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Updated: Jul 18, 2025
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Integrin-targeting disulfide-crosslinked micellar docetaxel eradicates lung and prostate cancer patient-derived
Dawei Ni1, Beibei Guo2, Zhangyan Zhong3
1Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China.
Abstract:
Actively targeted nanomedicines though conceptually attractive for tumor therapy are extremely hard to realize due to problems of premature drug leakage, excessive liver accretion, inadequate tumor uptake, and/or retarded drug release inside tumor cells. Here, we systemically studied the influence of disulfide crosslinking on the in vitro and in vivo performance of integrin-targeting micellar docetaxel (t-MDTX). Of note, t-M5DTX with a high disulfide content was clearly advantageous in terms of stability, intracellular drug release, anti-tumor activity toward αVβ3-overexpressing A549 cells, blood circulation and therapeutic efficacy in orthotopic A549-luc lung tumor-bearing mice. t-MDTX induced extraordinary tumor targetability with tumor-to-normal tissue ratios of 1.7-8.3. Further studies indicated that t-M5DTX could effectively eradicate αVβ3-overexpressing lung and prostate cancer patient-derived xenografts (PDX), in which ca. 80% mice became tumor-free. This integrin-targeting disulfide-crosslinked micellar docetaxel emerges as a promising actively targeted nanoformulation for tumor therapy. STATEMENT OF SIGNIFICANCE: Nanomedicines have a great potential in treating advanced tumor patients; however, their tumor-targeting ability and therapeutic efficacy remain unsatisfactory. In addition to PEGylation and ligand selection, particle size, stability and drug release behavior are also critical to their performance in vivo. In this paper, we find that small and cRGD-guided disulfide-crosslinked micellar docetaxel (t-MDTX) induces superior tumor uptake and retention but without increasing liver burden, leading to extraordinary selectivity and inhibition of αvβ3 overexpressing lung tumors. t-MDTX is further shown to effectively treat αvβ3-positive patient-derived tumor models, lending it a high potential for clinical translation.
Insights
Disulfide-crosslinked micellar docetaxel (t-MDTX) enhances tumor targeting and efficacy for cancer therapy. This nanomedicine improves stability, drug release, and significantly reduces tumor size in preclinical models.
Area of Science:
- Nanomedicine and Drug Delivery
- Cancer Therapy
- Biomaterials
Background:
- Actively targeted nanomedicines show promise for tumor therapy but face challenges like drug leakage, liver accumulation, and poor tumor uptake.
- Integrin receptors, such as αVβ3, are often overexpressed in tumors, making them attractive targets for selective drug delivery.
- Disulfide crosslinking can enhance nanoparticle stability and control drug release, potentially improving therapeutic outcomes.
Purpose of the Study:
- To investigate the influence of disulfide crosslinking on the in vitro and in vivo performance of integrin-targeting micellar docetaxel (t-MDTX).
- To evaluate the stability, drug release, tumor targeting, and anti-tumor efficacy of disulfide-crosslinked t-MDTX.
- To assess the therapeutic potential of t-MDTX in preclinical models of αVβ3-overexpressing cancers.
Main Methods:
- Systematic study of disulfide crosslinking in integrin-targeting micellar docetaxel (t-MDTX).
- In vitro evaluation of stability, intracellular drug release, and anti-tumor activity against αVβ3-overexpressing A549 cells.
- In vivo assessment in orthotopic A549-luc lung tumor-bearing mice and patient-derived xenograft (PDX) models, including pharmacokinetic and biodistribution studies.
Main Results:
- t-MDTX with high disulfide content demonstrated improved stability, controlled intracellular drug release, and enhanced anti-tumor activity.
- Extraordinary tumor targetability was observed, with tumor-to-normal tissue ratios ranging from 1.7 to 8.3.
- t-MDTX effectively eradicated αVβ3-overexpressing lung and prostate cancer PDX models, with approximately 80% of mice becoming tumor-free.
Conclusions:
- Disulfide crosslinking significantly enhances the performance of integrin-targeting micellar docetaxel, addressing key limitations of nanomedicine delivery.
- t-MDTX exhibits superior tumor uptake and retention without increased liver burden, leading to high selectivity and potent inhibition of αVβ3-overexpressing tumors.
- This disulfide-crosslinked, integrin-targeting nanomedicine represents a promising formulation with high potential for clinical translation in cancer therapy.
