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Optimum Therapeutics, Llc

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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.


Lu Z.,Optimum Therapeutics, Llc | Wang J.,Optimum Therapeutics, Llc | Wientjes M.G.,Ohio State University | Au J.L.-S.,Optimum Therapeutics, Llc | Au J.L.-S.,Ohio State University
Future Oncology | Year: 2010

Cancers originating from organs in the peritoneal cavity (e.g., ovarian, pancreatic, colorectal, gastric and liver) account for approximately 250,000 new cancer cases annually in the USA. Peritoneal metastases are common owing to locoregional spread and distant metastases of extraperitoneal cancers. A logical treatment is intraperitoneal therapy, as multiple studies have shown significant targeting advantage for this treatment, including significant survival benefits in stage III, surgically debulked ovarian cancer patients. However, the clinical use of intraperitoneal therapy has been limited, in part, by toxicity, owing to the use of indwelling catheters or high drug exposure, by inadequate drug penetration into bulky tumors (>1 cm) and by the lack of products specifically designed and approved for intraperitoneal treatments. This article provides an overview on the background of peritoneal metastasis, clinical research on intraperitoneal therapy, the pharmacokinetic basis of drug delivery in intraperitoneal therapy and our development of drug-loaded tumor-penetrating microparticles. © 2010 Future Medicine Ltd.


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.


Wang J.,Optimum Therapeutics, Llc | Lu Z.,Optimum Therapeutics, Llc | Gao Y.,Ohio State University | Wientjes M.G.,Optimum Therapeutics, Llc | And 3 more authors.
Nanomedicine | Year: 2011

Effectiveness of nanomedicines in cancer therapy is limited in part by inadequate delivery and transport in tumor interstitium. This article reviews the experimental approaches to improve nanomedicine delivery and transport in solid tumors. These approaches include tumor vasculature normalization, interstitial fluid pressure modulation, enzymatic extracellular matrix degradation, and apoptosis-inducing tumor priming technology. We advocate the latter approach due to its ease and practicality (accomplished with standard-of-care chemotherapy, such as paclitaxel) and tumor selectivity. Examples of applying tumor priming to deliver nanomedicines and to design drug/RNAi-loaded carriers are discussed. © 2011 Future Medicine Ltd.


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.


Cui M.,Optimum Therapeutics, Llc | Au J.L.-S.,Optimum Therapeutics, Llc | Au J.L.-S.,University of Oklahoma | Au J.L.-S.,Medical University of South Carolina | And 5 more authors.
Journal of Urology | Year: 2015

Purpose Survivin inhibits apoptosis and enables tumor cells to escape from therapy induced senescence. High survivin expression is associated with bladder cancer aggressiveness and recurrence. We evaluated whether survivin expression is reduced by siRNA and whether survivin silencing would enhance mitomycin C activity in human RT4 bladder transitional cell tumors in vitro and in vivo. Materials and Methods We assessed the effectiveness of siRNA therapy using 2 newly developed pegylated cationic liposome carriers, PCat and PPCat. Each has a fusogenic lipid to destabilize the endosomal membrane. PPCat further contains paclitaxel to enhance in vivo delivery and transfection of survivin siRNA. In vitro antitumor activity was evaluated by short-term MTT and long-term clonogenicity cytotoxicity assays. In vivo intravenous therapy was assessed in mice bearing subcutaneous tumors. Results Nontarget siRNA showed no antitumor activity in vitro or in vivo. Treatment of cultured cells with mitomycin C at a 50% cytotoxic concentration enhanced survivin mRNA and protein levels. Adding PPCat or PCat containing survivin siRNA reversed survivin induction and enhanced mitomycin C activity (p <0.05). In tumor bearing mice single agent mitomycin C delayed tumor growth and almost tripled the survivin protein level in residual tumors. Adding PPCat-survivin siRNA, which alone resulted in a minor survivin decrease of less than 10%, completely reversed mitomycin C induced survivin and enhanced mitomycin C activity (p <0.05). Conclusions Results indicate that there is effective in vivo survivin silencing and synergism between mitomycin C and PPCat-survivin siRNA. This combination represents a potentially useful chemo-gene therapy for bladder cancer. © 2015 American Urological Association Education and Research, Inc.


Au J.L.-S.,Ohio State University | Au J.L.-S.,Optimum Therapeutics, Llc | Guo P.,Optimum Therapeutics, Llc | Gao Y.,Ohio State University | And 4 more authors.
AAPS Journal | Year: 2014

This study established a multiscale computational model for intraperitoneal (IP) chemotherapy, to depict the time-dependent and spatial-dependent drug concentrations in peritoneal tumors as functions of drug properties (size, binding, diffusivity, permeability), transport mechanisms (diffusion, convection), spatial-dependent tumor heterogeneities (vessel density, cell density, pressure gradient), and physiological properties (peritoneal pressure, peritoneal fluid volume). Equations linked drug transport and clearance on three scales (tumor, IP cavity, whole organism). Paclitaxel was the test compound. The required model parameters (tumor diffusivity, tumor hydraulic conductivity, vessel permeability and surface area, microvascular hydrostatic pressure, drug association with cells) were obtained from literature reports, calculation, and/or experimental measurements. Drug concentration-time profiles in peritoneal fluid and plasma were the boundary conditions for tumor domain and blood vessels, respectively. The finite element method was used to numerically solve the nonlinear partial differential equations for fluid and solute transport. The resulting multiscale model accounted for intratumoral spatial heterogeneity, depicted diffusive and convective drug transport in tumor interstitium and across blood vessels, and provided drug flux and concentration as a function of time and spatial position in the tumor. Comparison of model-predicted tumor spatiokinetics with experimental results (autoradiographic data of 3H-paclitaxel in IP ovarian tumors in mice, 6 h posttreatment) showed good agreement (1% deviation for area under curve and 23% deviations for individual data points, which were several-fold lower compared to the experimental intertumor variations). The computational multiscale model provides a tool to quantify the effects of drug-, tumor-, and host-dependent variables on the concentrations and residence time of IP therapeutics in tumors. © 2014 American Association of Pharmaceutical Scientists.


Wientjes M.G.,Optimum Therapeutics, Llc | Yeung B.Z.,Optimum Therapeutics, Llc | Yeung B.Z.,University of Oklahoma | Lu Z.,Optimum Therapeutics, Llc | And 2 more authors.
Journal of Controlled Release | Year: 2014

Nanotechnology is widely used in cancer research. Models that predict nanoparticle transport and delivery in tumors (including subcellular compartments) would be useful tools. This study tested the hypothesis that diffusive transport of cationic liposomes in 3-dimensional (3D) systems can be predicted based on liposome-cell biointerface parameters (binding, uptake, retention) and liposome diffusivity. Liposomes comprising different amounts of cationic and fusogenic lipids (10-30 mol% DOTAP or 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine, 1-20 mol% DOPE or 1,2-dioleoyl-3-trimethylammonium-propane, + 25 to + 44 mV zeta potential) were studied. We (a) measured liposome-cell biointerface parameters in monolayer cultures, and (b) calculated effective diffusivity based on liposome size and spheroid composition. The resulting parameters were used to simulate the liposome concentration-depth profiles in 3D spheroids. The simulated results agreed with the experimental results for liposomes comprising 10-30 mol% DOTAP and 10 mol% DOPE, but not for liposomes with higher DOPE content. For the latter, model modifications to account for time-dependent extracellular concentration decrease and liposome size increase did not improve the predictions. The difference among low- and high-DOPE liposomes suggests the difference among low concentration-dependent DOPE properties in 3D systems that were not captured in monolayers. Taken together, our earlier and present studies indicate the diffusive transport of neutral, anionic and cationic nanoparticles (polystyrene beads and liposomes, 20-135 nm diameter, - 49 to + 44 mV) in 3D spheroids, with the exception of liposomes comprising > 10 mol% DOPE, can be predicted based on the nanoparticle-cell biointerface and nanoparticle diffusivity. Applying the model to low-DOPE liposomes showed that changes in surface charge affected the liposome localization in intratumoral subcompartments within spheroids. © 2014 Elsevier B.V.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 344.46K | Year: 2012

DESCRIPTION (provided by applicant): Bladder cancer is the fourth most common cancer in the US. 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 by grade 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 their efficacy is limited by two factors: inadequate drug delivery to tumors and low chemosensitivity (especially for the more aggressive tumors). We next 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 approach is needed for the remaining patients who are not adequately managed by intravesical MMC therapy. Survivin is a marker/predictor of bladder cancer aggressiveness and recurrence. We have developed a pegylated cationic lipid carrier (PCat) for survivin siRNA that knockdowns the protein expression in cultured cells and in tumor-bearing animals, and enhances the antitumor activity of chemotherapy in solid tumors. Because it has been reported that inhibition of survivin enhances the sensitivity of bladder tumors to MMC, we propose to evaluate the MMC and PCat-survivin siRNA combination as an option to produce superior antitumor activity and propose to develop this combination for treating nonmuscle-invading bladder cancer. The two aims of this R43 project are to identify the optimal conditions for combining the two agents and to identify the appropriate administration route for PCat-siRNA (i.e., intravesical instillation and/or submucosal injection). 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.


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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