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Gaithersburg, MD, United States

Sun H.,Houston Methodist Hospital | Zhu X.,Jilin University | Lu P.Y.,Sirnaomics | Rosato R.R.,Houston Methodist Hospital | And 2 more authors.
Molecular Therapy - Nucleic Acids | Year: 2014

Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed "chemical antibodies." In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy. © 2014 The American Society of Gene & Cell Therapy. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 269.30K | Year: 2010

DESCRIPTION (provided by applicant): Glioblastoma Multiforme (GBM), the most common brain cancer of adults, is among the most aggressive and deadly of neoplasm (WHO grade IV), and is accounted for more than 21% of all primary brain and CNS tumors. The annual incidence of GBM in the United States is 3.01 per 100,000 and is an incurable cancer with a median survival of approximately 12 months from diagnosis. Despite decades of intensive surgical treatment, chemotherapy, radiotherapy, and tremendous basic science and clinical research focused on combating this disease, the prognosis remains virtually unchanged, with survival rates still measured in months. The current genetic understanding of GBM has led to the identification of crucial intracellular molecules and their associated signaling pathways as potential therapeutic targets. We are taking the advantage of RNA interference (RNAi) technology for development of the targeted therapeutics. Three small interfering RNA (siRNA) cocktails targeting EGFR-VEGF-AGT, or EGFR-VEGF-MMP9, or EGFR-VEGF-TGF respectively, will be packaged with Histidine and Lysine polymer (HKP) and Saposin C DOPS liposome nanoparticles for treatment of GBM. The antitumor efficacy of these siRNA nanoparticle drugs will be evaluated with human glioma cell lines U87 and murine glioma cells SMA-560 cell tumor models. We will also characterize the HKP and SapC-DOPS nanoparticle systems with the most potent siRNA cocktail and selected a nanoparticle-siRNA cocktail formulation for GBM treatment with the favorable efficacy and safety profile. Lastly, we will evaluate combined regimen of the siRNA cocktail A with TMZ, or cocktail B and C with Avastin, using the U87 and SMA-560 cell tumor models, with the best nanoparticle delivery formulation. A novel therapeutic protocol will be ready for further preclinical study to support a Phase II grant application. PUBLIC HEALTH RELEVANCE: Glioblastoma Multiforme (GBM), the most common brain cancer of adults, is among the most aggressive and deadly of neoplasm (WHO grade IV), and is accounted for more than 21% of all primary brain and CNS tumors. The annual incidence of GBM in the United States is 3.01 per 100,000 and is an incurable cancer with a median survival of approximately 12 months from diagnosis. Despite decades of intensive surgical treatment, chemotherapy, radiotherapy, and tremendous basic science and clinical research focused on combating this disease, the prognosis remains virtually unchanged. We are proposing here to take the advantage of RNA interference (RNAi) technology for development of a novel targeted therapeutic with three small interfering RNA (siRNA) cocktails targeting EGFR-VEGF-AGT, or EGFR-VEGF-MMP9, or EGFR-VEGF-TGF respectively. Two nanoparticle systems, HKP and SapC-DOPS, will be applied with the most potent siRNA cocktail and in combination with the small molecule antagonist drug (TMZ) and monoclonal antibody drug (Avastin) for their antitumor efficacy using both xenograft (U87 cell) and syngeneic (SMA-560 cell) mouse tumor models.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 228.00K | Year: 2008

DESCRIPTION (provided by applicant): Millions of women have been treated for or are living with breast cancer, and tens of thousands of women are expected to die from the disease each year. As breast cancer disease remains the second leading cause of cance r death in women (after lung cancer), different types of treatment have been developed including surgery, radiation therapy, chemotherapy and hormone therapy. New types of therapies are also going through development and trials in order to treat this malig nant disease. This proposal is to use the breakthrough RNAi technology to develop a multi-targeted therapeutics to treat breast cancer. This proposed study is to take advantage of the HKP carriers with siRNA cocktails targeting three specific genes (EGFR, Raf-1 and mTOR) as an RNAi therapeutic protocol for treatment of breast cancer, and to combine the siRNA cocktail with Avastin to mimic a clinical regimen. The success of this approach will have tremendous scientific and therapeutic impacts for combating b reast cancer and many other cancers. PUBLIC HEALTH RELEVANCE: As breast cancer disease remains the second leading cause of cancer death in women (after lung cancer), various types of treatment have been developed including surgery, radiation therapy, chemo therapy and hormone therapy. Using the breakthrough RNAi technology, we are developing a multi-targeted therapeutics to treat breast cancer. This proposed study is to take advantage of the HKP carriers with siRNA cocktails targeting three specific genes as an RNAi therapeutic protocol for treatment of breast cancer, and to combine the siRNA cocktail with Avastin to mimic a clinical regimen. The outcome of the project is expected to be of significant value for the patients and pharmaceutical industry.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 221.35K | Year: 2012

DESCRIPTION (provided by applicant): The primary function of the skin is to serve as a protective barrier against the environment. Loss of the integrity of large portions of the skin as a result of wounds and wound-related infection may lead to major disability or even death. Every year in the United States more than 1.25 million people suffer burns and 6.5 million have chronic skin ulcers caused by diabetes and other diseases. As many as 15% of patients with diabetes will suffer from a diabetic foot ulcerand, of these patients, 6% will be hospitalized due to infection or other ulcer-related complications. Furthermore, diabetes is the leading cause of nontraumatic amputations of lower extremities in the United States, and approximately 14-24 % of patients with diabetes who develop a foot ulcer will have an amputation. Wounds in the elderly are also slower to heal and the problem is especially compounded in elderly diabetics. In addition, many traumatic wounds are incurred through accidents or from combat casualties and there is a need for an accelerated wound repair treatment for patients who undergo invasive surgery. Wounds incurred by members of the armed forces can be compounded by contamination and the risk of infection based on the environment in which the casualty is received. Consequently, wounds from traumatic injury, burns or diabetes pose an increased burden to the healthcare system and there is an immediate need for improved treatment options that promote and accelerate wound healing while minimizing or inhibiting the risk from infection during the healing process. Such a therapy which further promotes wound healing without scar formation would also be of significant benefit since scars over joints can limit limb motion and can have a strong psychological impact. Consequently, the primary goals in the treatment of wounds are rapid wound closure with minimal appearance of scarring. Recent advances in cellular and molecular biology have greatly expanded our understanding of the biologic processes involved in wound repair and tissue regeneration and have led to improvements in wound care. Cutaneous wound healing differs between fetal and adult skin. Wound repair in adult skin begins with an acute inflammatory phase and ends with the formation of a permanent scar. In contrast, early gestation fetal wounds heal in a near perfect fashion, rapidly and without the production of a scar. Amongst several other targets, factors such as transforming growth factor-ss1 (TGF-ss1), and COX-2 are upregulated in adult tissue and show reduced expression in fetal skin. Using RNA interference (RNAi) to down regulate a target gene expression, we have previously demonstrated that a multi-targeted siRNA cocktail targeting these genes can accelerate wound repair in acute wounds when administered in Histidine Lysine Polymer (HKP) - a branched cationic peptide. The treatment also showed reduced scarring and a return to normal histology of the skin. While these observations suggest a new therapeutic based on this approach, the topical administration of this material may not allow penetration across the tissue in the wound as reepithelialization occurs. The healing process itself may prevent further access of the siRNAs to the site of action within the wound bed. Chitosan - a cationicpolysaccharide - has also been used in wound treatments and can also carry siRNAs. In this proposal Aim 1 seeks to examine whether chitosan and HKP can be modified with transdermal peptides while maintaining their siRNA carrying capability. Aim 2 will evaluate the best carrier from Aim 1 to see if it can increase the degree of penetration of the siRNA formulation through the skin. Upon identification of the optimal delivery vehicle (which may be unmodified), Aim 3 will evaluate the multi- targeted siRNA cocktail formulation in young versus elderly mice in animal models of wound healing. We will further examine the cocktail for efficacy in healing wounds in young and elderly diabetic mice. Demonstration of improved rate of wound repair in these models will bethe first step towards migration of this therapy to the clinic to treat patients with similar conditions. Such a therapy may significantly improve wound healing in the elderly, reduce the complications from diabetes, burns or combat casualties and may help reduce the numbers of amputations that are performed on diabetic patients. PUBLIC HEALTH RELEVANCE: Ligand Directed Transdermal siRNA Delivery to Improve Wound Healing The primary function of the skin is to serve as a protective barrier against the environment. Loss of the integrity of large portions of the skin as a result of wounds and wound-related infection may lead to major disability or even death. Every year in the United States more than 1.25 million people suffer burns and 6.5 million havechronic skin ulcers caused by diabetes and other diseases. As many as 15% of patients with diabetes will suffer from a diabetic foot ulcer and, of these patients, 6% will be hospitalized due to infection or other ulcer-related complications. Furthermore,diabetes is the leading cause of nontraumatic amputations of lower extremities in the United States, and approximately 14-24 % of patients with diabetes who develop a foot ulcer will have an amputation. Wounds in the elderly are also slower to heal and theproblem is especially compounded in elderly diabetics. In addition, many traumatic wounds are incurred through accidents or from combat casualties and there is a need for an accelerated wound repair treatment which diminishes scar formation in patients who undergo invasive or cosmetic surgery. Consequently, wounds in the elderly, from traumatic injury, burns or diabetes pose an increased burden to the healthcare system and there is an immediate need for improved treatment options that promote and accelerate wound healing while minimizing or inhibiting the risk from infection during the healing process. We have previously determined that delivery of two siRNAs silencing two gene targets in parallel to a wound (using a cationic peptide (HKP)) markedly improves the rate of wound closure and also reduced scarring in both mouse and pig excisional wound models. This project will seek to improve upon this observation by developing novel topical delivery vehicles that can further penetrate across the tissue within awound. We will examine whether deeper siRNA delivery across a wound correlates with improved wound healing rate and further reduces scar formation in elderly animals and diabetic animal models. The outcome of this project will be the initial characterization of a valuable therapeutic option for treatment of patients with various types of skin wounds.


Huang L.-H.,China Jiliang University | Wang Q.,Sirnaomics | Ma Y.-C.,China Jiliang University | Lou J.-D.,Sirnaomics | Zhang C.,University of Tras os Montes e Alto Douro
Synthetic Communications | Year: 2011

A new reagent, manganese dioxide supported on kieselguhr, for effective oxidation of benzoins into corresponding benzils under heterogeneous and reflux conditions is described. The present oxidations are completed within 10 h with yields of 86-95%. The main advantages of the present procedure are that the preparation of supported reagent is more convenient and the reaction times are relatively short. Source

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