The major goal of this research is to develop a new nano and optical technology-based approach to treat residual disease in patients with advanced ovarian cancer.

The long term goal of this research is to develop a mechanism and nanotechnology-based image-guided combination regimens with photodynamic therapy (PDT), an FDA approved treatment for certain cancers and in clinical trials for Ovarian Cancer (OvCa).

The goal of this research is to introduce novel synergistic approaches to phototherapy, chemotherapy and photodynamic detection of brain cancer, using mutual prodrugs of ALA-derivatives.

The overall goal of this project is to improve the therapeutic effectiveness of aminolevulinic acid (ALA)-based photodynamic therapy by modulating protoporphyrin IX (PPIX) production, fluence rate, and light fractionation.

To establish whether the most effective antibiotic for a particular bacterial strain can be predicted, we will test our current S. aureus model system, with one additional or possibly two different antibiotics. For this purpose we are planning to use cefoxitin, a cephamycin antibiotic, grouped as a second generation cephalosporin. Cefoxitin resistance has also been shown to co-relate most efficiently to the MRSA phenotype. We will also validate the results with standard methods, similar to experiments we are currently performing with cefazolin.

Team Members: Huang-Chiao (Joe) Huang, Girgis Obaid, Bryan Spring, Joyce Liu, Yucheng Wang, Jerrin Kuriakose, Mans Broekgaarden, Anne-Laure Bulin Project Description: In the context of photodynamic therapy (PDT) and oncology, nanomedicine allows for incorporation of flexibility in designing regimens to overcome a broad spectrum of systemic and microenvironmental barriers to effective treatments. This project develops photo-responsive nanoconstructs that release enclosed theranostic agents preferentially at the desired site through both enhanced accumulation and selective activation. Actively targeted, multi-agent, photo-responsive nanoconstructs have been developed in the Hasan laboratory with the following broad goals: 1. Therapeutically induced targets: where one treatment (e.g. PDT) triggers or sensitizes the aberrant expression of biomarkers that can serve as molecular targets for the second insult (e.g. chemo-agent or molecular inhibitors). 2. Inherent targets: where nanoconstructs are driven by moieties (e.g. aptamers, monoclonal antibodies etc.) to direct against specific cancer–associated molecules. 3. Combinations of targets: where cooperatively targeting of both inherent targets and therapeutically induced targets maximizes the treatment benefits by activating several cell death pathways via nano constructs.

Team Members: Akilan Palanisami, Daniela Vecchio, Jerrin Kuriakose Project Description: Characterizing bacterial infections rapidly is key to effective treatment and identifying the spread of antibiotic resistance. Current testing of human specimens primarily relies on culture, which requires infrastructure unavailable at many clinics, especially in low/middle income countries, and is too slow inform initial treatment. This is especially critical in neonatal infections (e.g., urinary tract infections, sepsis, meningitis), where delays in effective treatment can result in lifelong disability or death. Due to this risk, powerful, broad spectrum antibiotics (e.g., 3rd generation cephalosporins) are empirically given. However, extended spectrum beta-lactamases (ESBL), which account for roughly one-third of the gram negative infections in SE Asia, can destroy penicillin and cephalosporin antibiotics, leading to initial treatment failure. To address this, we are developing a rapid, mobile platform which detects pathogen directly from human specimens (e.g., urine, cerebrospinal fluid, blood, etc.) and identify beta-lactamase related antibiotic susceptibility in less than 20 minutes. The platform uses disposable microfluidic cartridges into which human samples are injected. A “dark” probe which becomes fluorescent in the presence of ESBL is then introduced. By repeating the analysis in the presence of an antibiotic, information on the antibiotic susceptibility can also be obtained. This platform can directly improve patient management, reduce the development of resistance by promoting responsible antibiotic use and aid in hospital referrals of antibiotic resistant infections.

Team Members: Akilan Palanisami, Bryan Spring, Srivalleesha Mallidi Project Description: In the realm of theranostics, our group focuses on Optical imaging techniques such as fluorescence, photoacoustic and diffuse optical tomography for real-time image-guided resections, image-guided dosimetry and therapy monitoring. Specifically we focus on addressing challenges in dosimetry of photodynamic therapy and related combination therapies using optical imaging techniques. For example, we utilize imaging to establish nano-drug localization, tumor selectivity, design dose and predict recurrence. We also utilize optical imaging techniques to tease out the structural, functional, and molecular information regarding photodynamic mechanisms of action.

Team Members: Imran Rizvi, Emma Briars, Anne-Laure Bulin, Daniela Vecchio, Sriram Anbil, Ahmed Alkhateeb, Mans Broekgaarden Project Description: The goal of this project is to develop cell-based 3D and microfluidic tumor models that incorporate architectural, stromal and physical cues to identify determinants of tumor heterogeneity and treatment resistance. These models complement efforts in the Hasan group to identify molecular and phenotypic changes that lead to treatment failure and to target these resistance mechanisms with photodynamic therapy (PDT)-based combinations. The insights from these cell-based systems both inform and benefit from the framework in the Hasan group, including ongoing projects in quantitative optical imaging and targeted drug delivery to design and optimize PDT-based therapeutic strategies. The guiding principle is to design regimens that cooperate mechanistically with established and emerging agents in order to enhance treatment response while mitigating undesirable toxic side effects, ultimately producing durable improvements in outcomes for some of the most lethal tumors including advanced stage pancreatic and ovarian cancer.

Team Members: Huang-Chiao (Joe) Huang, Imran Rizvi, Joyce Liu, Srivalleesha Mallidi, Ahmed Alkhateeb, Mans Broekgaarden, Sriram Anbil, Emma Briars Project Description:  This project develops and optimizes PDT-based combinations for pancreatic cancer designed to target the therapeutic resistance pathways that lead to treatment failure and poor outcomes for this lethal malignancy. Due to the significant challenges associated with treating pancreatic cancer, achieving meaningful improvements in survival requires a multifaceted approach. To address these challenges, this project leverages cross-disciplinary expertise in the Hasan-Pogue NCI Program Project Grant including nanotechnology-enabled drug delivery, image-guided dosimetry and longitudinal treatment monitoring, 3D and in vivo tumor model development and exploitation of molecular escape pathways to develop rapidly translatable PDT-based combination regimens. The clinically-motivated therapies cooperate to improve overall response through a range of mechanistic interactions that include destruction of drug efflux pumps, modulation of the tumor microenvironment (e.g. hypoxia), inhibition of survival pathways and light-triggered drug delivery. These preclinical studies inform, and are guided by, ongoing discussions with clinical experts and industrial collaborators to help facilitate the translation of promising outcomes to patients.

Team Members: Amjad Khan, Emma Briars, Imran Rizvi, Srivalleesha Mallidi Project Description: Oral cancer represents over 30% of cancers reported in India, one of the highest oral cancer rates in the world, (attributed to the widespread popularity of chewing "gutka") and is the leading cause of cancer death among Indian men. The overall impact is increased morbidity, mortality and economic burden. The aim of this project to address the problem of oral cancer in India by using a low cost adaptation of photodynamic therapy (PDT), an active area of research in our group. The thrust of the study is to design a platform that can be used at sites without medical infrastructure and uses battery-powered light sources and smart phones along with d-aminolevulinic acid (ALA) as the photodynamic agent. We achieve this in four specific aims executed in two phases: (Aims 1and 2 UH2 phase), We initially adapt and calibrate current clinical PDT technologies for LMIC use then, (Aims 3 and 4 UH3 phase). conduct a validation study at the LMIC site (India) and establish a business plan for long term sustainability of low cost PDT as a global health technology for oral cancer treatment. This study will benefit a large population of Indian men and women not only in terms of the overall quality of life but also by decreasing the number of workdays lost thus mitigating physical suffering and societal economic burden. This quest for lowering healthcare costs will also have potential significance in the U.S. where oral cancer is the 8^th leading cause of cancer deaths amongst men. Finally, although the focus of this application is oral cancer in India, the findings would be applicable to other LMICs with high oral cancer burden and also could form the basis of low cost PDT for other cancers such as cancer of the uterine cervix, which remains a problem in emerging economy countries.