Title: Dual function theranostic constructs for photoacoustic image-guided surgery and photodynamic therapy. (R01 CA231606) (NIH/NCI)
About: The outcome of oral cancer resection surgery is affected to a large extent by the inability to identify tumor margins during surgical resection and the presence of residual microscopic disease post-surgery. This project focuses on the development of molecular targeted theranostic platforms for the management of oral cancers, with an aim of enhancing imaging contrast during tumor resection surgeries and sanitizing the surgical bed through post-operative photodynamic therapy.
Title: Molecular Response and Imaging-based Combination Strategies for Optimal PDT (P01 CA084203) (NIH/NCI)
About: Pancreatic cancer is the third-leading cause of cancer-related death in the US and is expected to become the second-leading cause after lung cancer in 2020. There are no specific symptoms to detect this cancer in the early stages and often diagnosed when it has metastasized to other parts of the body. Despite promising advances in chemotherapy combinations, which remains the standard of care for advanced disease, the 5-year survival rate for PDAC stands at a grim 9%. Therefore, new therapeutic strategies are urgently needed, and immunotherapy approaches are viewed as a promising option for several cancers, individually or in combination. However, the success of immunotherapy in Pancreatic cancer (e.g. PD-1 inhibitor: pembrolizumab) has been modest mainly due to the low immunogenicity of this tumor type. The paucity of tumor-infiltrating T cells in pancreatic cancer has been attributed to the high stromal content making them impenetrable. Photodynamic priming (PDP) effect associated with PDT increases tumor immunogenicity by inducing immunogenic cell death, enhanced tumor antigen presentation, and increased TIL recruitment into the tumors whereby creating the ideal situation to apply immunotherapy. PDP also increases tumor permeability via stromal/vascular modulation to sensitize the tumor for enhanced drug delivery and retention. The focus of this project is to develop clinically translatable combination therapy strategies for enhancing treatment outcomes in pancreatic cancer. Hasan lab is involved in this project to develop clinically relevant pancreatic tumor murine models and to evaluate the involvement of PDP to induce immunogenicity in pancreatic tumors, which would ultimately lead to enhancing benefits from current treatments, including immune checkpoint blockade therapies.
Multiplexed and dynamically targeted photoimmunotherapy of heterogeneous, chemoresistant micrometastases guided by online in vivo optical imaging of cell-surface biomarkers (R01CA226855) (NIH/NCI)
About: Microscopic tumor deposits missed by surgery cannot be resolved using current clinical imaging technologies and often harbor cell populations resistant to chemotherapy, representing a prominent source of cancer recurrence and mortality. The goal of this proposal is to develop a new paradigm for cancer therapy using multiplexed molecular imaging to detect residual cancer cells and to guide personalized photomedicine for targeting heterogeneous and chemoresistant micrometastases.
Title: Low-cost Enabling Technology for Image-guided Photodynamic Therapy (PDT) of Oral Cancers (1UH2 CA189901) (NIH/NCI)
About: This proposal aims to address the problem of oral cancer by using a low-cost adaptation of photodynamic therapy (PDT). This is an NCI-funded UH grant aimed at portable LED-based, low-cost technology-based ALA PDT treatment of oral cancer. In Aligarh India, under a clinical trial, 30 patients with early-stage oral cancer lesions have been treated with our device and yielded promising results. The project has been further extended for commercialization of the prototype device for wider distribution and to set up a large scale clinical testing of ALA PDT in a combination of vitamin supplements for oral cancer.
3D-Printed Superhydrophobic-Tipped Optical Fiber for Targeted Periodontal Photodynamic Therapy.(2R44DE026083) (NIH/through Singlet02 Therapeutics LLC)
About: Antimicrobial photodynamic therapy (aPDT) has emerged as a promising method for biofilm control and eradication of bacteria involved in the periodontal disease. The superhydrophobic (SH) device, an innovative device for the application of aPDT produces airborne singlet oxygen that can be deposited mainly in deep periodontal pockets without causing any staining, as no sensitizer molecule is released from the device. In addition, the properties of the SH device create the channels for air to diffuse to the sensitizer surface, thus ensuring enough oxygen for the action of aPDT to occur even in deep periodontal pockets, usually hypoxic microenvironments. In this study, the SH-TFDA device is being validated in vitro in a multispecies biofilm and in vivo in a rat ligature model. The grant is a collaborative NIH STTR Phase II work between SIngletO2 Therapeutics LLC and Hasan lab.
QLED activated tools for infection control/Ambulatory Photodynamic Therapy Blankets (DoD/AFOSR)
Wound infection remains a frequent cause of preventable disability for the U.S. armed forces. If sterilized, many wounds can heal without complication. Bacterial contamination of the wound bed ‘entrench’, the resulting infection leads to time and cost, in addition to delayed recovery times. PDT uses a photosensitizer together with light to generate reactive oxygen species that can neutralize pathogens without inhibiting wound healing. By including photosensitizers into the irrigation solution used to clean wounds and providing subsequent red light illumination, PDT can be integrated into the current standard of care for wound treatment to sterilize crevices within the wound bed. For broad clinical use, the illumination source must small, lightweight, portable, easy to use, and (ideally) disposable. By leveraging modern developments in thin-film QLED light sources, it has recently become possible to create light-emitting ‘quilts’ which can provide PDT illumination for extended periods of time. The development of a flexible and portable light-emitting quilt system to prevent wound colonizing bacteria (including multidrug-resistant bacteria) from progressing to infection and limit concomitant patient disability.
Research to Develop and Apply Biophotonics to Military Medicine Needs (DoD/AFOSR)
The major goals of this project are to further research in areas of military medicine. Dr. Hasan’s projects are entitled ‘Combating drug-resistant malaria by exploiting photosensitizer synthesis via parasite dependent nutrient acquisition pathways’ and ‘Identification of trauma-induced biomarkers using a smartphone-based microfluidic platform’.
Combating drug-resistant malaria by exploiting photosensitizer synthesis via parasite dependent nutrient acquisition pathways (DOD/AFOSR)
About: Malaria is one of the most devastating blood-borne parasitic diseases caused by Plasmodium falciparum. As the parasite has adapted to most of the known anti-malarial drugs there is a dire need for solutions to tackle drug resistance. In the Hasan lab, we are using light to treat drug-resistant acute malaria by selectively giving the parasites a lethal burn. For this, we are taking advantage of the malarial parasite’s own nutrient acquisition pathways (heme synthesis machinery) by first feeding it 5-aminolevulinic acid (ALA). When the parasites are overloaded with ALA, they generate excess protoporphyrin IX which is fluorescence and light-sensitive molecule. This makes the parasites responsive to light and susceptible to death by the chemistry produced by shining light. We are also expanding this approach for the diagnosis of malaria. Furthermore, the unique modality (photodynamic therapy) is also being extended to combat other bugs.
Identification of trauma-induced biomarkers using a smartphone-based microfluidic platform (DOD/AFOSR)
About: Advance identification of trauma patients at risk of poor outcomes remains a clinical challenge. If the patient survives the immediate effects of trauma and the resulting hypoxia/blood loss, the subsequent ischemia/re-perfusion injury and surgical intervention can produce an overwhelming systemic inflammatory response syndrome (SIRS). In the host’s attempt to return to homeostasis from the pro-inflammatory state, immune-paralysis may occur, resulting in increased susceptibility to sepsis and later mortality. These dual, sequential “hits” can also cause increased endothelial permeability with endothelial damage, dysfunction of microcirculation, and disseminated intravascular coagulation. Early identification of infectious SIRS allows the clinician the opportunity to treat these conditions before complications start to develop. Thus, this project evaluates the strategies for rapid detection of sepsis using pathogen-specific markers and inflammatory cell types.
Support Completed Within the Past Five Years
Title: Optical Imaging Guided Resection and Photodynamic Therapy of Glioma with Targeted Photoactivable Agents (R21 CA220143-01) (NIH/NCI)
About: This application proposes to build an advanced nanoparticle for treatment of glioblastoma (GBM) that will combine diagnostic capabilities using fluorescence and photoacoustic (PA) imaging and therapeutic capabilities with photodynamic therapy (PDT) and simultaneous delivery of a receptor tyrosine kinase inhibitor known to interact synergistically with PDT.
Title: Rapid Treatment Guidance for Antibiotic-Resistant Disease at the Point of Care (R21TW010202) (NIH/FIC)
About: This study will test a recently developed platform for characterizing bacterial infection at the POC for allowing clinicians to more effectively prescribe antibiotic therapies and to chart the spread of antibiotic resistance e.g., extended-spectrum beta-lactamase (ESBL). This platform will be validated on clinical specimens in Chiang Mai, Thailand.
Heterocellular 3-D Ovarian Tumor Arrays for Imaging and Mechanistic Combinations
About: The long-term goal of this research is to develop, integrate and validate key platform technologies to screen mechanism-based combination regimens with photodynamic therapy (PDT) for residual and recurrent OvCa. Heterocellular 3D printed tumor arrays that incorporate critical determinants of OvCa biology (endothelial and mesothelial cells with macrophages and fibroblasts) along with hyperspectral microscopy for simultaneous quantitative imaging of multiple biomarkers will provide exceptional insight into OvCa growth and treatment response on a high throughput platform.
Title: Bioluminescence-activated photodynamic therapy of breast cancer (R01 CA192878-01A1) (NIH)
About: The proposed research will develop and test novel photodynamic therapy (PDT) for killing cancer cells in the tumor margin and regional lymph nodes with minimal damage to normal tissues.
Ovarian Cancer PDT: Multi-intracellular targeting and Image-guided Dosimetry
About: The long term goal is to develop, integrate and validate key platform technologies to combine quantitative fluorescence imaging for drug delivery monitoring and customized dosimetry with “Targeted Phototoxic Multi-Inhibitor Liposomes” (TPMILs) that selectively target and simultaneously block interconnected survival pathways associated with aggressive ovarian cancer.
Research to Develop and Apply Biophotonics to Military Medicine Needs.
About: The major goals of this project are to further research in areas of military medicine. Dr. Hasan’s project is “Rapid Fluorescence-Based Antibiotic Susceptibility Assay”.
Targeted Photoactivable Nanocells: Image-based Drug Delivery and Dosimetry in GBM
About: The major goal of this research is to develop a combination of drug delivery nanoconstructs with magnetic resonance-guided optical imaging for the treatment of glioblastoma multiforme.
Image-Guided Phototherapy to Prevent Ovarian Cancer Recurrence (Boston University sub-contract)
About: This proposal aims to reduce the high rate of ovarian cancer (OvCa) recurrence and mortality by monitoring and selectively destroying residual, microscopic tumors using a “theranostic” platform that integrates fluorescence microendoscopy and near-infrared phototherapy.
Image Guided PDT for Glioma Using Photoactivatable Nanocarriers
About: The first goal of this project is to develop new nano-compositions, including targeting entities that show preferential accumulation in Glioblastoma multiforme. The second objective of the project is to test these compositions in imaging and therapy to reinforce image-guided platforms for the treatment of cancer.
Point of Care Technology Research Center in Primary Care: “Rapid Fluorescence-Based Determination of Antibiotic Susceptibility”
About: The goals of this cooperative agreement are to create and facilitate clinically-driven point-of-care solutions that address critical areas of unmet need in primary care, including funding, testing and evaluating prototype performance in simulated clinical environments and clinical living laboratories, transitioning prototypes into commercially licensable or start-up company opportunities, and disseminating lessons learned and best practices in innovation methodology in collaboration with other NIBIB Point of Care Technology Research Centers.
Continued Studies on the Effect of Combining Quaternary Alkaloids and Chemotherapeutic(s) in an Orthotropic Pancreatic Cancer Mouse Model.
About: In this continuation phase of the project, the inhibitory synergism of the optical isomers of morphinan alkaloids in combination with other agents in the pancreatic cancer model will be elaborated.