Finch G.,Pfizer |
Havel H.,Eli Lilly and Company |
Barton R.W.,Nanoviricides Inc. |
Diwan A.R.,Nanoviricides Inc. |
And 8 more authors.
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. Source
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
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. Source
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 500.00K | Year: 2006
DESCRIPTION (provided by applicant): Currently, first-line treatment of resectable solid tumors most commonly involves surgery followed by a regimen of chemotherapy and/or radiation. Unfortunately, this strategy often fails because of recurrent or metastatic disease. To change this paradigm, new cancer therapies must deliver multifaceted therapeutics to destroy the heterogeneous population of tumor cells present within solid tumors prior to surgical removal. The current proposal seeks to develop such tumor-targeted nanotherapies on a pegylated colloidal gold nanoparticle platform (cAu) designed to deliver a combination of potent anti-cancer drugs to solid tumors. The first drug developed (designated CYT-0691) actively targets and sequesters human tumor necrosis factor alpha (TNF) in solid tumors while avoiding uptake and clearance by the reticuloendothelial system (RES). The drug is comprised of TNF and thiolated polyethylene glycol (an RES avoidance molecule) that are covalently bound, as individual molecules, to the surface of 26 nm cAu nanoparticles. This proposal seeks to use TNF bound to pegylated cAu nanoparticles as the core of a family of new combinational cancer nanotherapies. These new nanotherapies will be assembled on a single particle of pegylated cAu and are designed to deliver both TNF and a second therapeutic that synergizes with the known actions of TNF on solid tumors. The multivalent nature of the proposed cAu nanodrugs will require us to further our current understanding of the nanoparticle platform and the interaction of the putative therapeutics with the cAu nanoparticle's surface. To meet this challenge, Cytlmmune has assembled a multidisciplinary team of experts to address the basic and applied challenges of making pegylated cAu nanoparticles a platform technology for developing tumor-targeted nanotherapeutics. The expertise of each team member will be brought to bear in addressing specific issues of surface binding chemistries to cAu nanoparticles, the synthesis and characterization of the cAu bound drugs, and the biologic characterization of each new pegylated cAu nanoparticle vector. Cytlmmune's collaborators include Dr. David Kingson of Virginia Tech., Dr. Dan Goia from Clarkson University, Drs. Viktor Struzhkin and Andrew Steele of the Geophysical Laboratory of the Carnegie Institute, and Drs. Paras Prasad and Haridas Pudavar of the Department of Chemistry at the University of Buffalo.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 99.10K | Year: 1999
Not Available Electrophoresis is a well-known technique that has been used for the deposition of various polymers carrying ionizable groups (electrophores) and for the separation of biological molecules. In the proposed SBIR program, we plan to use an electrophoretic processing technique, which will be modified to suit the electrodeposition of polymers with bulk room-temperature ferromagnetic and conducting ploymers with high conductivity. This technique will use solutions/dispersions of the appropriate ploymers after being synthesized and modified in-house. The deposited ploymers will be characterized using the appropriate techniques that will help identify and determine ferromagnetic and electrical characteristics. Upon successful conclusion of Phase I (achieving a polymer with conductivity > 103 S/cm and a ferromagnetic polymer with a permeability > 6, Phase II will be pursued towards optimization of the modified electrophoresis setup, therefore, enhancing the very characteristics sought after in the two polymer systems, and process scale up. After demonstrating feasibility of this approach in Phase I and the subsequent optimization and characterization work in Phase II, the Phase III program will have large implications on the scientific and practical approach towards inducing conductivity or ferromagnetic properties with levels beyond those achieved in polymers thus far.
Kingston D.G.I.,Virginia Polytechnic Institute and State University |
Tamarkin L.,CYTIMMUNE SCIENCES |
Paciotti G.F.,CYTIMMUNE SCIENCES
Pure and Applied Chemistry
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. Source