EVALUATION OF NEW PROBES AND APPROACHES FOR CORRELATING OPTICAL AND NUCLEAR IMAGING: APPLICATIONS IN CANCER DETECTION AND TREATMENT

Abstract

<p>The photophysical and biological properties of a series of novel molecules that can be used for dual-purpose molecular imaging (optical and nuclear) and therapy of cancer were evaluated. Specifically isostructural [2+1] Re/Tc complexes, a porphyrin conjugate and an antibody-recruiting small molecule construct capable of targeting prostate specific membrane antigen (PSMA) were assessed.</p> <p>The isostructural [2+1] metal complexes were synthesized to act as an optical probe when prepared using rhenium and a nuclear probe for SPECT when the core metal is ^99mTc. The rhenium analogues were incubated with MCF-7 cells and confocal imaging was used to visualize the uptake of a rhenium bipyridine cyclohexyl nicotinate derivative. Uptake of the ^99mTc complexes in MCF-7 cells were also measured and showed approximately 7% uptake for the pyridine methanol derivative and 5% for the cyclohexyl nicotinate derivative at 120 min. These results demonstrated the utility of the [2+1] isostructural compounds to create dual purpose optical/nuclear imaging agents.</p> <p>As a complementary approach to the [2+1] complexes, a series of targeted porphyrin derivatives were prepared and screened in vitro. A set of PSMA targeted chlorin e6 (Ce6) derivatives which act as isostructural molecular imaging probes and targeted photosensitizers for photodynamic therapy (PDT) were evaluated. Ce6 was linked to a potent glutamate-urea-lysine based inhibitor of prostate specific membrane antigen (PSMA), which is a transmembrane protein overexpressed in malignant prostate cancer. Studies in PSMA positive LNCaP cells showed greater uptake of the agents compared to cells with minimal PSMA expression.</p> <p>Building on the chlorin PSMA studies, a set of antibody-recruiting small molecules that target prostate cancer, and also act as a SPECT imaging agent (when radiolabeled with ¹²³I) or a radiotherapeutic (when labelled with ¹³¹I) were developed. These small molecules consist of a PSMA-inhibitor on one end and 2,4-dinitrophenyl (DNP) group on the other which recruits anti-DNP antibodies. A plate reader assay was developed using a PSMA-positive cell line and fluorescently labeled anti-DNP to observe binding and recruitment of antibodies through fluorescence. An iodine-containing derivative with a PEG₈ chain between the PSMA inhibitor and DNP was found to be potent (IC₅₀ = 14 nM) and is therefore an attractive candidate for combined radio- and antibody recruiting therapy.</p>