Synthesis and Characterization of Water-soluble Conjugates of Cabazitaxel Hemiesters-Dextran

Parhizkar, Elahehnaz; Ahmadi, Fatemeh; Daneshamouz, Saeid; Mohammadi-Samani, Soliman; Sakhteman, Amirhossein; Parhizkar, Golnaz

doi:10.2174/1871520617666170213120506

Cited by 7 publications

(3 citation statements)

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“…Previous studies with docetaxel and cabazitaxel have shown similar peaks for methylene of succinate at 2.7-3.2 ppm. 27,30 In the second and third steps, the LMW PEI was conjugated with PTX-SUC and LD, respectively, and utilized as a targeted carrier for the delivery of PTX.…”

Section: Discussionmentioning

confidence: 99%

“…PTX-succinate (PTX-SUC) was synthesized based on the previous studies reporting the conjugation of PTX to dextran. 27,28 In brief, 0.12 mmol PTX, 1.2 mmol succinic anhydride, and 0.48 mmol DMAP were dissolved in acetonitrile: chloroform (20%:80% vol/vol) and stirred at room temperature for 24 h. The reaction mixture was then mixed with 5 ml deionized water (three times) in order to remove excess DMAP and succinic anhydride. PTX-SUC was separated from unreacted PTX by thin-layer chromatography (TLC) for final purification.…”

Section: Synthesis Of Ptx-sucmentioning

confidence: 99%

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Targeted co‐delivery of paclitaxel and anti P‐gp shRNA by low molecular weight PEI decorated with L‐3,4‐dihydroxyphenylalanine

Kazemi

Parhizkar

Mohammadi-Samani

et al. 2022

Biotechnology Progress

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Co‐delivery of small chemotherapeutic molecules and nucleic acid materials via targeted carriers has attracted great attention for treatment of resistant tumors and reducing adverse effects. In this study, a targeted carrier for co‐delivery was prepared based on low‐molecular weight polyethylenimine (LMW PEI). Paclitaxel (PTX) was covalently conjugated onto PEI via a succinate linker. The PEI conjugate was decorated with L‐DOPA in order to target large neutral amino acid transporter‐1 (LAT‐1) that is over‐expressed on various cancer cells. This PEI conjugate was complexed with human ABCB1 shRNA plasmid to down‐regulate the expression of P‐glycoprotein, as one of the major efflux pumps inducing resistance against chemotherapeutics. The formation of PEI conjugate enhanced the solubility of PTX and resulted in the condensation and protection of plasmid DNA in nanosized polyplexes. The results of targeted delivery into the cells demonstrated that PEI conjugate transferred the payloads to the cells over‐expressing LAT‐1 transporter, while the biological effects on the cells lacking the transporter was negligible. Also, shRNA‐mediated down‐regulation of P‐gp led to the increase of toxic effects on the cells over‐expressing P‐gp. This study suggests a promising approach for co‐delivery of small molecules and nucleic acid materials in a targeted manner for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Synthesis Of Ptx-sucmentioning

confidence: 99%

Targeted co‐delivery of paclitaxel and anti P‐gp shRNA by low molecular weight PEI decorated with L‐3,4‐dihydroxyphenylalanine

Kazemi

Parhizkar

Mohammadi-Samani

et al. 2022

Biotechnology Progress

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“…CBT-GA was activated using pentafluorophenol (PFP) and further reacted with cCPP to form compound 6 . Briefly, CBT (30 mg, 0.036 mmol), glutaric anhydride (20.49 mg, 0.18 mmol), and DMAP (4.39 mg, 0.036 mmol) were dissolved in 5 mL of DCM in a one-pot reaction . The reaction mixture was stirred at room temperature under nitrogen for 3 h. The progress of the reaction was monitored by TLC using hexane:ethyl acetate (7:3, v / v ).…”

Section: Methodsmentioning

confidence: 99%

Targeted Delivery of Cabazitaxel Using Cyclic Cell-Penetrating Peptide and Biomarkers of Extracellular Matrix for Prostate and Breast Cancer Therapy

et al. 2021

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Targeted drug delivery for cancer therapy is an emerging area of research. Cancer cells overexpress certain biomarkers that can be exploited for their targeted therapy. Cyclic cell-penetrating peptides (cCPP) are increasingly assessed for intracellular cargo delivery in cancer cells. In this study, we have conjugated cabazitaxel (CBT) to the cCPP via an ester bond to assist CBT release in the tumor's acidic environment. Integrin targeting (RGDC, TP1) and extra domain B of fibronectin (EDB-Fn) targeting (CTVRTSAD, TP2) peptides were linked to the peptide−drug conjugate (cCPP-CBT) via a disulfide bond to provide targeting ability to the conjugates until they reach the tumor site. Conjugate 11 (TP1-cCPP-CBT) and conjugate 16 (TP2-cCPP-CBT) showed approximately 3−4-fold less antiproliferative activity on integrin and EDB-FN overexpressing cancer cell lines as compared to the CBT analogue used for comparison (CBT-GA, 5). Conjugates (11 and 16) were less toxic (31−34-fold less antiproliferative activity) to the normal human embryonic kidney (HEK-293) cells as compared to CBT. The flow cytometry and quantitative confocal microscopy data further confirm the selective efficacy of conjugates (TP1-cCPP-FAM (10) and TP1-cCPP-FAM (15)) toward biomarker overexpressing cancer cells. Furthermore, the stability and release studies of conjugate 11 revealed its therapeutic potential under different conditions, such as human plasma, different pHs, and redox conditions. This conjugation strategy was proven to enhance chemotherapeutics agents' efficacy and targeting and can be applied to other chemotherapeutic agents.

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Current development of cabazitaxel drug delivery systems

Sun

Lovell

Zhang

2022

WIREs Nanomed Nanobiotechnol

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The second-generation taxane cabazitaxel has been clinically approved for the treatment of metastatic castration-resistant prostate cancer after docetaxel failure. Compared with the first-generation taxanes paclitaxel and docetaxel, cabazitaxel has potent anticancer activity and is less prone to drug resistance due to its lower affinity for the P-gp efflux pump. The relatively high hydrophobicity of cabazitaxel and the poor aqueous colloidal stability of the commercial formulation, following its preparation for injection, presents opportunities for new cabazitaxel formulations with improved features. This review provides an overview of cabazitaxel drug formulations and hydrophobic taxane drug delivery systems in general, and particularly focuses on emerging cabazitaxel delivery systems discovered in the past 5 years.

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Synthesis and Characterization of Water-soluble Conjugates of Cabazitaxel Hemiesters-Dextran

Cited by 7 publications

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Targeted co‐delivery of paclitaxel and anti P‐gp shRNA by low molecular weight PEI decorated with L‐3,4‐dihydroxyphenylalanine

Targeted co‐delivery of paclitaxel and anti P‐gp shRNA by low molecular weight PEI decorated with L‐3,4‐dihydroxyphenylalanine

Targeted Delivery of Cabazitaxel Using Cyclic Cell-Penetrating Peptide and Biomarkers of Extracellular Matrix for Prostate and Breast Cancer Therapy

Current development of cabazitaxel drug delivery systems

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