Rationale: Although surgery and
radiation therapy in patients with low risk
prostate cancer appear appropriate and effective, those with high-risk localized disease almost always become
hormone refractory and then rapidly progress. A new treatment strategy is urgently needed for patients with high-risk localized
prostate cancer, particularly an approach that combines two drugs with different mechanisms. Combinations of
photodynamic therapy (
PDT) and
chemotherapy have shown synergistic effects in clinical trials, but are limited by off-target toxicity. Prostate specific membrane
antigen (PSMA) is a well-established
biomarker for
prostate cancer. Here we describe the use of a PSMA
ligand to selectively and simultaneously deliver a potent microtubule inhibiting agent,
monomethyl auristatin E (MMAE), and a
PDT agent, IR700, to
prostate cancers. Methods: Using a bifunctional PSMA
ligand PSMA-1-Cys-C6-Lys, we created a novel
theranostic molecule PSMA-1-MMAE-IR700. The molecule was tested in vitro and in vivo for selectivity and antitumor activity studies. Results: PSMA-1-MMAE-IR700 showed selective and specific uptake in PSMA-positive PC3pip cells, but not in PSMA-negative PC3flu cells both in vitro and in vivo. In in vitro cytotoxicity studies, when exposed to 690 nm light, PSMA-1-MMAE-IR700 demonstrated a synergistic effect leading to greater cytotoxicity for PC3pip cells when compared to PSMA-1-IR700 with light irradiation or PSMA-1-MMAE-IR700 without light irradiation. In vivo antitumor activity studies further showed that PSMA-1-MMAE-IR700 with light irradiation significantly inhibited PC3pip
tumor growth and prolonged survival time as compared to mice receiving an equimolar amount of PSMA-1-IR700 with light irradiation or PSMA-1-IR700-MMAE without light irradiation. Conclusion: We have synthesized a new multifunctional
theranostic molecule that combines imaging,
chemotherapy, and
PDT for
therapy against PSMA-expressing
cancer tissues. This work may provide a new treatment option for advanced
prostate cancer.