Advanced ovarian cancer is the most lethal gynecologic malignancy in the United States. Since the early stage disease is generally without symptoms, the majority of ovarian cancer cases are not diagnosed until after the disease has spread to numerous distant sites, known as micrometastases, in the abdominal cavity. Although improvements in surgery, radiation and chemotherapy, the five-year survival rate for the metastatic disease is only 43%. Thus, a major challenge relates to difficulties in removing the dozens or hundreds metastatic tumor nodules within the abdominal cavity. Here, we propose a fundamentally new controlled drug release system based on porphyrin-phospholipid doped (PoPD) liposomes, triggered directly by near infrared (NIR) light. Fluorescence endoscopy can utilize the high sensitivity and specificity of fluorescence contrast and high resolution of endoscopy. Photodynamic diagnosis (PDD) involves using photosensitizers (e.g. porphyrin-based compounds) that specifically accumulate in the cancerous tissue as exogenous fluorescent contrast has demonstrated promise for detecting malignancies. However, strong tissue absorption and scattering in living tissue distorts raw fluorescence signal, confounding the true fluorescence contrast. To address this issue, we propose a quantitative endoscopic approach by applying spatial frequency domain imaging to obtain absolute fluorescence concentration for enhanced visualization of micrometastases. We will develop a flexible fiber based dual-channel endoscopy system that allows both quantitative fluorescence imaging and adaptive beam-shaping for light-induced drug (PoPD) delivery to tumors of any size and shape. The system will be able to be inserted into the abdominal cavity with only a keyhole incision being made, which is already routinely done in the clinic. The system utilizes a highly sensitive CCD camera and spatial frequency modulation scheme with a digital micro-mirror device for quantitative fluorescence imaging of drug distribution, light-triggered drug release and adaptive light delivery for optimized treatment of micrometastases. We expect that our novel illumination and drug release strategy will provide versatile adjustment of light dose and shape with respect to spatial distribution of micrometastasis to achieve high doxorubicin deposition to destroy micrometastasis with minimal side effects to the surrounding tissues. This treatment will permit lower doxorubicin doses to be administered while simultaneously achieving more specific drug delivery in order to destroy the micrometastases and improve survival rates.
We propose to develop a fiber-based endoscopy system that allows both quantitative fluorescence imaging and adaptive beam-shaping for light-induced drug delivery to tumors of any size and shape. We expect this instrument will demarcate and destroy the micrometastases, improve survival rates of ovarian cancer patients.
|Luo, Dandan; Li, Nasi; Carter, Kevin A et al. (2016) Rapid Light-Triggered Drug Release in Liposomes Containing Small Amounts of Unsaturated and Porphyrin-Phospholipids. Small 12:3039-47|
|Luo, Dandan; Carter, Kevin A; Razi, Aida et al. (2016) Doxorubicin encapsulated in stealth liposomes conferred with light-triggered drug release. Biomaterials 75:193-202|
|Carter, Kevin A; Wang, Sophie; Geng, Jumin et al. (2016) Metal Chelation Modulates Phototherapeutic Properties of Mitoxantrone-Loaded Porphyrin-Phospholipid Liposomes. Mol Pharm 13:420-7|
|Luo, Dandan; Carter, Kevin A; Razi, Aida et al. (2015) Porphyrin-phospholipid liposomes with tunable leakiness. J Control Release 220:484-94|