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Li M.,Optimum Therapeutics, Llc
Methods in molecular biology (Clifton, N.J.) | Year: 2012

This chapter introduces the principles and development procedures for physiologically based pharmacokinetic (PBPK) models, and their application for nanoparticle toxicity studies. PBPK models describe the concentration-time or mass-time profiles of chemicals or nanoparticles in individual tissues and organs within the body. They have been used mostly for toxicology and pharmacology studies of small molecules, and their application for nanoparticles are in the early stages. Due to the biodistribution differences between nanoparticles and small molecules, modification may be necessary to build PBPK models for nanoparticles. PBPK models for nanoparticles may be applied to biodistribution predictions, data extrapolation, and property-biodistribution relationships, and, thus, can be a powerful tool in toxicity evaluation. Source


Ramani V.C.,University of Alabama at Birmingham | Purushothaman A.,University of Alabama at Birmingham | Stewart M.D.,University of Alabama at Birmingham | Thompson C.A.,University of Alabama at Birmingham | And 3 more authors.
FEBS Journal | Year: 2013

Heparanase is an endoglucuronidase that cleaves heparan sulfate chains of proteoglycans. In many malignancies, high heparanase expression and activity correlate with an aggressive tumour phenotype. A major consequence of heparanase action in cancer is a robust up-regulation of growth factor expression and increased shedding of syndecan-1 (a transmembrane heparan sulfate proteoglycan). Substantial evidence indicates that heparanase and syndecan-1 work together to drive growth factor signalling and regulate cell behaviours that enhance tumour growth, dissemination, angiogenesis and osteolysis. Preclinical and clinical studies have demonstrated that therapies targeting the heparanase/syndecan-1 axis hold promise for blocking the aggressive behaviour of cancer. Levels of the heparan sulfate proteoglycan syndecan-1 and the heparan sulfate degrading enzyme heparanase are elevated in many cancers. Together these two molecules form a powerful axis that promotes an aggressive tumor phenotype. This review focuses on the mechanism of action of the heparanase/syndecan-1 axis and emerging therapeutic strategies to target this axis. © 2013 The Authors Journal compilation © 2013 FEBS. Source


Wong H.L.,Ohio State University | Wong H.L.,Temple University | Shen Z.,Ohio State University | Lu Z.,Optimum Therapeutics, Llc | And 2 more authors.
Molecular Pharmaceutics | Year: 2011

The clinical development of siRNA cancer therapeutics is limited by the poor interstitial transport and inefficient transfection in solid tumors. We have shown that paclitaxel pretreatment, by inducing apoptosis, causes expansion of the interstitial space and thereby improves nanoparticle delivery and transport in tumor interstitium (referred to as paclitaxel tumor priming) and efficacy of nanomedicines in tumor-bearing animals. The present study evaluated whether paclitaxel tumor priming improves the delivery and transfection of siRNA in 2- and 3-dimensional cultures of human oropharyngeal carcinoma FaDu cells. We used the fluorescent siGLO and confocal microcopy to monitor transport, and used survivin siRNA and immunostaining and immunoblotting to monitor transfection. Survivin is a chemoresistance gene/protein, inducible by chemotherapy. siRNA was loaded in cationic liposomes. The results showed that pretreatment with 50-200 nM paclitaxel (24 or 48 h before siRNA) enhanced the total uptake of siGLO into monolayers (∼15%, p < 0.05), and the depth of penetration into 3-dimensional spheroids and tumor fragment histocultures (2.1- to 2.5-times greater area under the penetration-depth curve). In both monolayer cells and histocultures, paclitaxel pretreatment induced survivin upregulation (p < 0.05). Survivin siRNA alone decreased the survivin levels in a dose-dependent manner, and applying survivin siRNA after paclitaxel pretreatment completely abolished the paclitaxel-induced survivin increases. These findings indicate that paclitaxel tumor priming did not compromise the siRNA functionality. In summary, paclitaxel tumor priming improved the penetration, transfection and functionality of siRNA in tumors, thus offering a promising and practical means to develop chemo-siRNA cancer gene therapy. © 2011 American Chemical Society. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 841.75K | Year: 2006

DESCRIPTION (provided by applicant): Patients with advanced pancreatic cancer have a bleak prognosis, with a median survival time of less than 6 months. These patients usually present with multiple solid tumors in the peritoneal cavity; systemic intravenous (iv) therapy with various chemotherapeutic agents produce an overall response rate of


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 303.23K | Year: 2011

DESCRIPTION (provided by applicant): Bladder cancer is the fourth most common cancer in the US. Due to its easily accessible location and relatively early diagnosis, bladder cancer is one of the least lethal cancers and there are ~540,000 survivors in theUS. At presentation, gt80% of bladder tumors are organ-confined, separated clinically into two groups. The most common group is the nonmuscle-invading tumors, accounting for about 70-80% of cases. This group is managed by surgery, plus neo- or adjuvant intravesical immunotherapy or chemotherapy. Intravesical therapy involves instilling a drug solution into the bladder through an indwelling catheter. Recurrence is common and occurs in 40 to 80% of patients. Between 10 to 20% of recurrences are accompanied bygrade and/or stage progression (including the more fatal metastatic disease). The second group, the muscle-invading tumors, is managed by partial or complete cystectomy (removal of bladder), which presents significant risks and is not well-tolerated by older patients. The most commonly used chemotherapeutic agents for intravescial therapy are mitomycin C (MMC) and doxorubicin. Through a series of preclinical and clinical studies, our group has established that the efficacy of these agents is limited by two factors: inadequate drug delivery to tumors and low chemosensitivity (especially for the more aggressive tumors). Next, we identified a method that uses pharmacokinetic (PK) interventions to maximize the MMC delivery to nonmuscle-invading bladder tumors.This method was tested in a multi-center, randomized phase III trial; the results confirm our hypothesis that improving the drug delivery significantly improves the 5-yr recurrence-free rate (from 23.5% to 42.6%). These data also indicate that a new drugdelivery approach is needed for the remaining patients, those with muscle-invading tumors, who are not adequately managed by intravesical therapy. This R43 application proposes a new drug delivery approach via an alternative administration route: intra-bladder injection of controlled release formulations (CRF) of MMC and suramin, such that therapeutic active drug levels are delivered to deeper tissues. Suramin is used to enhance the sensitivity of human tumors to MMC by 2- to 3-fold. The two aims are to (a) develop biocompatible polymeric CRF of MMC and suramin and (b) conduct in vivo evaluation of the drug-loaded CRF to determine the feasibility of using intra-bladder CRF to treat deeper tumors. Upon demonstration of feasibility, we will investigate, in the later R44 project, the therapeutic efficacy of the combination in tumor-bearing animals (e.g., dogs with naturally occurring bladder tumors), in preparation for the eventual clinical evaluation. This R43 project has the potential to lead to a new treatment modality and significantly improve the management of bladder cancer while the disease is still localized in the bladder. Given the extremely high lifetime health care costs for these patients (over 10 billion in 2003 dollars), an additional potential benefit is cost containment. PUBLIC HEALTH RELEVANCE: This R43 project has the potential to lead to a new treatment modality and significantly improve the management of bladder cancer while the disease is still localized in the bladder. Given the extremely high lifetime health care costs for these patients (over 10 billion in 2003 dollars), an additional potential benefit is cost containment.

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