Porphyrins represent one of the oldest, most widely studied chemical structures, both in nature and in biomedical applications. Due to their tumor avidity and favorable photophysical properties, such as long wavelength absorption and emission, easy derivatization, high singlet oxygen quantum yield and low in vivo toxicity, porphyrins have found particular success for photodynamic therapy and fluorescence imaging of cancer. Additionally, they are excellent metal chelators, forming highly stable metallo-complexes, making porphyrins an efficient delivery vehicle for radioisotopes. Thus, there is great potential in the applications of these multi-modal porphyrin-based agents for cancer imaging and therapy. I have investigated the characteristics of various porphyrin-based probes and their potential application in different clinically relevant models. Here, I will discuss three types of porphyrin-based agents: 1) photodynamic molecular beacons (PPMMPB), 2) targeted peptide porphyrins (PPF) and 3) porphyrin-lipid nanovesicles, porphysomes. I will demonstrate that all of these porphyrin-based agents have potential clinical applications in various fields of cancer imaging and therapy. Although these three agents differ greatly, they all aim to increase the signal-to-background ratio of tumor to healthy tissue uptake of porphyrins, thereby increasing our ability to detect tumor tissue and better preserve healthy tissue during therapy.

Porphyrins represent one of the oldest, most widely studied chemical structures, both in nature and in biomedical applications. Due to their tumor avidity and favorable photophysical properties, such as long wavelength absorption and emission, easy derivatization, high singlet oxygen quantum yield and low in vivo toxicity, porphyrins have found particular success for photodynamic therapy and fluorescence imaging of cancer. Additionally, they are excellent metal chelators, forming highly stable metallo-complexes, making porphyrins an efficient delivery vehicle for radioisotopes. Thus, there is great potential in the applications of these multi-modal porphyrin-based agents for cancer imaging and therapy. I have investigated the characteristics of various porphyrin-based probes and their potential application in different clinically relevant models. Here, I will discuss three types of porphyrin-based agents: 1) photodynamic molecular beacons (PPMMPB), 2) targeted peptide porphyrins (PPF) and 3) porphyrin-lipid nanovesicles, porphysomes. I will demonstrate that all of these porphyrin-based agents have potential clinical applications in various fields of cancer imaging and therapy. Although these three agents differ greatly, they all aim to increase the signal-to-background ratio of tumor to healthy tissue uptake of porphyrins, thereby increasing our ability to detect tumor tissue and better preserve healthy tissue during therapy.

Significant progress has been made in the development of new agents against cancer and new ways of delivering existing and new agents. Yet, the major challenge to target and selectively kill cancer cells while affecting as few healthy cells as possible remains. When linked with tumor targeting moieties such as tumor-specific ligands or monoclonal antibodies, nanoparticles can be used to target cancer-specific receptors, tumor biomarkers as well as tumor vasculatures with high affinity and precision. Recently, the use of nanoparticles for drug delivery and targeting has emerged as one of the most exciting and clinically important areas in cancer nanotechnology. In this work, we tested the hypothesis that our novel ternary biomolecular nanostructures of folic acid (FA), biodegradable polymer, and paclitaxel will improve the delivery and tumor-specific distribution of the anticancer drug. The design was based on three principles: 1) Passive targeting via enhanced permeation and retention (EPR) effect; 2) active targeting via a tumor-specific ligand; and 3) prodrug that would release the drug upon delivery. First, self-assembled polymer-paclitaxel-FA nanostructures were synthesized. Their physicochemical properties were examined and biological efficacy was tested. The conjugates had significantly improved solubility in water, enabling cremophor-free formulation. Second, in vitro cellular toxicity and targeting ability of the nanostructures were investigated. In cancer cell lines with high folate receptor (FR) expression, the ternary conjugates were efficiently taken up whereas no detectable association was found in cells with minimal or no FR expression. Third, in vivo investigation in human xenograft mice models was carried out. Ternary nanostructures drastically inhibited tumor growth without inducing systemic toxicity or side effects. The ternary nanostructures displayed remarkable anti-angiogenic effect on tumor vasculature. Heparin-paclitaxel-FA was also very effective in drug resistant tumors, potentially overcoming multidrug resistance. Studies in other cancer models are in progress to determine the spectrum of applicability of these ternary nanostructures. The design principles applied in these nanoparticles can be extended to delivery and targeting of diagnostic and imaging agents. The ability to engineer multifunctional nanostructures will have a significant impact on cancer diagnostics, molecular profiling, and the integration of cancer therapy and imaging.