Spatiotemporally Controlled Light Therapy of Multiple Myeloma
The bone marrow microenvironment in hematological cancers such as multiple myeloma presents unique challenges to designing treatment strategies due to the presence of vital progenitor stem cells that exist alongside cancer cells. The serious side-effects of conventional chemotherapeutics are mainly attributable to their non-selectivity in distinguishing between non-cancerous stem cells and cancerous cells. As the biological mechanisms of cancer growth and resistance to conventional therapies are being unraveled, it is becoming clear that new therapeutic approaches are needed that increases treatment efficacy, prevents relapse, provides a cure and reduces off-target toxicity.
Cancer cells with increased oxidative stress and dependence on the antioxidant system are inherently susceptible to reactive oxygen species (ROS) mediated damage when compared to normal cells, providing a biological basis for therapeutic selectivity. Therefore, manipulating ROS levels by redox modulations through exogenous agents can selectively kill cancer cells with minimal toxicity to normal cells. Photodynamic therapy (PDT) is a promising technique that provides a high degree of spatiotemporal control through generation of cytotoxic ROS. Despite the promise of PDT, the shallow penetration of light in tissue confines its use to localized, superficial, or endoscope-accessible tissues. Another major limitation is that current photosensitizers (PS) rely on tissue oxygen to generate cytotoxic singlet oxygen free radicals. This feature precludes the effective application of PDT in the treatment of many tumors, which often have hypoxic regions, including the bone marrow.
We are employing a two-prong approach that addresses the issue of shallow penetration of light by employing Cerenkov radiation (CR), as well as the issues of oxygen dependence by using low light sensitive nanomaterials for effective CR-Induced Therapy (CRIT). CR from radiopharmaceuticals used in Positron Emission Tomography (PET) predominantly emits a continuous spectrum of ultraviolet (UV) light. Rapid attenuation of UV and blue light weighted CR in tissues meant that therapy could be confined to a loco-regional setting (< 1 mm), thus affording CRIT a high degree of spatiotemporal control and precision, avoiding off-target toxicity.
First demonstration of effective PDT in a disseminated disease model of multiple myeloma