Therapeutic Efficacy Of Docetaxel Research Articles

Dual-modified PCL-PEG nanoparticles for improved targeting and therapeutic efficacy of docetaxel against colorectal cancer

Polycaprolactone-poly (ethylene glycol) block copolymer (PCL-PEG) based nanoparticles were prepared for the intravenous administration of docetaxel (DTX). PCL-PEG-Tyr and PCL-PEG-Ang were synthesized by using tyrosine (Tyr) and angiopep-2 (Ang) as coupling ligands, and dual-modified PCL-PEG-based nanoparticles (PCL-PEG-Tyr/Ang) were prepared. The physicochemical properties, in vitro drug release, in vitro cytotoxicity, in vitro cellular uptake efficiency, in vivo biodistribution and in vivo antitumor efficacy of PCL-PEG-based nanoparticles were investigated. The PCL-PEG-based nanoparticles were spherical with a mean diameter of 100 nm and high encapsulation efficiencies (> 85%). The results of in vitro drug release showed that the PCL-PEG-based nanoparticles loaded with DTX had sustained-release characteristics. For in vitro cytotoxicity tests, the dual-modified PCL-PEG-based nanoparticles (PCL-PEG-Tyr/Ang) demonstrated the minimum IC50 value (2.94 µg/mL) compared with other PCL-PEG-based nanoparticles. In addition, the cellular uptake of coumarin-6 (C6) in HT29 cells was observed and determined in the PCL-PEG-Tyr/Ang nanoparticles group, which was significantly higher than that in the other PCL-PEG-based groups and C6 solution group. The results of in vivo imaging showed that dual-modified PCL-PEG nanoparticles had better tumor targeting than the other PCL-PEG-based nanoparticles. In the HT29 tumor-xenografted nude mice model, DTX-loaded PCL-PEG-Tyr/Ang nanoparticles also had a significantly higher inhibitory efficacy on tumor growth than Taxotere®-treated group. These results indicated that the dual-modified PCL-PEG-based nanoparticles (PCL-PEG-Tyr/Ang) could be a promising anticancer drug delivery system.

Docetaxel loaded mPEG-PLA nanoparticles for sarcoma therapy: preparation, characterization, pharmacokinetics, and anti-tumor efficacy

Sarcoma represents one of the most common malignant tumors with poor treatment outcomes and prognosis. Docetaxel (DTX) is acknowledged as one of the most important chemotherapy agents. The aim of this study was to improve the efficacy of docetaxel by incorporation into the mPEG-PLA nanoparticle (DTX NP) for the treatment of sarcoma. The DTX NP was prepared by emulsion solvent diffusion method and the prescription and preparation process were optimized through a single factor experiment. The optimized DTX NP was characterized by drug loading, encapsulation efficiency, drug release, etc. Then, the pharmacokinetics was conducted on rats and tumor-bearing ICR mice. Finally, the anti-tumor efficacy of DTX NP with different dosages was evaluated on tumor-bearing ICR mice. The optimized DTX NP was characterized by around 100 nm sphere nanoparticles, sustained in vitro drug release with no obvious burst drug release. Compared with DTX injection, the AUC of DTX NP increased by 94.7- and 35.1-fold on the rats and tumor-bearing ICR mice models, respectively. Moreover, the intra-tumoral drug concentration increased by 5.40-fold. The tumor inhibition rate of DTX NP reached 94.66%, which was 1.24 times that of DTX injection (76.11%) at the same dosage, and the bodyweight increase rate was also higher than the DTX injection. The study provided a DTX NP, which could significantly improve the bioavailability and therapeutic efficacy of DTX as well as reduced its toxicity. It possessed a certain prospect of application for sarcoma treatment.

Formulation optimization of Docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity.

Poor bioavailability of Docetaxel (DCT) arising due to its low aqueous solubility and permeability limits its clinical utility. The aim of the present study was to develop DCT loaded self-emulsified drug delivery systems (D-SEDDS) and evaluate its potential ability to improve the oral bioavailability and therapeutic efficacy of DCT. D-SEDDS were characterized for their in vitro antitumor activity, in situ single pass intestinal perfusion (SPIP), bioavailability, chylomicron flow blocking study and bio-distribution profile. The D-SEDDS were prepared using Capryol 90, Vitamin E TPGS, Gelucire 44/14 and Transcutol HP with a ratio of 32.7/29.4/8.3/29.6 using D-Optimal Mixture Design. The solubility of DCT was improved upto 50 mg/mL. The oral bioavailability of the D-SEDDS in rats (21.84 ± 3.12%) was increased by 3.19 fold than orally administered Taxotere (6.85 ± 1.82%). The enhanced bioavailability was probably due to increase in solubility and permeability. In SPIP, effective permeability of D-SEDDS was significantly higher than Taxotere. D-SEDDS showed 25 fold more in vitro cytotoxic activity compared to free DCT. Chylomicron flow blocking study and tissue distribution demonstrated the intestinal lymphatic transport of D-SEDDS and higher retention in tumor than Taxotere. The data suggests that D-SEDDS showed desired stability, enhanced oral bioavailability and in vitro antitumor efficacy.

Multiple effects of magnesium isoglycyrrhizinate on the disposition of docetaxel in docetaxel-induced liver injury

1. Magnesium isoglycyrrhizinate (MgIg) has been extensively used in treating liver injury which is the common adverse reaction of docetaxel (DOC). Due to the narrow therapeutic window, small changes in pharmacokinetic profiles can alter the toxicity and therapeutic efficacy of DOC significantly. The study aimed to explore the effects of MgIg on the disposition of DOC and the potential mechanism in DOC-induced liver injury.2. Pharmacokinetics and tissues distribution behaviors showed that there was no significant difference between DOC group (DOCG) and MgIg + DOC group (MDOCG). The mRNA and protein levels of cytochrome P450 3A1 (CYP3A1) in liver, intestine, and kidney were significantly upregulated, and the P-glycoprotein (P-gp) was obviously downregulated in MDOCG when compared with DOCG.3. Immunoglobulin M (IgM), CD8+ were upregulated in DOCG; while in MDOCG, IgM, CD8+ recovered to normal levels and complement C3; CD4+ were upregulated.4. MgIg had no significant effects on the disposition of DOC in docetaxel-induced liver injury. Additional, potential drug–drug interaction may happen if MgIg co-administered with antitumor drugs which are the substrates of CYP3A4 or P-gp. Hepatoprotective mechanism of MgIg perhaps was through upregulation of C3, CD4+ and downregulation of IgM, CD8+.

Abstract 3499: Improving therapeutic efficacy of Docetaxel in breast cancer

Abstract Chemotherapy is the preferred choice for treatment of advance breast cancer (BrCa). In most cases, cytotoxic drugs are used at or near a maximum tolerated dose (MTD) to achieve maximum response and eradicate the neoplastic cells, at the same time MTD doses are often toxic and have severe side effects. Lower dose i.e. “optimal biological response modifier dose” (OBRMD) provides potentially beneficial responses, but is not capable of achieving optimal clinical response. Hence, the focus of this study was to achieve the optimal therapeutic outcome of Docetaxel (DTX) at a lower dose by using it in combination with Apigenin (API), a dietary flavonoid present in fruits and vegetables. Effect of DTX and API, either alone or in combination on BrCa cells viability and apoptosis was determined by MTT assay and flow cytometry, respectively. We further investigated the mechanism of enhanced efficacy of DTX using western blot analysis and real time qPCR. Significant decrease in cell viability was observed when cells were treated with low dose DTX in combination with API as compared to either of the agent used individually in MDA-MB-231, MDA-MB-468 and MCF 10A cells. Real time analysis showed that API up regulates pro-apoptotic molecules and down regulates anti-apoptotic molecules when using in combination with DTX. These findings suggest that Apigenin is capable of reducing the effective dose of docetaxel. Hence, this new modality may have better therapeutic outcome with minimal or no toxicity. Citation Format: Jeronay King, Hina Mir, Neeraj Kapur, Shailesh Singh. Improving therapeutic efficacy of Docetaxel in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3499. doi:10.1158/1538-7445.AM2015-3499

Abstract 761: Phase I interaction study of docetaxel with supplementation of St. John's wort

Abstract Introduction St. John's wort (SJW, Hypericum perforatum) is a herbal antidepressant, which is often used by cancer patients. In healthy volunteers, SJW has previously been shown to induce hepatic CYP3A4 using the selective CYP3A4 substrate midazolam (Wang et al., 2001). In cancer patients, CYP3A4 induction by SJW could result in a decreased exposure to anticancer drugs metabolized by CYP3A4 (e.g. docetaxel), possibly resulting in a decreased therapeutic effect. Induction of docetaxel metabolism by the SJW constituent hyperforin has already been established in vitro (Komoroski et al., 2005). This pharmacokinetic interaction, however, has never been studied before in a clinical setting. Therefore, the aim of this study was to assess the effects of SJW on the pharmacokinetics of docetaxel in cancer patients. Methods In a one-sequence crossover study performed at the Netherlands Cancer Institute and approved by the Institute's Medical Ethical Committee, ten cancer patients received two cycles of docetaxel (135 mg, 60 min IV infusion). Seven days after cycle 1 (docetaxel alone), a commercial SJW extract in a recommended dose of one tablet (containing 300 mg SJW extract) three times daily was supplemented for fourteen days. After this supplementation period, cycle 2 of docetaxel was administered. During cycle 1 and cycle 2, blood samples were collected from 0-48 h after the start of the docetaxel infusion for pharmacokinetic analysis of docetaxel. Docetaxel plasma concentrations were determined by a validated LC-MS/MS assay (Kuppens et al., 2005). The pharmacokinetic endpoint for docetaxel was the area under the plasma concentration-time curve from time 0 to 48 h (AUC0-48), reflecting systemic exposure to docetaxel. By comparing the AUC0-48 of docetaxel in cycle 1 and 2, the effect of SJW on docetaxel pharmacokinetics was determined. Statistical analysis was performed with a paired Student's t test (α = 0.05). Differences in AUC0-48 between cycle 1 and 2 were considered clinically relevant if the 90% CI of the geometric mean ratio was not completely within no-effect limits of 0.80-1.25. Results (preliminary) In eight evaluable patients, supplementation of SJW decreased the mean docetaxel AUC0-48 from 2745 ± 650 to 2364 ± 483 ng/mL*h (p = 0.048, geometric mean ratio 0.86 (90% CI: 0.81-0.92)). Conclusion In this study, the observed decrease of docetaxel AUC0-48 after SJW administration was statistically significant, possibly even clinically relevant. This result indicates that concomitant use of the present SJW formulation in the recommended dose may decrease the therapeutic efficacy of docetaxel and presumably also other anticancer drugs primarily metabolized by CYP3A4. Acknowledgements This study was supported by the Dutch Cancer Society grant UU 2007-3795. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 761. doi:1538-7445.AM2012-761

Continuous and intermittent dosing of lonafarnib potentiates the therapeutic efficacy of docetaxel on preclinical human prostate cancer models

Lonafarnib is a potent, selective farnesyltransferase inhibitor (FTI) undergoing clinical studies for the treatment of solid tumors and hematological malignancies. Preclinically, a number of FTIs, including lonafarnib, interact with taxanes to inhibit cancer cell growth in an additive/synergistic manner. These observations provided rationale for investigating the effects of combining lonafarnib and docetaxel on preclinical prostate cancer models. To date, docetaxel is the only chemotherapeutic agent in clinical use for hormone-refractory prostate cancer. In vitro experiments with 22Rv1, LNCaP, DU-145, PC3 and PC3-M prostate cancer cell lines showed significantly enhanced inhibition of cell proliferation and apoptosis when lonafarnib was added to docetaxel. In human tumor xenograft models, continuous coadministration of lonafarnib with docetaxel caused marked tumor regressions (24-47%) in tumors from all of the cell types as well as parental CWR22 xenografts. Intermittent dosing of lonafarnib (5 days on then 5 days off) coadministered with docetaxel produced similar regressions in hormone-refractory 22Rv1 tumors. 22Rv1 tumors progressing on docetaxel treatment also responded to treatment with intermittent lonafarnib (5 days on then 5 days off). Moreover, animals did not exhibit any signs of toxicity during coadministration of lonafarnib and docetaxel. In conclusion, coadministration of continuous and intermittent lonafarnib enhanced the antitumor activity of docetaxel in a panel of prostate cancer models. An intermittent dosing schedule of lonafarnib coadministered with docetaxel may allow enhanced efficacy to that of continuous dosing by improving the tolerability of higher doses of lonafarnib.