Fluorescent Probes for Cancer Cell Imaging
Cancer continues to be the major and most challenging healthcare problem all around the world. Globally, over 14 million patients were diagnosed with cancer just in 2012, and it is expected to be around 22 million patients per year in the coming decades. Despite worldwide research effort, cancer is the second most common cause of death in the United States and responsible for 25% of deaths in developing countries. There is no doubt that the mortality rate of cancer can potentially be decreased with early and precise diagnosis in combination with effective and fast treatment strategies. Current clinical diagnostic methods utilize the morphological analysis of cancerous cells (cytology) or tissues (pathology) as well as imaging techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), X-Ray, endoscopy and ultrasound. Both cytology and pathology are effective to distinguish cancer cells from healthy cells but they are not successful at detecting cancer at early stages. Moreover, most of the time, these methods are more effective when combined with some other imaging techniques. On the other hand, advanced imaging techniques listed above have low sensitivity, limited selectivity and complicated operational principles with expensive maintenance. Thus, the development of early diagnostic methods for cancer, before the tumor becomes metastatic, still holds a great challenge. To that end, fluorescence imaging has emerged as a promising tool since it offers some advantages such as real-time imaging in natural environment, spatial & temporal resolution, high sensitivity & selectivity, tunable emission wavelengths, easy and cheap operation as well as non-destructive nature to cells. In our group we are interested in mainly two different classes of fluorescent probes, which are small molecular and bioluminescent probes, and use them for both in vitro and in vivo cancer cell imaging.
Targeted Drug Delivery and Theranostic Applications
Chemotherapy and radiotherapy are two very well-known and widely used therapies against cancer all around the world. Most of the related drugs are highly successful in combination with early diagnosis. However the major problem with these conventional methods is the selectivity or in other words destructive side effects. Although, most of the known chemotherapy drugs today in the clinic are really effective against cancer cells, they kill the surrounding healthy cells at the same time, which dramatically affecting the progress of therapy and daily life of patients. Selective killing of cancer cells while bypassing the healthy cells is a major research goal for many scientists in developing new anticancer therapeutics. In our research, we are linking fluorescent probes with chemotherapeutic drugs through tumor-responsive linkers to design a targeted drug delivery (pro-drug) and imaging systems. Combining both therapy and the diagnosis within the same system is known as theranostics. This type of combined applications led us to monitor bio-distribution, transport mechanisms, therapeutic efficacy and kinetics of our probe-drug conjugates, which are all critical to get best results from the therapy.
Activatable Photosensitizers for Photodynamic Therapy
Photodynamic therapy (PDT) is a developing treatment modality for several cancer types, which utilizes reactive singlet oxygen that is generated by light activated and well-designed photosensitizers (PDT drug, PDT agent) to kill the cancer cells. First step in the PDT process is the irradiation of the photosensitizer, which is injected into the bloodstream and accumulated within the tumor, by light to excite an electron to singlet-excited state. Inter-system crossing follows this step and the electron is transferred to triplet-excited state. One of the basic methods to satisfy inter-system crossing is the addition of heavy atoms (ex: Br, I, Se) to the core structure of the photosensitizers. Heavy-atoms favor inter-system crossing, which is normally forbidden by enhancing spin-orbit coupling. In the last step, triplet-excited state energy is transferred to nearby molecular oxygen and excites it to generate singlet oxygen. Upon generation of singlet oxygen, it reacts with vital bio-molecules causing oxidative damage, which results in cell death. In addition to direct killing of cancer cells, PDT also restricts the follow of nutrients and oxygen to cancer cells by damaging the vasculatures around tumor regions and at the same time activates immune system against cancer cells. The advantages and importance of PDT are more pronounced when it is compared with widely used conventional chemotherapy and radiotherapy, since these therapies have serious side effects and they damage the immune system of patients. Although PDT is highly promising, its broader applicability in clinical treatments is restricted due to some basic problems. The first one is the limited penetration of the irradiation light through tissues, which leaves the deeper tumors out from the scope of PDT. Studies have shown that photosensitizers should absorb at the red or near-IR region of the electromagnetic spectrum to get the best penetration depth. The second major problem of the PDT is the oxygen deficiency (hypoxia) in cancer cells. During PDT singlet oxygen generation is highly dependent on oxygen, which decreases the efficacy of the treatment on hypoxic cancer cells. In addition to this, further oxygen consumption of PDT agents aggravates tumor hypoxia. Accordingly, some of the signaling pathways are turned-on under severe hypoxia and cause angiogenesis, proliferation and metastasis of hypoxic cancer cells. The third problem that PDT should address is to satisfy the activation of singlet oxygen generation only in cancer cells without giving harm to healthy cells. Accordingly, in our research we are trying to design new generation PDT drugs that can address all aforementioned chronic problems of PDT.