Browsing by Author "Krishnan, Sunil"
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Item Developing a Reliable Mouse Model for Cancer Therapy-Induced Cardiovascular Toxicity in Cancer Patients and Survivors(Frontiers, 2018) Ko, Kyung Ae; Wang, Yin; Kotla, Sivareddy; Fujii, Yuka; Vu, Hang Thi; Venkatesulu, Bhanu P.; Thomas, Tamlyn N.; Medina, Jan L.; Gi, Young Jin; Hada, Megumi; Grande-Allen, Jane; Patel, Zarana S.; Milgrom, Sarah A.; Krishnan, Sunil; Fujiwara, Keigi; Abe, Jun-IchiBACKGROUND: The high incidence of cardiovascular events in cancer survivors has long been noted, but the mechanistic insights of cardiovascular toxicity of cancer treatments, especially for vessel diseases, remain unclear. It is well known that atherosclerotic plaque formation begins in the area exposed to disturbed blood flow, but the relationship between cancer therapy and disturbed flow in regulating plaque formation has not been well studied. Therefore, we had two goals for this study; (1) Generate an affordable, reliable, and reproducible mouse model to recapitulate the cancer therapy-induced cardiovascular events in cancer survivors, and (2) Establish a mouse model to investigate the interplay between disturbed flow and various cancer therapies in the process of atherosclerotic plaque formation. METHODS AND RESULTS: We examined the effects of two cancer drugs and ionizing radiation (IR) on disturbed blood flow-induced plaque formation using a mouse carotid artery partial ligation (PCL) model of atherosclerosis. We found that doxorubicin and cisplatin, which are commonly used anti-cancer drugs, had no effect on plaque formation in partially ligated carotid arteries. Similarly, PCL-induced plaque formation was not affected in mice that received IR (2 Gy) and PCL surgery performed one week later. In contrast, when PCL surgery was performed 26 days after IR treatment, not only the atherosclerotic plaque formation but also the necrotic core formation was significantly enhanced. Lastly, we found a significant increase in p90RSK phosphorylation in the plaques from the IR-treated group compared to those from the non-IR treated group. CONCLUSIONS: Our results demonstrate that IR not only increases atherosclerotic events but also vulnerable plaque formation. These increases were a somewhat delayed effect of IR as they were observed in mice with PCL surgery performed 26 days, but not 10 days, after IR exposure. A proper animal model must be developed to study how to minimize the cardiovascular toxicity due to cancer treatment.Item Immunogenicity of Externally Activated Nanoparticles for Cancer Therapy(MDPI, 2020) Sahin, Onur; Meiyazhagan, Ashokkumar; Ajayan, Pulickel M.; Krishnan, SunilNanoparticles activated by external beams, such as ionizing radiation, laser light, or magnetic fields, have attracted significant research interest as a possible modality for treating solid tumors. From producing hyperthermic conditions to generating reactive oxygen species, a wide range of externally activated mechanisms have been explored for producing cytotoxicity within tumors with high spatiotemporal control. To further improve tumoricidal effects, recent trends in the literature have focused on stimulating the immune system through externally activated treatment strategies that result in immunogenic cell death. By releasing inflammatory compounds known to initiate an immune response, treatment methods can take advantage of immune system pathways for a durable and robust systemic anti-tumor response. In this review, we discuss recent advancements in radiosensitizing and hyperthermic nanoparticles that have been tuned for promoting immunogenic cell death. Our review covers both preclinical and clinical results, as well as an overview of possible future work.Item Pancreatic tumor microenvironmental acidosis and hypoxia transform gold nanorods into cell-penetrant particles for potent radiosensitization(AAAS, 2022) Rauta, Pradipta Ranjan; Mackeyev, Yuri; Sanders, Keith; Kim, Joseph B.K.; Gonzalez, Valeria V.; Zahra, Yasmin; Shohayeb, Muhammad A.; Abousaida, Belal; Vijay, Geraldine V.; Tezcan, Okan; Derry, Paul; Liopo, Anton V.; Zubarev, Eugene R.; Carter, Rickey; Singh, Pankaj; Krishnan, SunilCoating nanoparticles with stealth epilayers increases circulation time by evading opsonization, macrophage phagocytosis, and reticuloendothelial sequestration. However, this also reduces internalization by cancer cells upon reaching the tumor. We designed gold nanorods (GNRs) with an epilayer that retains stealth properties in circulation but transforms spontaneously in the acidotic tumor microenvironment to a cell-penetrating particle. We used a customized stoichiometric ratio of l-glutamic acid and l-lysine within an amphiphilic polymer of poly(l-glutamic acid-co-l-lysine), or P(Glu-co-Lys), to effect this transformation in acidotic environments. P(Glu-co-Lys)-GNRs were internalized by cancer cells to facilitate potent in vitro radiosensitization. When administered intravenously in mice, they accumulate in the periphery and core of tumors without any signs of serum biochemical or hematological alterations, normal organ histopathological abnormalities, or overt deterioration in animal health. Furthermore, P(Glu-co-Lys)-GNRs penetrated the tumor microenvironment to accumulate in the hypoxic cores of tumors to potently radiosensitize heterotopic and orthotopic pancreatic cancers in vivo.Item Radiosensitizing Nanoparticles for Cancer Therapy(2021-04-29) Sahin, Onur; Ajayan, Pulickel; Krishnan, SunilThe focus of this work is on the synthesis and application of nanoparticles made from rare earth oxides as radiosensitizers in cancer therapy. While radiation therapy is the standard of care for treating many tumors found within the body, radiation toxicity can occur in healthy tissue as radiation travels through the body to reach the tumor. By selectively increasing the cytotoxicity of radiation only within the tumor tissue, radiosensitizing nanoparticles offer a potential avenue for decreasing the radiative dose given to patients during treatment, and thus mitigating harmful side effects. The mechanism of radiosensitization used in this study is known as X-ray excited photodynamic therapy. In this method of radiosensitization, X-rays are used to indirectly excite a photosensitizer found in deep tissue environments, which results in the generation of reactive oxygen species. As the terminology suggests, these reactive oxygen species easily react with the organic compounds that make up the structure and functionality of cells, thereby reducing their functionality and inducing the death of tumor cells. Rare earth oxides have not yet been thoroughly explored as a potential material for X-ray excited photodynamic therapy. This study will discuss the significant role these materials could play in the radiosensitization field. While this work focuses on applications towards pancreatic tumors, the use of these materials for X-ray photodynamic therapy could be generalized for many other tumor types found in deep tissue environments.Item Targeting pancreatic cancer with magneto-fluorescent theranostic gold nanoshells(Future Medicine, 2014) Chen, Wenxue; Ayala-Orozco, Ciceron; Biswal, Nrusingh C.; Perez-Torres, Carlos; Bartels, Marc; Bardhan, Rizia; Stinnet, Gary; Liu, Xian-De; Ji, Baoan; Deorukhkar, Amit; Brown, Lisa V.; Guha, Sushovan; Pautler, Robia G.; Krishnan, Sunil; Halas, Naomi J.; Joshi, AmitAim: We report a magneto-fluorescent theranostic nanocomplex targeted to neutrophil gelatinase-associated lipocalin (NGAL) for imaging and therapy of pancreatic cancer. Materials & methods: Gold nanoshells resonant at 810 nm were encapsulated in silica epilayers doped with iron oxide and the near-infrared (NIR) dye indocyanine green, resulting in theranostic gold nanoshells (TGNS), which were subsequently conjugated with antibodies targeting NGAL in AsPC-1-derived xenografts in nude mice. Results: Anti-NGAL-conjugated TGNS specifically targeted pancreatic cancer cells in vitro and in vivo providing contrast for both NIR fluorescence and T2-weighted MRI with higher tumor contrast than can be obtained using long-circulating, but nontargeted, PEGylated nanoparticles. The nanocomplexes also enabled highly specific cancer cell death via NIR photothermal therapy in vitro. Conclusion: TGNS with embedded NIR and magnetic resonance contrasts can be specifically targeted to pancreatic cancer cells with expression of early disease marker NGAL, and enable molecularly targeted imaging and photothermal therapy.