Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer

Wang, Xinning; Shirke, Aditi; Walker, Ethan; Sun, Rongcan; Ramamurthy, Gopolakrishnan; Wang, Jing; Shan, Lingpeng; Mangadlao, Joey Dacula; Dong, Zhipeng; Li, Jing; Wang, Ziying; Schluchter, Mark D.; Luo, Dong Hua; Wang, Yu; Stauffer, Shaun R.; Brady‐Kalnay, Susann M.; Hoimes, Christopher J.; Lee, Zhenghong; Basilion, James P

doi:10.3390/cancers13030417

Cited by 19 publications

(39 citation statements)

References 71 publications

(39 reference statements)

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“…PSMA-1-Cys-C6-Lys (Glu-CO-Glu'-Amc-Ahx-Glu-Glu-Glu-Cys-C6-Lys) was synthesized manually by solid phase peptide synthesis method as reported previously 57 , 58 , 60 . VcMMAE was purchased from Creative Biolabs (Shirley, NY).…”

Section: Methodsmentioning

confidence: 99%

“…HPLC was performed on a Shimadzu HPLC system equipped with a SPD-20A prominence UV/visible detector and monitored at 220 nm and 254 nm 57 , 58 , 60 . Semi-preparative HPLC was achieved using Luna 5m C18(2) 100 Å column (250mm × 10mm × 5 mm; Phenomenex) at a flow rate of 2.5 mL/min.…”

Section: Methodsmentioning

confidence: 99%

“…PSMA-1-VcMMAE was synthesized as previously reported 60 . Briefly, PSMA-1-Cys-C6-Lys (2.6 mg, 2 μmol) ( Figure S2 ) was dissolved in phosphate buffered saline (PBS), the pH of the solution was adjusted to 7.5 - 8.0, then Vc-MMAE (3.0 mg, 2.2 μmol) (BOC Sci.)…”

Section: Methodsmentioning

confidence: 99%

“…PC3pip cells (5 × 10 5 ) was suspended in 200 uL of 50 mM Tris buffer, pH 7.5. The cells were incubated at 37 °C with different concentrations of PSMA-1-MMAE-IR700 or ZJ24 in the presence of 12 nM of 3 H-ZJ24 for 1 h 57 , 58 , 60 . The cells were then washed 3 times with cold PBS and cell-associated radioactivity was measured by scintillation counting.…”

Section: Methodsmentioning

confidence: 99%

“…Combination of PDT with chemotherapy can provide a second treatment to kill remaining cancer cells that survive PDT and has been shown to be more effective than either treatment alone 35 - 38 . Recently, we reported a PSMA-targeted chemotherapeutic prodrug PSMA-1-VcMMAE for the treatment of prostate cancer, which was effective but not decisive against prostate cancer 60 . It is hypothesized that combination of PSMA-targeted PDT and PSMA-targeted MMAE will improve the antitumor efficacy.…”

Section: Introductionmentioning

confidence: 99%

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

Wang¹,

Sun²,

Wang³

et al. 2022

Theranostics

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Wang¹,

Sun²,

Wang³

et al. 2022

Theranostics

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Small Molecule‐Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs

Zhang,

Hu,

Aras

et al. 2024

ChemMedChem

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Conventional chemotherapy is insufficient for precise cancer treatment due to its lack of selectivity and inevitable side effects. Targeted drugs have emerged as a promising solution for precise cancer treatment. A common strategy is to conjugate therapeutic agents with ligands that can specifically bind to tumor cells, providing targeted therapy. Similar to the more successful antibody drug conjugates (ADCs), small molecule drug conjugates (SMDCs) are another promising class of targeted drugs, consisting of three parts: targeting ligand, cleavable linker and payload. Compared to ADCs, SMDCs have the advantages of smaller size, better permeability, simpler preparation process and non‐immunogenicity, making them a promising alternative to ADCs. This review describes the characteristics of the targeting ligand, linker and payload of SMDCs and the criteria for selecting a suitable one. We also discuss recently reported SMDCs and list some successful SMDCs that have entered clinical trials.

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Evaluation of a photodynamic therapy agent using a canine prostate cancer model

et al. 2023

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Background Male dogs can develop spontaneous prostate cancer, which is similar physiologically to human disease. Recently, Tweedle and coworkers have developed an orthotopic canine prostate model allowing implanted tumors and therapeutic agents to be tested in a more translational large animal model. We used the canine model to evaluate prostate‐specific membrane antigen (PSMA)‐targeted gold nanoparticles as a theranostic approach for fluorescence (FL) imaging and photodynamic therapy (PDT) of early stage prostate cancer. Methods Dogs (four in total) were immunosuppressed with a cyclosporine‐based immunosuppressant regimen and their prostate glands were injected with Ace‐1‐hPSMA cells using transabdominal ultrasound (US) guidance. Intraprostatic tumors grew in 4–5 weeks and were monitored by ultrasound (US). When tumors reached an appropriate size, dogs were injected intravenously (iv) with PSMA‐targeted nano agents (AuNPs‐Pc158) and underwent surgery 24 h later to expose the prostate tumors for FL imaging and PDT. Ex vivo FL imaging and histopathological studies were performed to confirm PDT efficacy. Results All dogs had tumor growth in the prostate gland as revealed by US. Twenty‐four hours after injection of PSMA‐targeted nano agents (AuNPs‐Pc158), the tumors were imaged using a Curadel FL imaging device. While normal prostate tissue had minimal fluorescent signal, the prostate tumors had significantly increased FL. PDT was activated by irradiating specific fluorescent tumor areas with laser light (672 nm). PDT bleached the FL signal, while fluorescent signals from the other unexposed tumor tissues were unaffected. Histological analysis of tumors and adjacent prostate revealed that PDT damaged the irradiated areas to a depth of 1–2 mms with the presence of necrosis, hemorrhage, secondary inflammation, and occasional focal thrombosis. The nonirradiated areas showed no visible damages by PDT. Conclusion We have successfully established a PSMA‐expressing canine orthotopic prostate tumor model and used the model to evaluate the PSMA‐targeted nano agents (AuNPs‐Pc158) in the application of FL imaging and PDT. It was demonstrated that the nano agents allowed visualization of the cancer cells and enabled their destruction when they were irradiated with a specific wavelength of light.

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Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer

Cited by 19 publications

References 71 publications

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

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

Small Molecule‐Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs

Evaluation of a photodynamic therapy agent using a canine prostate cancer model

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