Optimization of near-infrared bifunctional cancer imaging and photodynamic therapy agents through structure activity relationship studies

Abstract

Cancer imaging has an important role in the detection and diagnosis both before and after anti-cancer treatment. In certain clinical interventions such as surgery, there remains an unmet need to have real time imaging techniques which can assist the surgeon in complete resection of tumors. In highly inflamed areas such as tumor margins, it can be exceptionally difficult to distinguish between normal and malignant tissue. Fluorescence optical imaging is a real time imaging modality which could aid in distinguishing tumor and non-tumor tissue through the use of tumor specific fluorescence agents (fluorophores). The practice of using these fluorophores to assist in discerning malignant tissue is a clinical practice known as image guided therapy. This technique is still being validated and can be improved upon with the use of better fluorophores which would allow clinicians to detect malignant cells deeper in tissue. Deeper detection can occur through the use of near-infrared (NIR) fluorophores which absorb light at wavelengths where there is little interference and hindrance from endogenous light absorbers present in patient. Additionally, another light based intraoperative practice such as photodynamic therapy (PDT) might be further able to enhance long term survival outcomes. PDT could work in this setting to further destroy cancerous tissue but in a less invasive manner than surgery. Previous work from our laboratory has revolved around the deep red absorbing chlorophyll-a derivate 3-(1'-hexyloxy)ethyl-3-devinyl-pyropheophorbide-a (HPPH). In our laboratory's work, we have shown that HPPH is an exceedingly well tolerated second generation photosensitizer which can effectively improve survival outcome with PDT. Our laboratory used these abilities of HPPH and in the first of its kind study, HPPH was conjugated to a NIR absorbing cyanine dye (CD) to develop a single agent which could use long wavelength light for selective fluorescence detection and PDT treatment of tumors. While imaging and treatment was successful with this compound, it also had a few drawbacks. One of the problems encountered was the high amount of bifunctional drug required to successfully treat the tumor by PDT verses the HPPH alone. It is believed that this was due to quenching of singlet oxygen by the CD upon activation of the PS and also due to energy transfer through Förster Resonance Energy Transfer (FRET). Therefore, we hypothesize that structure activity relationship studies (SAR) on a series of imaging and therapeutic agents will enable us to develop a single agent with near infrared fluorescence image guided photodynamic therapy. Overall, we have demonstrated the benefit that rational drug design through SAR can have on the development of bifunctional agents which can be used for both fluorescence optical imaging and photodynamic therapy. The compounds established from this work have been designed to have favorable optical imaging capabilities, tumor selectivity, and therapeutic potential. It is these characteristics that make the agents ideal candidates for further studies into their ability to be used as real time image guided therapeutic agents for the improvement of long term survival rates. (Abstract shortened by UMI.)