“The In Vitro Possible Photodiagnosis and Photodynamic Therapy Treatment of Colon Cancer”
Dr Cherie Kruger
Title of the project
“The In Vitro Possible Photodiagnosis and Photodynamic Therapy Treatment of Colon Cancer”.
Colorectal cancer (CRC) is the fourth most common cancer in South Africa (SA), and the sixth most lethal. Approximately 25% of patients will have synchronous metastatic disease at the time of their primary CRC diagnosis. Patient survival is highly dependent on the tumor stage at the time of diagnosis. Although chemotherapy is used in most stages of the disease, surgical resection of the primary tumour and metastases remains the most successful treatment modality to achieve cure or prolong survival, however tend to induce unwanted side effects. Moreover, reduced sensitivity to chemotherapy is still a major obstacle in effective treatment of advanced disease, due to the fact that CRC is mostly asymptomatic until it progresses to advanced stages.
Current screening and diagnostic methods for CRC range from semi-invasive procedures such as colonoscopy to noninvasive stool-based tests. The combination of the absence of symptoms, the semi-invasive nature of currently used methods, and the suboptimal accuracy of fecal blood tests, results in CRC diagnosis usually at advanced stages in a significant number of individuals. Thus, the implementation of screening programs aimed at early detection is essential to reduce incidence and mortality rates. To date, no data on CRC early detection and screening methods have been published in SA. Thus, early detection and screening methods, as well as new combinative unconventional treatment methods which can target, identify and treat colon cancer require investigation, in order to reduce the mortality of this malignancy.
The Photodynamic method is a promising technique both for immune fluorescent diagnosis (PDD-Photodynamic Diagnosis) and therapy (PDT-Photodynamic Therapy) for numerous cancer-related diseases, such as colon cancer. PDD and PDT demand present three basic elements: 1) photosensitizers (PS), responsible for sensitivity of diseased cancer tissue, 2) source of light causing mobilization of photosensitizers and 3) oxygen dissolved in tissue being treated. The effectiveness of either PDT or PDD is dependent on PS concentration in examined tissues and wavelength of light applied. Generally, a lower wavelength of light is used in PDD for diagnostic tools, whereas higher wavelengths of light are applied in PDT treatments for tissue destruction.
In an effort to increase host immunofluorescent PS accumulation specificity, in cancer tumors in order to enhance PDT ROS generation, as well as allow for confirmatory PDD, significant effort has been devoted towards the synthesis and characterization of bio-conjugate markers. Synthesis of monoclonal antibody (mAb) specific biomarkers with either nanoparticles (NP) and/or PS, further enhances NP-PS passive drug delivery, by targeting only tumorous cancer cells which express antigenic determinate matching sites and so ensures actively specific delivery. Thus the incorporation of cell-targeting peptides or antibodies onto an NP surface, which carries a PS is highly desirable in PDT and PDD therapeutic applications, as it enables selective cell tumour cell targeting, for identification and possible destruction.
Despite significant efforts to develop PS modified nanostructures for efficient PDD and PDT it currently remains a challenge to develop a nanostructured drug delivery system based on surface-functionalised AuNPs that combines colon targeted tumour molecular recognition with effective production of reactive singlet oxygen from PSs under PDT irradiation and allows for early PDD and so requires continued investigation. In the proposed study we would like to develop a photodynamic multicomponent nanoparticle-based system that is capable of enhanced and efficient PDT PPD PS-drug delivery, which specifically targets CRC cells and so when used in combination can be utilized for early identification, diagnosis and treatment of CRC.
Therefore the aim of this study is to combine an efficient singlet oxygen generating hydrophillic sulphonated metal PC PS Zinc Phthalocyanine Tetrasulfonic Acid (ZnPcS4) with CRC specific targeting antibodies (GCC) on the surface of heterobifunctional PEG stabilized AuNPs to enhance PS-drug delivery and specificity in colon cancer cells, so specific PDD can be investigated, with possible PDT cell death enhancement, with minimal damage to surrounding healthy tissues, since it has not been accomplished to date. Overall this study could have the potential to develop an early CRC detection method (PDD), with the possibility to yield a good prognosis and fewer side effects (PDT).