectively. We then performed immunophenotyping studies to analyze shifts in immune cell populations after each treatment within the tumor itself as well as in secondary lymphoid organs. These studies demonstrated an initial infiltration of macrophages and granulocytes followed by increased CD4+ and CD8+ effector-memory cells. This was coupled with a decreased level of regulatory T cells in peripheral lymph nodes as well as decreased myeloid-derived suppressor cell infiltration in the bladder. Taken together, these data demonstrate the ability of properly delivered interleukin-12-based therapies to engage adaptive immunity within the tumor itself as well as throughout the body and strengthen the case for clinical translation of chitosan/interleukin-12 as an intravesical treatment for bladder cancer.}, number={1}, journal={ONCOIMMUNOLOGY}, author={Smith, Sean G. and Baltz, John L. and Koppolu, Bhanu Prasanth and Ravindranathan, Sruthi and Nguyen, Khue and Zaharoff, David A.}, year={2017} }
 @article{jayanthi_koppolu_nguyen_smith_felber_kumar_zaharoff_2017, title={Modulation of Interleukin-12 activity in the presence of heparin}, volume={7}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-017-05382-1}, abstractNote={Glycosaminoglycans (GAGs), especially heparin and heparan sulfate (HS), modulate the functions of numerous cytokines. The aims of this multidisciplinary research were to characterize heparin binding to interleukin-12 (IL-12) and determine the mechanism(s) by which heparin influences IL-12 bioactivity. Heparin and HS were found to bind human IL-12 (hIL-12) with low micromolar affinity and increase hIL-12 bioactivity by more than 6-fold. Conversely, other GAGs did not demonstrate significant binding, nor did their addition affect hIL-12 bioactivity. Biophysical studies demonstrated that heparin induced only minor conformational changes while size-exclusion chromatography and small angle X-ray scattering studies indicated that heparin induced dimerization of hIL-12. Heparin modestly protected hIL-12 from proteolytic degradation, however, this was not a likely mechanism for increased cytokine activity in vitro. Flow cytometry studies revealed that heparin increased the amount of hIL-12 bound to cell surfaces. Heparin also facilitated hIL-12 binding and signaling in cells in which both hIL-12 receptor subunits were functionally deleted. Results of this study demonstrate a new role for heparin in modulating the biological activity of IL-12.}, journal={SCIENTIFIC REPORTS}, author={Jayanthi, Srinivas and Koppolu, Bhanu Prasanth and Nguyen, Khue G. and Smith, Sean G. and Felber, Barbara K. and Kumar, Thallapuranam Krishnaswamy Suresh and Zaharoff, David A.}, year={2017}, month={Jul} }