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WELLESLEY, MA, United States

Talekar M.,University of Auckland | Ganta S.,Nemucore Medical Innovations, Inc. | Singh A.,Northeastern University | Amiji M.,Northeastern University | And 4 more authors.
Pharmaceutical Research | Year: 2012

Purpose Ovarian cancer is a debilitating disease, which needs multi-pronged approach of targeted drug delivery and enhanced efficacy with the use of combination therapeutics. In this study, we have examined the anticancer activity of PIK75 incorporated in surface functionalized nanoemulsions for targeted delivery to SKOV-3 cells. A pro-apoptotic molecule C6- ceramide was also co-delivered to augment therapeutic efficacy. Methods EGFR and FR functionalized nanoemulsions incorporating PIK75 and C6-ceramide were characterized for particle size, surface charge, entrapment efficiency and morphology. Fluorescence and quantitative uptake studies were conducted in SKOV-3 cells to determine intracellular distribution. Cell viability was assessed using MTT assay while mechanism of cytotoxicity was evaluated using capsase-3/7, TUNEL and hROS assay. Results Cytotoxicity assay showed 57% decrease in IC50 value of PIK75 following treatment with EGFR targeted nanoemulsion and 40% decrease following treatment with FR targeted nanoemulsion. Combination therapy with PIK75 and ceramide enhanced the cytotoxicity of PIK75 compared to therapy with individual formulations. The increase in cytotoxicity was attributed to increase in cellular apoptosis and hROS activity. Conclusion The results of this study showed that the targeted system improved cytotoxicity of PIK75 compared to the nontargeted system. Combination therapy with ceramide augmented PIK75's therapeutic activity. © Springer Science+Business Media, LLC 2012. Source

Kalariya M.,Northeastern University | Ganta S.,Nemucore Medical Innovations, Inc. | Amiji M.,Northeastern University
Pharmaceutical Research | Year: 2012

Purpose: To develop a multi-compartmental vaccine delivery system for safe and efficient delivery of the gp100 peptide antigen in melanoma immunotherapy. Methods: Water-in-oil-in-water (W/O/W) multiple emulsionbased multi-compartmental vaccine delivery system containing the gp100 peptide was prepared by a two-step emulsification method. In vivo prophylactic and active immunization effectiveness of the novel squalane oil-containing gp100 vaccine was evaluated in the murine B16 melanoma model and compared with that of an incomplete Freund's adjuvant (IFA)-based vaccine. Results: Morphological evaluation of the W/O/W multiple emulsions showed that the oil-droplets were homogenously dispersed with the gp100 peptide encapsulated in an inner aqueous phase. Immunization with the gp100 peptide delivered in the W/O/W multiple emulsions-based vaccine resulted in increased protection against tumor challenge compared to IFA-based vaccine (p<0.05, n08) signifying induction of enhanced anti-tumor immunity. In addition, serum Th1 cytokine levels and immuno-histochemistry of excised tumor tissues indicated activation and local infiltration of antigen specific cytotoxic T-lymphocytes into and/or surrounding the tumor mass. Moreover, the newly developed vaccine formulation did not induce any overt systemic toxicity. Conclusion Novel W/O/W multiple emulsions-based vaccine efficiently delivers the gp100 peptide antigen to induce cellmediated anti-tumor immunity and offers an alternate, safe vaccine delivery system. © Springer Science+Business Media, LLC 2012. Source

Abeylath S.C.,Northeastern University | Ganta S.,Nemucore Medical Innovations, Inc. | Iyer A.K.,Northeastern University | Amiji M.,Northeastern University
Accounts of Chemical Research | Year: 2011

By definition, multifunctional nanosystems include several features within a single construct so that these devices can target tumors or other disease tissue, facilitate in vivo imaging, and deliver a therapeutic agent. Investigations of these nanosystems are rapidly progressing and provide new opportunities in the management of cancer. Tumor-targeted nanosystems are currently designed based primarily on the intrinsic physico-chemical properties of off-the-shelf polymers. Following fabrication, the surfaces of these nanoscale structures are functionalized for passive or active targeted delivery to the tumors.In this Account, we describe a novel approach for the construction of multifunctional polymeric nanosystems based on combinatorial design principles. Combinatorial approaches offer several advantages over conventional methods because they allow for the integration of multiple components with varied properties into a nanosystem via self-assembly or chemical conjugation. High-throughput synthesis and screening is required in polymer design because polymer composition directly affects properties including drug loading, retention in circulation, and targeting of the nanosystems.The first approach relies on the self-assembly of macromolecular building blocks with specific functionalities in aqueous media to yield a large variety of nanoparticle systems. These self-assembled nanosystems with diverse functionalities can then be rapidly screened in a high-throughput fashion for selection of ideal formulations, or hits, which are further evaluated for safety and efficacy. In another approach, a library of a large number of polymeric materials is synthesized using different monomers. Each of the formed polymers is screened for the selection of the best candidates for nanoparticle fabrication. The combinatorial design principles allow for the selection of those nanosystems with the most favorable properties based on the type of payload, route of administration, and the desired target for imaging and delivery. © 2011 American Chemical Society. Source

A novel nanoemulsion formulation useful for the delivery of docetaxel chemotherapeutic agents is provided, as well as methods of their preparation and use in cancer patients and for cancer imaging.

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2015

DESCRIPTION provided by applicant Ovarian cancer is a highly lethal gynecologic cancer with an estimated new cases and approximately deaths in the USA per year In a large majority of the patients cancer reoccurs after initial treatment and manifest resistance to conventional and novel chemotherapeutic agents thereby representing a formidable clinical challenge which could be mitigated by the production of novel targeted therapies Recently the Donahoe laboratory at the Massachusetts General Hospital MGH showed that recombinant human M llerian Inhibiting Substance rhMIS specifically targets ovarian cancer cell populations that respond poorly to the currently used chemotherapeutic agents indicating that MIS could be used as an innovative targeted medicine to address recurrent multidrug resistant ovarian cancer In vivo when MIS was tested in mice as a single agent it was found to inhibit tumor growth in experiments lasting to days Additionally since MIS receptor expression is limited in endogenous tissue systemic toxicity of rhMIS is expected to be low A significant unmet need hindering the progress of an rhMIS treatment for ovarian cancer is the development of scaled production of the protein with reasonable economics This R proposal describes the parallel molecular biology processing methods to scale production of a new construct that provides for enhanced cleavage purity and potency for use as a standard preparation to study in preclinical trials and for subsequent use in phase I clinical trials against human ovarian cancer the latter of which will be the subject of another grant for which the MIS produced by the present proposal will lay the foundation for the eventual material used The team from Nemucore Medical Innovations NMI Blue Sky BioServices and MGH propose as the subject of this R application to develop and characterize the methods and processes required to produce rhMIS in single use disposable biomanufacturing equipment NMI is establishing a modular biomanufacturing facility compliant with the FDAandapos s pharmaceutical quality system guidance to enable such novel biotherapeutics as rhMIS for clinical investigation PUBLIC HEALTH RELEVANCE Ovarian cancer is a highly lethal gynecologic cancer After initial diagnosis and treatment most patientsandapos tumors disappear but a large majority of these cancers reemerge and manifest resistance to most therapeutic agents Clearly treatment of ovarian cancer represents a formidable clinical challenge and could benefit from the development of new therapies The objective of this proposal is to define a new way to scale production of recombinant human M llerian Inhibiting Substance rhMIS since our recent work has demonstrated that rhMIS specifically targets ovarian cancer cell populations that respond poorly to the currently used chemotherapeutic agents

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