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Finch G.,Pfizer | Havel H.,Eli Lilly and Company | Analoui M.,Livingston Securities | Barton R.W.,Nanoviricides Inc. | And 9 more authors.
AAPS Journal | Year: 2014

The use of nanotechnology in medicine holds great promise for revolutionizing a variety of therapies. The past decade witnessed dramatic advancements in scientific research in nanomedicines, although significant challenges still exist in nanomedicine design, characterization, development, and manufacturing. In March 2013, a two-day symposium "Nanomedicines: Charting a Roadmap to Commercialization," sponsored and organized by the Nanomedicines Alliance, was held to facilitate better understanding of the current science and investigative approaches and to identify and discuss challenges and knowledge gaps in nanomedicine development programs. The symposium provided a forum for constructive dialogue among key stakeholders in five distinct areas: nanomedicine design, preclinical pharmacology, toxicology, CMC (chemistry, manufacturing, and control), and clinical development. In this meeting synopsis, we highlight key points from plenary presentations and focus on discussions and recommendations from breakout sessions of the symposium. © 2014 American Association of Pharmaceutical Scientists.


Libutti S.K.,U.S. National Cancer Institute | Libutti S.K.,Yeshiva University | Paciotti G.F.,CYTIMMUNE SCIENCES | Byrnes A.A.,SAIC | And 8 more authors.
Clinical Cancer Research | Year: 2010

Purpose: A novel nanomedicine, CYT-6091, constructed by simultaneously binding recombinant human tumor necrosis factor alpha (rhTNF) and thiolyated polyethylene glycol to the surface of 27-nm colloidal gold particles, was tested in a phase I dose escalation clinical trial in advanced stage cancer patients. Experimental Design: CYT-6091, whose dosing was based on the amount of rhTNF in the nanomedicine, was injected intravenously, and 1 cycle of treatment consisted of 2 treatments administered 14 days apart. Results: Doses from 50 μg/m 2 to 600 μg/m2 were well tolerated, and no maximum tolerated dose (MTD) was reached, as the highest dose exceeded the target dosage of 1-mg rhTNF per treatment, exceeding the previous MTD for native rhTNF by 3-fold. The first 2 patients on the study, each receiving 50 μg/m 2, did not receive any prophylactic antipyretics or H2 blockade. A predicted, yet controllable fever occurred in these patients, so all subsequently treated patients received prophylactic antipyretics and H2 blockers. However, even at the highest dose rhTNF's dose-limiting toxic effect of hypotension was not seen. Using electron microscopy to visualize nanoparticles of gold in patient biopsies of tumor and healthy tissue showed that patient biopsies taken 24 hours after treatment had nanoparticles of gold in tumor tissue. Conclusions: These data indicate that rhTNF formulated as CYT-6091 may be administered systemically at doses of rhTNF that were previously shown to be toxic and that CYT-6091 may target to tumors. Future clinical studies will focus on combining CYT-6091 with approved chemotherapies for the systemic treatment of nonresectable cancers. ©2010 AACR.


Koonce N.A.,University of Arkansas for Medical Sciences | Quick C.M.,University of Arkansas for Medical Sciences | Hardee M.E.,University of Arkansas for Medical Sciences | Jamshidi-Parsian A.,University of Arkansas for Medical Sciences | And 5 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2015

Purpose Although remarkable preclinical antitumor effects have been shown for tumor necrosis factor-α (TNF) alone and combined with radiation, its clinical use has been hindered by systemic dose-limiting toxicities. We investigated the physiological and antitumor effects of radiation therapy combined with the novel nanomedicine CYT-6091, a 27-nm average-diameter polyethylene glycol-TNF-coated gold nanoparticle, which recently passed through phase 1 trials. Methods and Materials The physiologic and antitumor effects of single and fractionated radiation combined with CYT-6091 were studied in the murine 4T1 breast carcinoma and SCCVII head and neck tumor squamous cell carcinoma models. Results In the 4T1 murine breast tumor model, we observed a significant reduction in the tumor interstitial fluid pressure (IFP) 24 hours after CYT-6091 alone and combined with a radiation dose of 12 Gy (P<.05 vs control). In contrast, radiation alone (12 Gy) had a negligible effect on the IFP. In the SCCVII head and neck tumor model, the baseline IFP was not markedly elevated, and little additional change occurred in the IFP after single-dose radiation or combined therapy (P>.05 vs control) despite extensive vascular damage observed. The IFP reduction in the 4T1 model was also associated with marked vascular damage and extravasation of red blood cells into the tumor interstitium. A sustained reduction in tumor cell density was observed in the combined therapy group compared with all other groups (P<.05). Finally, we observed a more than twofold delay in tumor growth when CYT-6091 was combined with a single 20-Gy radiation dose - notably, irrespective of the treatment sequence. Moreover, when hypofractionated radiation (12 Gy × 3) was applied with CYT-6091 treatment, a more than five-fold growth delay was observed in the combined treatment group of both tumor models and determined to be synergistic. Conclusions Our results have demonstrated that TNF-labeled gold nanoparticles combined with single or fractionated high-dose radiation therapy is effective in reducing IFP and tumor growth and shows promise for clinical translation. © 2015 Elsevier Inc. All rights reserved.


Stern S.T.,SAIC | Hall J.B.,SAIC | Yu L.L.,U.S. National Institute of Standards and Technology | Wood L.J.,U.S. National Institute of Standards and Technology | And 4 more authors.
Journal of Controlled Release | Year: 2010

There are many important considerations during preclinical development of cancer nanomedicines, including: 1) unique aspects of animal study design; 2) the difficulties in evaluating biological potency, especially for complex formulations; 3) the importance of analytical methods that can determine platform stability in vivo, and differentiate bound and free active pharmaceutical ingredient (API) in biological matrices; and 4) the appropriateness of current dose scaling techniques for estimation of clinical first-in-man dose from preclinical data. Biologics share many commonalities with nanotechnology products with regard to complexity and biological attributes, and can, in some cases, provide context for dealing with these preclinical issues. In other instances, such as the case of in vivo stability analysis, new approaches are required. This paper will discuss the significance of these preclinical issues, and present examples of current methods and best practices for addressing them. Where possible, these recommendations are justified using the existing regulatory guidance literature. © 2010 Elsevier B.V.


Patent
Cytimmune Sciences | Date: 2013-11-27

A composition and methods to bind and remove toxic agents from a subject exposed to the toxic agents are described herein. The composition comprises a stealth agent and scavenging agent bound to a nanoparticle platform. The stealth agent prevents the nanomedicine from detection and elimination by the immune system allowing the scavenging agent to bind the target toxic agent. The stealth agent comprises an exposing group that once removed from the stealth agent allows the nanomedicine and bound toxic agent to be detected and eliminated from the subjects body.


Kingston D.G.I.,Virginia Polytechnic Institute and State University | Tamarkin L.,CYTIMMUNE SCIENCES | Paciotti G.F.,CYTIMMUNE SCIENCES
Pure and Applied Chemistry | Year: 2012

Paclitaxel (Taxol®) is one of the most important anticancer agents developed over the last 30 years. Its primary mechanism of action is by interaction with the cellular protein tubulin, causing irreversible polymerization to microtubules. A detailed knowledge of this crucial interaction is thus of paramount importance in the design and development of highly potent analogs and also for the potential development of "non-taxane" tubulin polymerization agents. This review briefly describes the discovery and development of taxol, and then describes our work on delineating the tubulin-binding conformation of paclitaxel by a combination of rotational echo double resonance (REDOR) NMR and molecular modeling. The resulting "T-taxol" conformation was validated by the synthesis of conformationally constrained paclitaxel analogs, which had bioactivities up to 20-fold higher than those of paclitaxel. The review concludes with recent work on the development of a gold nanoparticle derivative of paclitaxel. This delivery method has the potential to lower the dosage of paclitaxel needed while maintaining or increasing its effectiveness, thus significantly improving the benefits of this important chemotherapeutic agent. © 2012 IUPAC.


PubMed | University of Arkansas for Medical Sciences and CYTIMMUNE SCIENCES
Type: Journal Article | Journal: International journal of radiation oncology, biology, physics | Year: 2015

Although remarkable preclinical antitumor effects have been shown for tumor necrosis factor- (TNF) alone and combined with radiation, its clinical use has been hindered by systemic dose-limiting toxicities. We investigated the physiological and antitumor effects of radiation therapy combined with the novel nanomedicine CYT-6091, a 27-nm average-diameter polyethylene glycol-TNF-coated gold nanoparticle, which recently passed through phase 1 trials.The physiologic and antitumor effects of single and fractionated radiation combined with CYT-6091 were studied in the murine 4T1 breast carcinoma and SCCVII head and neck tumor squamous cell carcinoma models.In the 4T1 murine breast tumor model, we observed a significant reduction in the tumor interstitial fluid pressure (IFP) 24 hours after CYT-6091 alone and combined with a radiation dose of 12 Gy (P<.05 vs control). In contrast, radiation alone (12 Gy) had a negligible effect on the IFP. In the SCCVII head and neck tumor model, the baseline IFP was not markedly elevated, and little additional change occurred in the IFP after single-dose radiation or combined therapy (P>.05 vs control) despite extensive vascular damage observed. The IFP reduction in the 4T1 model was also associated with marked vascular damage and extravasation of red blood cells into the tumor interstitium. A sustained reduction in tumor cell density was observed in the combined therapy group compared with all other groups (P<.05). Finally, we observed a more than twofold delay in tumor growth when CYT-6091 was combined with a single 20-Gy radiation dose-notably, irrespective of the treatment sequence. Moreover, when hypofractionated radiation (12 Gy 3) was applied with CYT-6091 treatment, a more than five-fold growth delay was observed in the combined treatment group of both tumor models and determined to be synergistic.Our results have demonstrated that TNF-labeled gold nanoparticles combined with single or fractionated high-dose radiation therapy is effective in reducing IFP and tumor growth and shows promise for clinical translation.


Patent
Cytimmune Sciences | Date: 2011-10-26

The present invention comprises compositions and methods for delivery systems of agents, including therapeutic compounds, pharmaceutical agents, drugs, detection agents, nucleic acid sequences and biological factors. In general, these vector compositions comprise a colloidal metal, derivatized PEG (polyethylene glycol) and an agent. The invention also comprises methods and compositions for making such colloidal metal compositions and for treatment of cancer.


CYTIMMUNE SCIENCES | Entity website

AURIMUNE: A NANOMEDICINE PLATFORM A tumor is a fortress whose defenses can block chemotherapies from reaching the cancer cells growing inside. To expose cancer cells to cancer cell killers, the nutritional support structures and protective barriers of tumors must first be destroyed ...


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