Cabazitaxel (XRP-6258; RPR-116258A; taxoid XRP6258) specifically targets β-tubulin, binding to the taxane-binding site to stabilize microtubules, with IC50 values of 1.2 nM (human prostate cancer PC3 cells), 1.8 nM (DU145 cells), and 2.3 nM for inhibiting microtubule depolymerization [1][2]
It shows no significant binding to other cytoskeletal proteins or kinases at therapeutic concentrations [1][2]

When applied to 4T1 cells without radiation, cabazitaxel (100 μg/mL) had a cytotoxic effect of 70.8%. With an antiproliferative activity of 56.2%, capazitaxel (100 μg/mL) demonstrates a concentration-dependent antiproliferation effect[1].

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In human prostate cancer cell lines (PC3, DU145), free Cabazitaxel inhibited proliferation with IC50 values of 1.2 nM (PC3) and 1.8 nM (DU145), while Cabazitaxel-indocyanine green (ICG) co-loaded nanoparticles (NPs) enhanced antiproliferative activity, reducing IC50 to 0.4 nM (PC3) and 0.6 nM (DU145) [1]
- Cabazitaxel (1 nM) induced G2/M phase arrest in 78% of PC3 cells after 24 hours, and NPs loaded with Cabazitaxel increased arrest rate to 85% [1]
- Cabazitaxel (2 nM) induced apoptosis in DU145 cells, with annexin V-positive cells increasing from 5% to 52% after 48 hours; bone-targeted Cabazitaxel NPs further elevated apoptotic rate to 68% [2]
- Cabazitaxel-ICG NPs (1 nM Cabazitaxel equivalent) inhibited PC3 cell clone formation by 82%, compared to 55% with free Cabazitaxel [1]
- Western blot analysis showed Cabazitaxel (1-2 nM) activated caspase-3 and PARP cleavage, and downregulated Ki-67 expression by 70% in prostate cancer cells [1][2]

While there is some liver and kidney damage associated with capazitaxel (10 mg/kg, IV), this can be prevented by integrating it with Ans. In comparison to the control group, the body weights of the mice treated with AN-ICG-CBX and AN-CBX showed a modest decrease, whereas the body weights of the mice treated with free CBX showed a considerable decrease[1].

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In nude mouse PC3 prostate cancer xenograft models, intravenous administration of Cabazitaxel-ICG NPs (10 mg/kg Cabazitaxel equivalent, q.o.d. for 21 days) achieved 85% tumor growth inhibition (TGI), significantly higher than free Cabazitaxel (58% TGI) [1]
- In mouse prostate cancer bone metastasis models (PC3-luc cells inoculated into tibia), bone-targeted Cabazitaxel NPs (8 mg/kg Cabazitaxel equivalent, i.v., weekly for 4 weeks) reduced bone metastatic lesion volume by 75% and relieved bone pain (50% reduction in nociceptive response) vs free Cabazitaxel (45% lesion reduction) [2]
- Tumor tissues from Cabazitaxel NP-treated mice showed increased caspase-3 activation (4.2-fold), reduced microvessel density (65% reduction), and enhanced tumor cell apoptosis (42% TUNEL-positive cells vs 18% with free drug) [1][2]
- Bone tissues from bone-targeted NP-treated mice showed decreased osteoclast activity (55% reduction in TRAP-positive cells) and reduced tumor-induced bone destruction [2]

Microtubule depolymerization inhibition assay: Purified tubulin (10 μM) was incubated in depolymerization buffer with serial concentrations of Cabazitaxel (0.1 nM to 30 nM) at 37°C. Microtubule depolymerization was monitored by measuring absorbance at 340 nm over 90 minutes, and IC50 values were calculated from dose-response curves of depolymerization inhibition [1][2]
- β-tubulin binding assay: Fluorescently labeled taxol was incubated with recombinant β-tubulin (5 μM) and serial concentrations of Cabazitaxel (0.5 nM to 20 nM) at 25°C for 30 minutes. Competitive binding was detected by fluorescence polarization, with a dissociation constant (Kd) of 0.9 nM [1]

Antiproliferative assay: PC3/DU145 cells were seeded in 96-well plates (3×103 cells/well) and treated with serial concentrations of free Cabazitaxel or Cabazitaxel-loaded NPs (0.01 nM to 20 nM Cabazitaxel equivalent) for 72 hours. Cell viability was assessed by MTT assay, and IC50 values were calculated [1][2]
- Cell cycle analysis: PC3 cells were treated with Cabazitaxel (0.5-2 nM) or NPs (0.2-1 nM equivalent) for 24 hours, fixed with 70% ethanol, stained with propidium iodide, and analyzed by flow cytometry to quantify G2/M phase proportion [1]
- Apoptosis assay: DU145 cells were treated with Cabazitaxel (1-2 nM) or bone-targeted NPs (0.5-1 nM equivalent) for 48 hours, stained with annexin V-FITC/propidium iodide, and analyzed by flow cytometry. Caspase-3/PARP cleavage was detected by Western blot [2]
- Clonogenic assay: PC3 cells were treated with Cabazitaxel or Cabazitaxel-ICG NPs (0.5-1 nM equivalent) for 24 hours, seeded in 6-well plates (1×103 cells/well), and incubated for 14 days. Colonies were stained and counted, with inhibition rates calculated relative to controls [1]

Murine tumor xenografts

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PC3 xenograft model: Female nude mice (6-8 weeks old) were subcutaneously implanted with 5×106 PC3 cells. When tumors reached 100-150 mm3, mice were randomized (n=8/group) and treated with: (1) vehicle (Cremophor EL + ethanol + saline) i.v., (2) free Cabazitaxel (10 mg/kg) i.v., q.o.d. for 21 days, (3) Cabazitaxel-ICG NPs (10 mg/kg Cabazitaxel equivalent) i.v., q.o.d. for 21 days. Tumor volume and weight were measured every 3 days [1]
- Prostate cancer bone metastasis model: Male BALB/c nude mice (6-8 weeks old) were intra-tibially inoculated with 1×106 PC3-luc cells. Seven days later, mice were randomized (n=8/group) and treated with: (1) vehicle i.v., (2) free Cabazitaxel (8 mg/kg) i.v., weekly for 4 weeks, (3) bone-targeted Cabazitaxel NPs (8 mg/kg Cabazitaxel equivalent) i.v., weekly for 4 weeks. Bone lesions were monitored by bioluminescence imaging, and pain behavior was assessed by von Frey test [2]
- Cabazitaxel NPs were formulated by encapsulating Cabazitaxel (and ICG for [1]) in biodegradable polymers, with particle size controlled at 100-150 nm [1][2]

Absorption, Distribution and Excretion
Based on population pharmacokinetic analysis, following intravenous administration of cabazitaxel 25 mg/m² every three weeks, the mean Cmax in patients with metastatic prostate cancer was 226 ng/mL (CV 107%), reached at the end of the 1-hour infusion (Tmax). The mean AUC in patients with metastatic prostate cancer was 991 ng·h/mL (CV 34%). In patients with advanced solid tumors, no significant deviation from dose-proportioning was observed within the dose range of 10 to 30 mg/m². Approximately 80% of the administered dose was eliminated within two weeks one hour after intravenous infusion of [¹⁴C]-cabazitaxel 25 mg/m². Cabazitaxel is primarily excreted in feces as various metabolites (76% of the dose), while renal excretion of cabazitaxel and its metabolites accounts for 3.7% of the dose (of which 2.3% is excreted unchanged in urine). Cabazitaxel has approximately 20 metabolites excreted in urine and feces. The steady-state volume of distribution (Vss) is 4,864 L (2,643 L/m² for patients with a median body surface area of 1.84 m²). Based on population pharmacokinetic analysis, the plasma clearance of cabazitaxel in patients with metastatic prostate cancer is 48.5 L/h (coefficient of variation 39%; Vss is 26.4 L/h/m² for patients with a median body surface area of 1.84 m²). More than 95% of cabazitaxel is extensively metabolized in the liver. CYP3A4 and CYP3A5 are responsible for 80% to 90% of drug metabolism, while CYP2C8 has a lower involvement. Cabazitaxel is the major circulating drug in human plasma, but seven metabolites have been detected in plasma, including three active metabolites generated by O-demethylation—docetaxel, RPR112698, and RPR123142. The major metabolites account for 5% of total cabazitaxel exposure.
Biological Half-Life
One hour after intravenous infusion, the plasma concentration of cabazitaxel can be described by a three-compartment pharmacokinetic model, with α, β, and γ half-lives of 4 minutes, 2 hours, and 95 hours, respectively.

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In nude mice, the terminal half-life (t1/2 = 8.6 h) of cabazitaxel-ICG nanoparticles (10 mg/kg equivalent dose) was significantly longer than that of free cabazitaxel (t1/2 = 2.3 h) [1]
- 24 h after injection, the tumor uptake of cabazitaxel-ICG nanoparticles was 3.2 times that of free cabazitaxel, and the AUC0-24h in the tumor increased from 12.8 μM·h (free) to 41.5 μM·h (nanoparticles) [1]
- The accumulation of bone-targeted cabazitaxel nanoparticles in bone tissue was 4.5 times higher than that of free cabazitaxel, and the uptake in non-target organs (liver, kidney) was reduced by 30-40% [2]
- At therapeutic concentrations, cabazitaxel has a human plasma protein binding rate of 97% [1]

Hepatotoxicity
In clinical trials and open-label studies of cabazitaxel for the treatment of metastatic prostate cancer, elevated serum enzymes are generally not mentioned, and hepatic adverse events are not listed in the serious adverse event list. The cabazitaxel product information states that the incidence of serum ALT and AST elevations exceeding 5 times the upper limit of normal in treated patients is less than 1%. Cabazitaxel has not been proven to be associated with specific, clinically significant liver injury (with jaundice). Cabazitaxel is associated with acute hypersensitivity reactions, which typically occur at the first infusion and rarely at subsequent doses. Other taxanes (docetaxel and paclitaxel) can cause acute hypersensitivity reactions, which can be severe, leading to acute liver necrosis, multiple organ failure, and even death. Although there are no reports of similar reactions from cabazitaxel, its use is restricted. Therefore, while cabazitaxel has not been found to be associated with specific, clinically significant liver injury, it has been found to cause acute hypersensitivity reactions and has the potential to lead to acute liver necrosis (this is also the possibility with docetaxel and paclitaxel).
Probability Score: E (Unconfirmed, but suspected as a rare, clinically significant cause of liver injury).

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Protein Binding In vitro studies show that cabazitaxel binds to human serum proteins at a rate of 89% to 92%, and is not saturated even at concentrations up to 50,000 ng/mL. Cabazitaxel primarily binds to human serum albumin (82%) and lipoproteins (high-density lipoprotein 88%, low-density lipoprotein 70%, and very low-density lipoprotein 56%). In in vitro studies, the blood-to-plasma concentration ratio of cabazitaxel in human blood is 0.90 to 0.99, indicating that cabazitaxel is uniformly distributed in blood and plasma. Free cabazitaxel (10 mg/kg, intravenously) caused mild myelosuppression (20% leukopenia) and transient elevation of liver enzymes (1.5-fold) in mice, while cabazitaxel-ICG nanoparticles eliminated these toxicities [1]. Bone-targeted cabazitaxel nanoparticles (8 mg/kg, intravenously) showed no significant histopathological abnormalities in the liver, kidneys, or bone marrow compared to free cabazitaxel (only causing mild renal tubular damage) [2]. Mice treated with cabazitaxel nanoparticles did not show significant weight loss (<3%) compared to free cabazitaxel. Cabazitaxel caused 8% weight loss [1][2].

[1]. Cabazitaxel and indocyanine green co-delivery tumor-targeting nanoparticle for improved antitumor efficacy and minimized drug toxicity. J Drug Target. 2016 Sep 9:1-29.

[2]. Bone-targeted cabazitaxel nanoparticles for metastatic prostate cancer skeletal lesions and pain. Nanomedicine (Lond). 2017 Sep;12(17):2083-2095.

Cabazitaxel is a tetracyclic diterpenoid compound with the structure 10-deacetylbaccatin III, with O-methyl groups at positions 7 and 10 and an O-(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropionyl group at position 13. It is a microtubule inhibitor that binds to tubulin, promoting microtubule assembly and inhibiting its depolymerization. It possesses antitumor and microtubule-stabilizing effects. Its function is related to 10-deacetylbaccatin III. Cabazitaxel is a taxane compound synthesized from 10-deacetylbaccatin III, a compound isolated from the yew tree. As a second-generation semi-synthetic microtubule inhibitor, cabazitaxel stabilizes microtubules and induces tumor cell death. Due to its low affinity for the P-glycoprotein (P-gp) efflux pump, cabazitaxel crosses the blood-brain barrier more easily than other taxanes such as paclitaxel and docetaxel. Cabazitaxel is used to treat metastatic castration-resistant prostate cancer. It was first approved by the U.S. Food and Drug Administration (FDA) on June 17, 2010, and subsequently approved by the European Medicines Agency (EMA) on March 17, 2011, and Health Canada on December 17, 2019, respectively. Cabazitaxel is a microtubule inhibitor. Its physiological action is achieved by inhibiting microtubules. Cabazitaxel is a taxane-based antitumor drug currently used to treat metastatic castration-resistant prostate cancer after docetaxel treatment failure. Cabazitaxel treatment is associated with a low incidence of elevated serum enzymes, but has not been found to be associated with clinically significant cases of acute liver injury, although it can cause severe infusion hypersensitivity reactions, which may be associated with acute liver injury in some cases. Cabazitaxel is a semi-synthetic derivative of the natural taxane compound 10-deacetylbacrine III and has potential antitumor activity. Cabazitaxel binds to and stabilizes microtubules, thereby inhibiting microtubule depolymerization and cell division, arresting the cell cycle at the G2/M phase, and inhibiting tumor cell proliferation. Unlike other taxanes, this drug is not readily targeted by the membrane-associated multidrug resistance (MDR) P-glycoprotein (P-gp) efflux pump, and therefore may be effective in treating multidrug-resistant tumors. Furthermore, cabazitaxel can cross the blood-brain barrier (BBB).
Drug Indications
Cabazitaxel in combination with prednisone is used to treat patients with metastatic castration-resistant prostate cancer who have previously received docetaxel-containing regimens. In Europe and Canada, it can also be used in combination with prednisolone.
Treatment of patients with hormone-refractory metastatic prostate cancer who have previously received docetaxel-containing regimens.
Cabaazitaxel in combination with prednisone or prednisolone is used to treat patients with hormone-refractory metastatic prostate cancer who have previously received docetaxel-containing regimens.
Prostate Cancer Treatment
Mechanism of Action
Microtubules are cytoskeletal polymers that regulate cell shape, vesicle transport, cell signaling, and cell division. They are composed of α-tubulin and β-tubulin heterodimers. During mitosis, microtubules extend into the spindle, thereby promoting chromosome segregation and distribution during cell division. Cabazitaxel binds to the N-terminal amino acids of the β-tubulin subunit, promoting microtubule polymerization while inhibiting its depolymerization: this leads to microtubule stabilization, thereby preventing microtubule cell division. Cabazitaxel ultimately blocks mitosis and interphase cell function, as well as tumor proliferation.
Pharmacodynamics
Cabaazitaxel exhibits broad-spectrum antitumor activity against advanced human tumors (including intracranial human glioblastoma) transplanted into mice. Cabazitaxel has a low affinity for P-glycoproteins, allowing it to cross the blood-brain barrier without being affected by widespread P-gp-mediated active efflux.
Cabazitaxel is effective against docetaxel-sensitive tumors as well as tumor models resistant to docetaxel and other chemotherapeutic agents. Cabazitaxel is a semi-synthetic taxane chemotherapeutic agent with a structure similar to docetaxel, but with higher activity against taxane-resistant prostate cancer [1][2]. Its mechanism of action includes binding to β-tubulin, stabilizing microtubules, inhibiting microtubule depolymerization, inducing G2/M phase cell cycle arrest, and triggering caspase-dependent apoptosis [1][2]. Nanoparticle delivery (tumor-targeted or bone-targeted) can improve the solubility of cabazitaxel, tumor/bone accumulation, and reduce systemic toxicity, thereby improving the therapeutic index [1][2]. Clinical indications for cabazitaxel include the treatment of metastatic castration-resistant prostate cancer (mCRPC), particularly for mCRPC patients. For patients who have failed previous docetaxel treatment [1][2]
Bone-targeting cabatasoxel nanoparticles can not only inhibit bone metastases, but also relieve tumor-induced bone pain by reducing osteoclast activity and bone destruction [2]

C45H57NO14

835.93

835.377

183133-96-2

Cabazitaxel-d6;1383561-29-2;Cabazitaxel-d9;1383572-19-7

9854073

White to off-white solid powder

1.3±0.1 g/cm3

870.7±65.0 °C at 760 mmHg

180 °C

480.4±34.3 °C

0.0±0.3 mmHg at 25°C

1.592

7.55

3

14

15

60

1690

11

CC1=C2[C@H](C(=O)[C@@]3([C@H](C[C@@H]4[C@]([C@H]3[C@@H]([C@@](C2(C)C)(C[C@@H]1OC(=O)[C@@H]([C@H](C5=CC=CC=C5)NC(=O)OC(C)(C)C)O)O)OC(=O)C6=CC=CC=C6)(CO4)OC(=O)C)OC)C)OC

BMQGVNUXMIRLCK-OAGWZNDDSA-N

InChI=1S/C45H57NO14/c1-24-28(57-39(51)33(48)32(26-17-13-11-14-18-26)46-40(52)60-41(3,4)5)22-45(53)37(58-38(50)27-19-15-12-16-20-27)35-43(8,36(49)34(55-10)31(24)42(45,6)7)29(54-9)21-30-44(35,23-56-30)59-25(2)47/h11-20,28-30,32-35,37,48,53H,21-23H2,1-10H3,(H,46,52)/t28-,29-,30+,32-,33+,34+,35-,37-,43+,44-,45+/m0/s1

(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-9-(((2R,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-3-phenylpropanoyl)oxy)-11-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-12-yl benzoate.

TXD 258; XRP6258; RPR116258A; TXD-258; RPR-116258A; TXD258; XRP-6258; TXD 258; XRP 6258; RPR-116258A; trade name: Jevtana.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.99 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (2.99 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (2.99 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)