UCSC Biomedical Research - Prof. Pradip Mascharak

Dr. Pradip Mascharak’s bioinorganic chemistry laboratory conducts basic and applied research regarding metal-based, nitric oxide (NO) carriers that release NO when activated by light. In cancer cells, NO induces apoptosis (programmed cell death), which is the primary cellular mechanism of tumor clearing in chemotherapeutic treatments. Unlike conventional chemotherapy where the drug is distributed systemically, Mascharak’s synthetic “NO donors” allow unique control over where, when, and how much NO is released. This “photodynamic” approach has intriguing implications for the development of drugs in treating skin and other cancers.

Research has shown that high, localized concentrations of NO result in apoptosis in many cell types. Thus, in principle, a targeted release of NO at the tumor site could be used to selectively trigger cell death exclusively in that area. Unfortunately, currently available NO pro-drugs release NO spontaneously and ubiquitously throughout the body. Although this is advantageous in the systemic treatment of high blood pressure or infection, localized tumor malignancies do not respond to this therapy. In contrast, Dr. Mascharak’s method of light-targeted NO delivery promises a localized chemotherapeutic approach to treating cancers. Such localized treatment could alleviate many of the painful side effects that chemotherapy patients currently experience. Indeed, these harsh side effects remain the primary obstacle to the efficacy of conventional cancer treatment.

Dr. Mascharak focuses primarily on the synthesis and chemistry of light-activated NO donors. They have synthesized various metal-based NO carriers (metal nitrosyls) that contain ruthenium (Ru), iron (Fe) or manganese (Mn). The incorporation of different metals at the core of these NO-carriers essentially “tunes” the wavelength of light that drives NO release. For example, rational choice of Ru, Fe or Mn selectively tunes the photosensitivity for NO release from ultra-violet (UV), to visible (Vis), to near infrared (NIR) light.

In proof of concept studies, Mascharak and co-workers have shown these NO donors to deliver NO to biological targets, like proteins or DNA, in a light-dependent manner. In collaboration with Prof. John Fukuto’s and Prof. Louis Ignarro’s groups at UCLA, researchers have activated soluble guanylate cyclase to promote smooth muscle relaxation via a Mn-NO complex triggered with visible light.

Design of Next-Generation NO Donors to Treat Skin Cancer:
Photosensitization via Light Harvesting Chromophores

A more complex challenge has been the design of metal nitrosyls that safely deliver NO in tumor treatment. For example, Ru-NO complexes are very stable under biological conditions and readily release NO upon exposure to UV light. However, since overexposure to UV light is the cause of the malady in the first place, use of such harsh wavelengths of light would be inappropriate in photodynamic therapy. Photodynamic treatment of skin cancer requires light in the visible (450-650 nm) or near IR (650-900 nm) region. These wavelengths readily penetrate skin and do not cause any further damage to genetic material.

To solve this problem, Mascharak's group has attached various dyes to the Ru-NO carriers, rendering them sensitive to visible light. These novel NO donors are efficient “light-harvesters” in the visible region and, thus, readily deliver NO to cellular targets. This same strategy could in principle be employed to synthesize other metal nitrosyls with enhanced photo-activity in the near IR region.

When embedded in biocompatible polymers and exposed to light, manganese-based NO carriers in these samples allow spatial control over NO release. Dark areas were masked to show the light-selective release of NO.

As an alternative mode of delivery, the Mascharak lab is incorporating their NO carriers into bio-compatible polymer matrices. So far, they have successfully embedded the NO pro-drugs within innocuous “sol-gels” (a type of liquid bandage) and medical-grade HEMA plastics. As shown in Figure 3, a carefully shaped implant could provide a physician enhanced spatial control over NO delivery.

Encapsulation of the NO carrier avoids the problems of systemic NO release and its undesirable side effects (sudden drop in blood pressure). At this time, the Mascharak lab is testing various fiber-optic endoscopes for delivery of NO to internal malignancies, like those encountered in prostate or breast cancers. In principle, placement of the nitrosyl-polymer hybrid in close proximity to the tumor (either micro-surgically or as skin patch) followed by light activation could release a “burst” of NO, thus driving apoptosis and tumor shrinkage.

Professor Mascharak’s research is now moving from basic chemistry to applied biological science. The next step is the testing of these NO pro-drugs in 3-D tissue cultures, as well as in animal models. Such advanced testing is prerequisite to guarantee the safety and efficacy of this new class of photodynamic agents for chemotherapy with humans.