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Novel therapeutic approach in treatment of glioblastoma using sustained delivery of Connxin43 carboxy-terminal peptide encapsulated in biodegradable nanoparticles in combination with temozolomide

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44CA195937-02A1
Agency Tracking Number: R44CA195937
Amount: $1,596,893.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: 102
Solicitation Number: PA18-591
Solicitation Year: 2018
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-09-06
Award End Date (Contract End Date): 2021-08-31
Small Business Information
Mount Pleasant, SC 29464-5641
United States
DUNS: 602545654
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (843) 388-3276
Business Contact
Phone: (843) 860-8785
Research Institution

Glioblastoma (GBM) is an incurable cancer even with aggressive therapies such as surgical resection followed
by radiotherapy and chemotherapy using temozolomide (TMZ). Efforts to improve surgical resection or the
efficacy of irradiation are limited by the potential damage these interventions cause to the brain. In contrast,
sensitizing GBM to TMZ is an appealing strategy because TMZ has excellent brain penetration and a low
toxicity profile. Recent research suggests that targeting the gap junction protein connexin 43 (Cx43) holds
promise for enhancing TMZ sensitivity in GBM. A synthetic peptide, aCT1, which comprises the carboxy-
terminus of Cx43, and has demonstrated therapeutic efficacy in promoting healing of acute and chronic
wounds, has been developed in order to explore the potential of targeting Cx43 and overcoming TMZ
resistance in GBM. FirstString Research has currently advanced Granexin® gel, the topical formulation of
aCT1 peptide, through three Phase 2 human clinical trials for scar reduction and the treatment of chronic
wounds. Preliminary data demonstrated that Cx43 expression inversely correlates with TMZ sensitivity and
GBM patient survival, and demonstrated that aCT1 significantly increases TMZ sensitivity in vitro and in vivo,
thus encouraging further investigation into its therapeutic potential in sensitizing GBM tumors to TMZ. During
the Phase I SBIR, to facilitate efficient and targeted drug delivery, a controlled and sustained biodegradable
aCT1 nanoparticle system of therapeutic delivery was developed and validated in vitro and in vivo models of
GBM. Biodegradable aCT1-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were developed,
optimized and validated, specifically with characteristics necessary for targeted convection-enhanced delivery
(CED) in GBM patients (FDA approved copolymer; andlt;150nm +\- 40 in diameter, controlled and sustained aCT1
release profile). The objective of this Phase II SBIR proposal is to translate the success of our Phase I data
through more extensive pre-clinical development. Aim I will involve intracranial injection of aCT1-NPs into the
brains of GBM mice followed by TMZ treatment and mechanism of action studies. We will monitor tumor
growth using MRI and analyze mouse survival. Aim II will validate the efficacy and safety of combinatorial
aCT1-NP and TMZ treatment in a veterinary clinical trial in high-grade spontaneous canine gliomas. Canine
gliomas have many of the characteristics of human tumors, thus permitting precise extrapolation of efficacy
and safety data from canine therapy studies to human trials. We will enroll companion dogs with spontaneous
tumors into a specific protocol involving CED of aCT1-NPs in association with TMZ. Efficacy evaluation will
involve comprehensive neuroimaging response assessment, neurobiobehavioral evaluation, and survival.
Safety analyses will involve adverse event reporting and toxicokinetic analyses. Successful completion of
these aims will validate CED delivery of aCT1-NP as a novel combinational therapy for lethal GBM and will lay
foundation for potential clinical trials in newly diagnosed GBM patients in the near future.PROJECT NARRATIVE
Glioblastoma is a very aggressive type of brain tumor and one of the most deadly diseases with no efficient
therapy to cure it. The proposed research aims at developing a new combinational therapy to enhance the
effectiveness of temozolomide, the front line chemotherapy for glioblastoma. Therefore, this work will have an
important impact on therapeutic intervention for glioblastoma and is relevant to public health and NIHandapos;s

* Information listed above is at the time of submission. *

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