SBIR-STTR Award

Transitional cell carcinoma (TCC) of the bladder is the fifth most common form of cancer in the United States, with over 79,000 new cases expected for 2017. For early stage carcinomas, the most common treatment regimen is to initially perform transurethral resection of bladder tumor (TURBT) using an invasive cystoscopic approach with non-specific fluorescent dyes to highlight the lesions. Even then, small lesions are often missed leading to the cancer recurring in up to 70% of patients and further progresses to advanced cancer in up to 20% of patients following TURBT. Compared to cystoscopy, high resolution ultrasound (HRUS) is low-cost, minimally invasive, and provides an in-depth view of the smooth muscle layer and surrounding tissues of the bladder with spatial resolution as low as 30 ?m. Despite advances in HRUS, current imaging systems are limited to anatomical data, as it can neither provide functional or molecular imaging data, nor facilitate any interventional approach, alone. The implementation of a targeted contrast enhancement is necessary to elevate the data acquired from even the most advanced system. Clinically approved ultrasound contrast agents operate on the principle that the speed of sound is drastically different high molecular weight gases than in soft tissue. While highly echogenic, these agents are too large and too short-lived to be useful for functional imaging. To improve upon this approach, sub-micron ultrasound agents are being used experimentally, though the resulting agents are limited and have not been applied to TCC. Clinical applications resulting from this approach will benefit by 1) improvement of current screening methods (expedited, cheaper and dynamic), and 2) facilitation of specific delivery of intravesical treatment, specifically with non-invasive monitoring. We propose a material based on mesoporous silica nanoparticles (MSN), functionalized for diagnostic HRUS as well as interventional imaging following delivery of a therapeutic agent. We propose a rigorous in vitro / in vivo testing methodology to characterize the MSN and optimize its diagnostic and therapeutic capabilities. Upon completion the MSN would fulfill a desperately needed alternative to the current invasive and TCC treatment. If successful, the end product represents a highly marketable cost effective material that can be deployed clinically, ultimately improving patient outcomes. Our team of biomedical engineers, radiologists, urology researchers and clinicians are uniquely poised to carry out this research. The use of biocompatible materials and a short peptide for targeting, as opposed to many pre-clinical studies which involve monoclonal antibodies, ensures that the proposed material is of immediate clinical and commercial relevance. This proposal paves the way for SBIR Phase II studies, in which long-term survival and the scale-up of synthesis for commercial purposes will be evaluated.

Public Health Relevance Statement:
Project Narrative In bladder cancer, screening constraints lead to missed lesions resulting in grave consequences. The harsh environment of the bladder hinders effectiveness of anti-tumor drugs, allowing cancer to recur in up to 70% of patients and proceed to advanced stage in up to 20% of patients. In this project, we will evaluate a nanomaterial contrast agent with dual purpose: 1) to specifically bind cancer cells for accurate diagnosis through functionalization making it visible with ultrasound, and 2) to carry a therapeutic payload of epirubicin or other known anti-tumor agents, while simultaneously protecting the healthy bladder from their tumoricidal effects. This novel approach will ultimately lead to improved outcomes and provide evidence for the clinical and commercial potential benefits of our platform nanotechnology.

Project Terms:
accurate diagnosis; Advanced Malignant Neoplasm; advanced system; Adverse effects; Anatomy; Antimitotic Agents; Antineoplastic Agents; antitumor agent; antitumor drug; Artificial nanoparticles; base; Binding; Biocompatible Materials; Biomedical Engineering; Bladder; Bladder Neoplasm; Bladder Tissue; bladder transitional cell carcinoma; cancer cell; cancer therapy; Carcinoma; Chemicals; chemotherapy; Clinic; Clinical; clinical application; Clinical Trials; Collaborations; commercialization; common treatment; contrast enhanced; Contrast Media; cost; cost effective; Cultured Tumor Cells; Custom; Cystoscopy; Data; Development; Diagnostic; Documentation; Drug Delivery Systems; drug synthesis; Early Diagnosis; Early treatment; Effectiveness; Ensure; Environment; Epirubicin; experimental study; Exposure to; Faculty; Fluorescent Dyes; Functional Imaging; Gases; Goals; Image; image processing; imaging modality; imaging system; Imaging Techniques; improved; improved outcome; In Vitro; in vivo; in vivo evaluation; Injections; Intervention; intravesical; Intravesical Administration; Iowa; Laboratories; Lead; Lesion; Magnetic Resonance Imaging; Malignant neoplasm of urinary bladder; Malignant Neoplasms; Measurement; Methodology; Methods; Mind; minimally invasive; Modality; Modeling; molecular imaging; Molecular Weight; Monitor; Monoclonal Antibodies; mouse model; MRI Scans; Mus; nano; nanomaterials; nanoparticle; Nanotechnology; neoplastic cell; non-invasive monitor; novel; novel strategies; Nucleosome Core Particle; Outcome; particle; Patient-Focused Outcomes; Patients; Peptides; Pharmaceutical Preparations; Phase; phase 2 study; preclinical study; prognostic; prototype; radiologist; Research; Research Personnel; Resolution; scale up; Schedule; screening; Series; Silicon Dioxide; Small Business Innovation Research Grant; Smooth Muscle; soft tissue; sound; Specificity; Speed; submicron; success; targeted delivery; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; tool; Transitional Cell Carcinoma; Translating; Transurethral Resection; Treatment Protocols; tumor; tumor growth; Tumor Markers; Ultrasonography; United States; Universities; Urology

/: Transitional cell carcinoma (TCC) of the bladder is the fifth most common formof cancer in the U.S., with over 80,000 new cases expected in 2019. For early-stage carcinomas, patientsreceive intravesical bacillus Calmette-Guerin (BCG) immunotherapy, or transurethral resection of the bladdertumor (TURBT) with intravesical chemotherapy. Both are associated with a high rate of recurrence andeventual progression. BCG fails many patients who are immunocompromised or who experience adversereactions, while TURBT with chemotherapy fails because the chemotherapeutic agent is not sufficientlyretained in the bladder to penetrate lesions that aren't resected. Thus, there is a need for an improved drugformulation for early-stage (CIS, Ta, T1, T2) TCC capable of 1) penetrating the tumor beyond the superficialcell layers, and 2) increasing the dwell/contact time between the chemotherapeutic agent and the cancer cells.To that end, NanoMedTrix (NMTx) has developed a particle based on mesoporous silica nanoparticles (MSN)that carries known chemotherapeutic agents and is designed to improve their specificity, dwell time, and tumorpenetration. Our Phase I SBIR project exceeded our goals and demonstrated the safety and efficacy of the MSNparticles in carrying and releasing epirubicin in vivo in a murine TCC orthotopic model and in vitro using culturedhuman TCC cells. Through our participation in the NIH I-CORPS program we spoke with key opinion leaders(urologic oncologists) in the clinical bladder cancer space. As a result, we are completing our Phase I work usingthe MSN to deliver clinically relevant doses of gemcitabine, docetaxel, and mitomycin-c in the same model.Following our Phase I success, our Phase II SBIR is designed to complete the acquisition of data required bythe FDA for initiation of IND approval of NMTx MSN in human clinical trials. Specific Aim 1 describes thenecessary in vitro tasks: optimizing particle chemistry and validating our larger canine model using cultured cellsand canine TCC organoids. Specific Aim 2 describes completion of murine orthotopic studies and the start ofpre-clinical trials in dogs with spontaneously occurring TCC. Specific Aim 3 lays out our plan for carrying outcGMP synthesis, packaging, and analysis of our IND.Beyond setting the stage for FDA IND approval and first-in-human clinical trials, Phase II completion willstrengthen our position with investors/partners in the pharmaceutical industry, with whom we will partner in SBIRPhase IIB, Phase III and beyond to expand clinical trials and ultimately commercialize the technology. We arecontinuing to work with the urology contacts we made in I-CORPS who are eager to participate in clinical trials,and we have received interest from Pharma companies (Bristol-Myers Squibb, Urovant, and others). Ourproprietary technology will provide licensees with improved performance from established chemotherapeuticsthat have already gone off-patent, thus making our technology attractive both clinically and commercially.Ultimate commercial success of this SBIR work will greatly benefit human health while reducing medical costs.

Public Health Relevance Statement:
Project Narrative In bladder cancer, BCG immunotherapy and intravesical chemotherapy are superficial and are associated with high rates of recurrence and progression; hence, there is a need for novel therapies that 1) are retained longer by the tumor cells specifically; and 2) penetrate the tumor to its origin in the detrusor muscle. In Phase I of our project all goals were met and exceeded, as we validated the ability of our novel nanomaterial to meet these needs in a mouse model. This Phase II project is designed to test this work using larger animals (the spontaneous canine TCC model) and to begin cGMP production/analytics as a key step toward first-in-human clinical trials.

Project Terms:
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