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Updated: Jun 6, 2026
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
A PSMA-targeted dextran-based conjugate eradicates PSMA-overexpressing prostate tumors while abolishing cabazitaxel
Li Yang1, Tingchao Liu1, Meng Huo1
1National Glycoengineering Research Center, Shandong University, Qingdao 266237, China; Shandong Center of Technology Innovation for Carbohydrate, Shandong University, Qingdao 266237, China; Shandong Key Laboratory of Carbohydrate and Carbohydrate-conjugate Drugs, Shandong University, Qingdao 266237, China.
Background:
High expression of prostate-specific membrane antigen (PSMA) is observed in advanced prostate cancer, supplying a promising target for precision therapeutic interventions. Despite its efficacy in metastatic castration-resistant disease, cabazitaxel (CTX) is limited by severe systemic toxicity and a narrow therapeutic index, underscoring the urgent demand for tumor-selective delivery systems.
Methods:
A novel PSMA-targeted dextran-based conjugate, Dextran-CTX-GLA-EuK, was synthesized via click chemistry by conjugating CTX, γ-linolenic acid (GLA), and a Glu-urea-Lys (EuK) PSMA-targeting ligand to bifunctionalized dextran. Critical in vitro and in vivo PSMA blocking experiments (using the PSMA inhibitor 2-PMPA) were performed to validate its targeting specificity. A thorough myelosuppression study was performed in murine models to evaluate the systemic hematological safety profile. The biodistribution profile and in vivo antitumor efficacy of the conjugate were evaluated in murine xenograft models.
Results:
The conjugate Dextran-CTX-GLA-EuK exhibited favorable physicochemical properties, high water solubility, and strong PSMA-binding affinity. In vitro and in vivo PSMA blocking experiments conclusively verifying its PSMA-mediated specific cellular internalization and tumor accumulation. In PSMA-overexpressing xenograft models, the conjugate demonstrated selective tumor enrichment, with intratumoral CTX levels up to 98.3-fold higher than those of parent CTX, while reducing exposure in normal tissues. Dextran-CTX-GLA-EuK exerted prominent dose-dependent tumor growth inhibition, attaining a 96.6% suppression rate at a 10 mg/kg dosage in PC-3/PSMA tumors and prolonging the survival of 22Rv1 tumor-bearing mice. Importantly, comprehensive myelosuppression assays revealed that the conjugate only induced a transient reduction in white blood cell and neutrophil counts (which rapidly recovered to baseline) without impairing bone marrow hematopoietic function; unlike CTX, the conjugate did not cause significant weight loss, organ toxicity, or hematological abnormalities in tumor-bearing mice.
Conclusions:
These findings demonstrate that Dextran-CTX-GLA-EuK synergizes active targeting with dextran-based delivery, enhancing antitumor efficacy while abolishing dose-limiting toxicities. This strategy offers a clinically translatable approach for PSMA-directed therapy in prostate cancer.
Insights
A novel dextran-based conjugate, Dextran-CTX-GLA-EuK, targets prostate-specific membrane antigen (PSMA) in advanced prostate cancer. This PSMA-targeted therapy enhances antitumor efficacy and reduces toxicity compared to cabazitaxel.
Area of Science:
- Oncology
- Drug Delivery
- Nanomedicine
Background:
- Prostate-specific membrane antigen (PSMA) is highly expressed in advanced prostate cancer, making it a target for precision medicine.
- Cabazitaxel (CTX) is effective but causes severe systemic toxicity, necessitating targeted delivery systems.
Purpose of the Study:
- To develop and evaluate a novel PSMA-targeted dextran-based conjugate (Dextran-CTX-GLA-EuK) for improved prostate cancer therapy.
- To assess the conjugate's specificity, efficacy, and safety profile in preclinical models.
Main Methods:
- Synthesis of Dextran-CTX-GLA-EuK using click chemistry, conjugating CTX, GLA, and a PSMA-targeting ligand (EuK) to dextran.
- Validation of PSMA targeting specificity through in vitro and in vivo PSMA blocking experiments.
- Evaluation of myelosuppression, biodistribution, and antitumor efficacy in murine models.
Main Results:
- The conjugate demonstrated favorable physicochemical properties, high PSMA-binding affinity, and specific cellular internalization.
- Dextran-CTX-GLA-EuK achieved selective tumor enrichment, with significantly higher intratumoral CTX levels and reduced normal tissue exposure.
- The conjugate exhibited potent dose-dependent tumor growth inhibition and prolonged survival, with minimal systemic toxicity compared to parent CTX.
Conclusions:
- Dextran-CTX-GLA-EuK effectively combines active targeting with dextran-based delivery, enhancing antitumor efficacy while eliminating dose-limiting toxicities.
- This strategy represents a clinically translatable approach for PSMA-directed prostate cancer therapy.
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