Potomac, MD, United States

Synergene Therapeutics Inc

Potomac, MD, United States
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Senzer N.,Mary Crowley Cancer Research Centers | Senzer N.,Medical City Dallas Hospital | Nemunaitis J.,Mary Crowley Cancer Research Centers | Nemunaitis J.,Medical City Dallas Hospital | And 9 more authors.
Molecular Therapy | Year: 2013

Selective delivery of therapeutic molecules to primary and metastatic tumors is optimal for effective cancer therapy. A liposomal nanodelivery complex (scL) for systemic, tumor-targeting delivery of anticancer therapeutics has been developed. scL employs an anti-transferrin receptor (TfR), scFv as the targeting molecule. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, is present in most human cancers. Rather than being transiently permissive for tumor initiation, persistence of p53 dysfunction is a continuing requirement for maintaining tumor growth. Herein, we report results of a first-in-man Phase I clinical trial of restoration of the normal human tumor suppressor gene p53 using the scL nanocomplex (SGT-53). Minimal side effects were observed in this trial in patients with advanced solid tumors. Furthermore, the majority of patients demonstrated stable disease. One patient with adenoid cystic carcinoma had his status changed from unresectable to resectable after one treatment cycle. More significantly, we observed an accumulation of the transgene in metastatic tumors, but not in normal skin tissue, in a dose-related manner. These results show not only that systemically delivered SGT-53 is well tolerated and exhibits anticancer activity, but also supply evidence of targeted tumor delivery of SGT-53 to metastatic lesions. © The American Society of Gene & Cell Therapy.

PubMed | Georgetown University, Mary Crowley Cancer Research Centers and Synergene Therapeutics Inc
Type: Journal Article | Journal: Molecular therapy : the journal of the American Society of Gene Therapy | Year: 2016

Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, occurs in most human cancers. SGT-53 is a liposomal nanocomplex designed for systemic, tumor-targeting delivery of the wt p53 gene. In this nanodelivery system, an anti-transferrin receptor single-chain antibody fragment serves as the targeting moiety. In an initial phase 1 trial in patients with advanced solid tumors, SGT-53 demonstrated tumor-specific targeting, was shown to be well tolerated, and was associated with an antitumor effect in several patients. Our preclinical studies have also demonstrated enhanced antitumor activity with the combination of SGT-53 and docetaxel. Thus, this dose-escalation trial was undertaken to assess the combination of SGT-53 and docetaxel for safety and potential efficacy in 14 advanced cancer patients. Results reveal that the combination of SGT-53 (maximum dose, 3.6mg DNA/infusion) and docetaxel (75mg/m(2)/infusion) was well tolerated. Moreover, clinical activity involving 12 evaluable patients was observed. Three of these patients achieved RECIST-verified partial responses with tumor reductions of -47%, -51%, and -79%. Two others had stable disease with significant shrinkage (-25% and -16%). These results support phase 2 testing of SGT-53 in combination with docetaxel.

Bawa R.,Bawa Biotechnology Consulting LLC | Bawa R.,Rensselaer Polytechnic Institute | Bawa R.,Synergene Therapeutics Inc
European Journal of Nanomedicine | Year: 2010

There is enormous excitement and expectation surrounding the multidisciplinary field of nanotechnology. This carries over to nanomedicine - the application of nanotechnology to healthcare - which is already influencing the pharmaceutical industry, especially in the design, formulation and delivery of therapeutics. Nanopharmaceuticals are a relatively new class of therapeutic-containing nanomaterials that often have unique " nanoproperties" (physiochemical properties) due to their small size (compared with their bulk-phase counterparts) a high surface-to-volume ratio and the possibility of modulating their properties. Basically they are nanoparticles intended for a broad spectrum of clinical therapeutic applications with the potential to target a particular organ or tissue site, either passively or actively. Nanopharmaceuticals present novel reformulation opportunities for active agents (e.g., single molecule drugs, proteins, nucleic acids, etc.) that were previously insoluble or could not be targeted to a specific site of the body where they were needed. In other words, those therapeutic agents that were previously unsuitable for traditional oral or injectable drug formulations could now be "nanoformulated" for delivery to specific biological targets due to superior pharmacokinetics/ pharmacodynamics and/or active intracellular delivery. As a result, this approach has the ability to reduce toxicity and enhance bioavailability, thereby improving efficacy and patient compliance. Nanopharmaceuticals can also increase drug half-life by reducing immunogenicity and diminishing drug metabolism. With these advantages, nanopharmaceuticals have the ability to extend the economic life of proprietary drugs, thereby creating additional revenue streams. As a result, they have the potential to impact drug commercialization and the healthcare landscape. Inevitably they will become an integral part of mainstream medicine. A large number of the US Food and Drug Administration (FDA)-approved nanopharmaceuticals have already been launched while many more are in various phases of clinical trials.

Kim S.-S.,Georgetown University | Rait A.,Georgetown University | Kim E.,Synergene Therapeutics Inc | Pirollo K.F.,Georgetown University | Chang E.H.,Georgetown University
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2015

Development of temozolomide (TMZ) resistance contributes to the poor prognosis for glioblastoma multiforme (GBM) patients. It was previously demonstrated that delivery of exogenous wild-type tumor suppressor gene p53 via a tumor-targeted nanocomplex (SGT-53) which crosses the blood-brain barrier could sensitize highly TMZ-resistant GBM tumors to TMZ. Here we assessed whether SGT-53 could inhibit development of TMZ resistance. SGT-53 significantly chemosensitized TMZ-sensitive human GBM cell lines (U87 and U251), in vitro and in vivo. Furthermore, in an intracranial GBM tumor model, two cycles of concurrent treatment with systemically administered SGT-53 and TMZ inhibited tumor growth, increased apoptosis and most importantly, significantly prolonged median survival. In contrast TMZ alone had no significant effect on median survival compared to a single cycle of TMZ. These results suggest that combining SGT-53 with TMZ appears to limit development of TMZ resistance, prolonging its anti-tumor effect and could be a more effective therapy for GBM. © 2015 Elsevier Inc.

Kim S.-S.,Georgetown University | Rait A.,Georgetown University | Rubab F.,Synergene Therapeutics Inc | Rao A.K.,Georgetown University | And 5 more authors.
Molecular Therapy | Year: 2014

Cancer stem-like cells (CSCs) have been implicated in recurrence and treatment resistance in many human cancers. Thus, a CSC-targeted drug delivery strategy to eliminate CSCs is a desirable approach for developing a more effective anticancer therapy. We have developed a tumor-targeting nanodelivery platform (scL) for systemic administration of molecular medicines. Following treatment with the scL nanocomplex carrying various payloads, we have observed exquisite tumor-targeting specificity and significant antitumor response with long-term survival benefit in numerous animal models. We hypothesized that this observed efficacy might be attributed, at least in part, to elimination of CSCs. Here, we demonstrate the ability of scL to target both CSCs and differentiated nonstem cancer cells (non-CSCs) in various mouse models including subcutaneous and intracranial xenografts, syngeneic, and chemically induced tumors. We also show that systemic administration of scL carrying the wtp53 gene was able to induce tumor growth inhibition and the death of both CSCs and non-CSCs in subcutaneous colorectal cancer xenografts suggesting that this could be an effective method to reduce cancer recurrence and treatment resistance. This scL nanocomplex is being evaluated in a number of clinical trials where it has been shown to be well tolerated with indications of anticancer activity. © The American Society of Gene & Cell Therapy.

Kim S.-S.,Georgetown University | Rait A.,Georgetown University | Kim E.,Synergene Therapeutics Inc | Pirollo K.F.,Georgetown University | And 4 more authors.
ACS Nano | Year: 2014

Temozolomide (TMZ)-resistance in glioblastoma multiforme (GBM) has been linked to upregulation of O6-methylguanine-DNA methyltransferase (MGMT). Wild-type (wt) p53 was previously shown to down-modulate MGMT. However, p53 therapy for GBM is limited by lack of efficient delivery across the blood brain barrier (BBB). We have developed a systemic nanodelivery platform (scL) for tumor-specific targeting (primary and metastatic), which is currently in multiple clinical trials. This self-assembling nanocomplex is formed by simple mixing of the components in a defined order and a specific ratio. Here, we demonstrate that scL crosses the BBB and efficiently targets GBM, as well as cancer stem cells (CSCs), which have been implicated in recurrence and treatment resistance in many human cancers. Moreover, systemic delivery of scL-p53 down-modulates MGMT and induces apoptosis in intracranial GBM xenografts. The combination of scL-p53 and TMZ increased the antitumor efficacy of TMZ with enhanced survival benefit in a mouse model of highly TMZ-resistant GBM. scL-p53 also sensitized both CSCs and bulk tumor cells to TMZ, increasing apoptosis. These results suggest that combining scL-p53 with standard TMZ treatment could be a more effective therapy for GBM. © 2014 American Chemical Society.

Kim S.-S.,Georgetown University | Harford J.B.,Synergene Therapeutics Inc | Pirollo K.F.,Georgetown University | Chang E.H.,Georgetown University
Biochemical and Biophysical Research Communications | Year: 2015

Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood-brain barrier (BBB) play a major role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review. © 2015 Elsevier Inc. All rights reserved.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 498.33K | Year: 2011

SBIR Phase II to develop a LYOPHILLIZED form of Optimized scL-gad-d complex

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 222.90K | Year: 2014

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