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Prostate-Specific Membrane Antigen (PSMA)-Directed Dendrimer-Camptothecin Conjugate for Targeted Treatment of
Anubhav Dhull1, Anunay James Pulukuri1, Aqib Iqbal Dar1
1Department of Chemistry, College of Arts and Sciences, Washington State University, Pullman, Washington 99164, United States.
Abstract:
Prostate cancer (PC) remains a major global health challenge, particularly in its advanced, treatment-resistant form. Although Camptothecin (Campto) is a potent topoisomerase I inhibitor with strong antiproliferative and pro-apoptotic activity, its clinical utility is limited by poor aqueous solubility, instability, and systemic toxicity. To address these challenges, we developed a prostate-specific membrane antigen (PSMA)-targeted dendrimer-Camptothecin conjugate (PD-Campto-CTT1298) that improves drug solubility, enables receptor-mediated uptake, and enhances therapeutic effects. This platform was synthesized by conjugating Campto and a high-affinity PSMA ligand (CTT1298) to a generation-4 hydroxyl-terminated PAMAM dendrimer (PD) via copper-catalyzed and strain-promoted azide-alkyne cycloaddition reactions. The resulting conjugate exhibited high aqueous solubility, formulation stability, and efficient drug loading. In vitro drug release studies demonstrated pH- and esterase-responsive Campto release mimicking the tumor microenvironment. PD-Campto-CTT1298 showed selective uptake in PSMA-positive PC cells (PC3-PIP, C4-2B), leading to enhanced cytotoxicity, apoptosis induction, mitochondrial dysfunction, and reactive oxygen species generation. Confocal imaging and flow cytometry confirmed receptor-specific internalization via clathrin-mediated endocytosis. Moreover, PD-Campto-CTT1298 suppressed VEGF-A secretion and disrupted angiogenesis in HUVEC tube formation assays, indicating antiangiogenic activity. Combination therapy with Olaparib demonstrated synergistic effects. Overall, PD-Campto-CTT1298 represents a promising strategy for PSMA-targeted prodrug delivery, offering a multifaceted therapeutic approach through enhanced solubility, intracellular release, and PSMA-positive tumor-specific enhanced cytotoxicity.
Insights
A novel dendrimer-Camptothecin conjugate targets prostate-specific membrane antigen (PSMA) in advanced prostate cancer. This PSMA-targeted drug delivery system enhances solubility and cytotoxicity, offering a promising new treatment strategy.
Area of Science:
- Oncology
- Drug Delivery
- Nanotechnology
Background:
- Prostate cancer (PC) presents a significant challenge, especially in advanced, treatment-resistant stages.
- Camptothecin (Campto) shows potent anticancer activity but suffers from poor solubility, instability, and toxicity.
- Current treatments for advanced PC often face limitations in efficacy and side effects.
Purpose of the Study:
- To develop a prostate-specific membrane antigen (PSMA)-targeted dendrimer-Camptothecin conjugate (PD-Campto-CTT1298) for improved PC therapy.
- To enhance drug solubility, stability, and targeted delivery of Campto.
- To evaluate the efficacy and mechanism of action of the novel conjugate in PSMA-positive PC models.
Main Methods:
- Conjugation of Campto and a PSMA ligand (CTT1298) to a generation-4 PAMAM dendrimer (PD) using click chemistry.
- Assessment of conjugate solubility, stability, drug loading, and in vitro drug release kinetics.
- Evaluation of PD-Campto-CTT1298 uptake, cytotoxicity, apoptosis, mitochondrial dysfunction, and ROS generation in PSMA-positive PC cells.
- Analysis of antiangiogenic effects and combination therapy with Olaparib.
Main Results:
- The PD-Campto-CTT1298 conjugate demonstrated high aqueous solubility, stability, and efficient drug loading.
- pH- and esterase-responsive Campto release was observed, mimicking the tumor microenvironment.
- Selective uptake in PSMA-positive PC cells led to enhanced cytotoxicity, apoptosis, and mitochondrial dysfunction.
- The conjugate exhibited antiangiogenic activity by suppressing VEGF-A and disrupting angiogenesis.
- Combination therapy with Olaparib showed synergistic effects.
Conclusions:
- PD-Campto-CTT1298 is a promising PSMA-targeted prodrug delivery platform for advanced prostate cancer.
- The conjugate offers enhanced solubility, targeted delivery, and potent anti-tumor activity.
- This strategy provides a multifaceted therapeutic approach, including enhanced cytotoxicity and antiangiogenic effects.
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