A low molecular weight multifunctional theranostic molecule for the treatment of prostate cancer

Abstract

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.

A Novel PSMA-Targeted Probe for NIRF-Guided Surgery and Photodynamic Therapy: Synthesis and Preclinical Validation

“…All these data taken together suggest that PDT alone is not enough to kill the tumours completely [ 53 ]. This is a known Achilles heel for clinical translatability of targeted photodynamic therapy in general.…”

What Is New in the Management of High-Risk Localized Prostate Cancer?

“…Additionally, this group also has a significantly high risk of metastatic disease as well as mortality related to prostate cancer with approximately 85% dying within 10 years post-diagnosis [ 4 ]. The treatment of these patients with single modality regimens such as radical prostatectomy or radiation therapy has proven to have a poor treatment response with high failure rates as well as more than 50% chances of both clinical and biochemical progressions at 5 years [ 5 ]. Most of these patients are offered a combination of radiotherapy with hormonal therapy, which is often considered an inadequate therapeutic approach and is associated with significant adverse effects.…”

“…One of the approaches is combining chemotherapy with photodynamic therapy (PDT). Recently, a new multifunctional theranostic molecule has been developed, it involves a combination of chemotherapy, imaging, and PDT for therapy against prostate-specific membrane antigen (PSMA) [ 5 ]. It involves the use of a PSMA ligand to deliver a potent microtubule inhibiting agent selectively and simultaneously, Monomethyl Auristatin E (MMAE), and a PDT agent, IR700, to prostate cancers [ 5 ].…”

“…Recently, a new multifunctional theranostic molecule has been developed, it involves a combination of chemotherapy, imaging, and PDT for therapy against prostate-specific membrane antigen (PSMA) [ 5 ]. It involves the use of a PSMA ligand to deliver a potent microtubule inhibiting agent selectively and simultaneously, Monomethyl Auristatin E (MMAE), and a PDT agent, IR700, to prostate cancers [ 5 ]. In comparison with individual treatment with PDT or chemotherapy alone, this multifunctional molecule has shown selective uptake in PSMA-positive tumours with significant antitumor activity [ 5 ].…”

“…It involves the use of a PSMA ligand to deliver a potent microtubule inhibiting agent selectively and simultaneously, Monomethyl Auristatin E (MMAE), and a PDT agent, IR700, to prostate cancers [ 5 ]. In comparison with individual treatment with PDT or chemotherapy alone, this multifunctional molecule has shown selective uptake in PSMA-positive tumours with significant antitumor activity [ 5 ]. This study suggests that it can be used during surgery to help in identifying tumours using real-time fluorescence image-guided surgery (FIGS) and provide PDT as well as chemotherapy to kill any unresected cancer cells [ 5 ].…”