Nanoparticle drug loading as a design parameter to improve docetaxel pharmacokinetics and efficacy

Nanoparticle (NP) drug loading is one of the key defining characteristics of an NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT^®), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel.     

Docetaxel-loaded nanoparticles based on star-shaped mannitol-core PLGA-TPGS diblock copolymer for breast cancer therapy

A star-shaped biodegradable polymer, mannitol-core poly(d,l-lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate (M-PLGA-TPGS), was synthesized in order to provide a novel nanoformulation for breast cancer chemotherapy. This novel copolymer was prepared by a core-first approach via three stages of chemical reaction, and was characterized by nuclear magnetic resonance, gel permeation chromatography and thermogravimetric analysis. The docetaxel-loaded M-PLGA-TPGS nanoparticles (NPs), prepared by a modified nanoprecipitation method, were observed to be near-spherical shape with narrow size distribution. Confocal laser scanning microscopy showed that the uptake level of M-PLGA-TPGS NPs was higher than that of PLGA NPs and PLGA-TPGS NPs in MCF-7 cells. A significantly higher level of cytotoxicity was achieved with docetaxel-loaded M-PLGA-TPGS NPs than with commercial Taxotere®, docetaxel-loaded PLGA-TPGS and PLGA NPs. Examination of the drug loading and encapsulation efficiency proved that star-shaped M-PLGA-TPGS could carry higher levels of drug than linear polymer. The in vivo experiment showed docetaxel-loaded M-PLGA-TPGS NPs to have the highest anti-tumor efficacy. In conclusion, the star-like M-PLGA-TPGS copolymer shows potential as a promising drug-loaded biomaterial that can be applied in developing novel nanoformulations for breast cancer therapy.     

Cost-effectiveness analysis of second-line chemotherapy strategies for patients with advanced non-squamous non-small cell lung cancer

Lung cancer is the most widespread type of cancer and the primary cause of cancer-related death in the world. In this study, we aimed to analyze the cost-effectiveness of second-line chemotherapy strategies based on gemcitabine, pemetrexed, and docetaxel for advanced non-squamous non-small cell lung cancer patients in China.A Markov model based on three states, progression-free survival, progressed survival and death, was constructed to simulate the progression of the disease in a 6-year horizon. Sensitivity analysis was performed to evaluate the robustness of the model. The primary outcome of the model was the incremental cost-effectiveness ratio at a willingness-to-pay threshold of 3× per capita GDP of China in 2018 ($29 383). The baseline model results showed that the quality-adjusted life years over the course of the disease associated with second-line chemotherapy strategies were 0.233, 0.417 and 0.272 for gemcitabine, pemetrexed and docetaxel, respectively, and the corresponding total costs were $5321.02, $12 143.94, and $9479.42. Gemcitabine, pemetrexed and docetaxel resulted in the incremental cost-effectiveness ratios of $37 081.09 and $106 625.64 per quality-adjusted life year gained. The incremental cost-effectiveness ratio of pemetrexed and docetaxel compared with gemcitabine exceeded the willingness-to-pay threshold. One-way sensitivity analysis showed that the utility value of gemcitabine in the progressed survival state was the most influential parameter.     

Docetaxel inhibits bone resorption through suppression of osteoclast formation and function in different manners

Osteoclasts are formed from the monocyte-macrophage lineage in response to receptor activator of nuclear factor κB ligand (RANKL) expressed by osteoblasts. Bone is the most common site of breast cancer metastasis, and osteoclasts play roles in the metastasis. The taxane-derived compounds paclitaxel and docetaxel are used for the treatment of malignant diseases, including breast cancer. Here we explored the effects of docetaxel on osteoclastic bone resorption in mouse culture systems. Osteoclasts were formed within 6 days in cocultures of osteoblasts and bone marrow cells treated with 1,25-dihydroxyvitamin D₃ plus prostaglandin E₂. Docetaxel at 10⁻⁸ M inhibited osteoclast formation in the coculture when added for the entire culture period or for the first 3 days. Docetaxel, even at 10⁻⁶ M added for the final 3 days, failed to inhibit osteoclast formation. Osteoprotegerin, a decoy receptor of RANKL, completely inhibited osteoclast formation when added for the final 3 days. Docetaxel at 10⁻⁸ M inhibited the proliferation of osteoblasts and bone marrow cells. RANKL mRNA expression induced by 1,25-dihydroxyvitamin D₃ plus prostaglandin E₂ in osteoblasts was not affected by docetaxel even at 10⁻⁶ M. Docetaxel at 10⁻⁶ M, but not at 10⁻⁸ M, inhibited pit-forming activity of osteoclasts cultured on dentine. Actin ring formation and l-glutamate secretion by osteoclasts were also inhibited by docetaxel at 10⁻⁶ M. Thus, docetaxel inhibits bone resorption in two different manners: inhibition of osteoclast formation at 10⁻⁸ M and of osteoclast function at 10⁻⁶ M. These results suggest that taxanes have beneficial effects in the treatment of bone metastatic cancers. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Phase I/II Trial of Docetaxel and Carboplatin as a First-Line Therapy in Patients with Stage IV Non-Small-Cell Lung Cancer

A phase I/II study was conducted to determine the maximum-tolerated dose, the safety and tolerability, and the clinical efficacy of carboplatin and docetaxel in combination in patients with stage IV non–small-cell lung cancer. Patients with measurable, previously untreated, good performance status, and stage IV non–small-cell lung cancer were eligible. Increasing doses of docetaxel were given in combination with a fixed dose of carboplatin except at level 5. Cycles were repeated every four weeks. Seventy-seven patients were registered. In phase I, 27 patients were entered at five different dose levels. A docetaxel dose of 60 mg/m² and carboplatin area under the concentration time curve 6 was recommended for phase II, and an additional 50 patients were entered at this level for a total of 56 patients. Grade 3/4 neutropenia was the most common adverse event and occurred in 70% of the patients. Two patients had febrile neutropenia. Fifty-six patients were assessable for response; 21 partial responses were observed for an overall response rate of 37.5%. The median time to tumor progression was 4.0 months (range, 1.0–21.0 months), and the median survival was 12.9 months (range, 0.4–51.3 months). The one-year survival rate was 46.4%. The combination of docetaxel 60 mg/m² and carboplatin area under the concentration time curve 6 is feasible and effective in patients with stage IV non–small-cell lung cancer.     

Antiproliferative activity of bortezomib alone and in combination with cisplatin or docetaxel in head and neck squamous cell carcinoma cell lines

Purpose

Proteasome inhibition has been shown to be effective in multiple myeloma and solid tumor models. In this in vitro study, we investigated the antitumor effect of bortezomib (Velcade^®) in squamous cell carcinoma of the head and neck (SCCHN) cell lines and examined the interaction of the drug with docetaxel (TAX) and cisplatin (CDDP).

Methods

Dose escalation studies were performed with eight squamous cell carcinoma cell lines using bortezomib alone or in combination with TAX or CDDP. Growth inhibitory and proapoptotic effects were measured quantitatively using cytohistology and western blot analysis.

Results

Bortezomib alone showed a significant antiproliferative activity in all SCCHN cell lines (P = 0.012), and the activity was further enhanced by the addition of TAX or CDDP (P ≤ 0.036). When the combination of bortezomib and CDDP was used, the dose of the latter could be reduced to yield the same antiproliferative effect as the cytotoxic drug alone (P < 0.012).

Conclusions

Our results indicate that bortezomib increases the cytotoxic activity of TAX and CDDP in SCCHN cell lines. In vivo and in the clinical setting, the addition of bortezomib may allow to reduce the doses of TAX or CDDP to decrease the systemic toxicity of these drugs.

     

Four consecutive multicenter phase II trials of adjuvant chemoradiation in patients with completely resected high-risk gastric cancer: the experience of the German AIO/ARO/CAO group

Purpose

Feasibility and efficacy of four different adjuvant radiochemotherapy regimens in patients with completely resected gastric cancer were evaluated in consecutive cooperative phase II trials using different 5-fluorouracil (5-FU)-based combination chemotherapies (CTX) and 5-FU-enhanced radiotherapy.

Methods

Between 2000 and 2005, 157 patients with completely resected gastric adenocarcinoma were included. The study design was based on two cycles of CTX and irradiation with 45 Gy plus concomitant 5-FU 225 mg/m² per 24 h between these two cycles. CTX cycles consisted of 5-FU, folinic acid (FA), cisplatin plus paclitaxel (FLPP); 5-FU, FA and cisplatin (FLP); 5-FU, FA and irinotecan (FLI); or 5-FU, cisplatin plus docetaxel (FPD).

Results

Median follow-up for all four trials was 18 months (range, 1–64) without significant difference between the four regimens: FLPP 30 months (2–46+), FLP 18 months (1–64+), FLI 15 months (1–26), FPD 10 months (5–19+). Treatment associated toxicity was tolerable and did not differ significantly between the four CTX regimens. Across all patients grade ¾, toxicities during the first cycle/chemoradiation/second cycle consisted of leukocytopenia 4%/2%/30%, anorexia 5%/10%/6%, diarrhea 6%/1%/3%, nausea 2%/7%/2%. Early death occurred in one patient due to Pneumocystis carinii pneumonia. Median progression free survival was 23 months for FLPP, 18 months for FLP, 14 months for FLI, 9 months for FPD (not significant). One-year-overall survival rates were 95% for FLPP, 82% for FLP, 94% for FLI, 86% for FPD.

Conclusion

Adjuvant radiochemotherapy in patients with gastric cancer can be safely given continuous infusion of 5-FU at 225 mg/m² per day. In addition, a variety of 5-FU-based multiagent chemotherapy regimen with defined activity in gastric cancer appears both safe and effective when given prior and after radiochemotherapy in this setting.

     

多西他赛联合泼尼松治疗激素难治性前列腺癌

目的 观察多西他赛联合泼尼松3周方案治疗激素难治性前列腺癌的疗效.方法 2004年9月至2007年1月对13例激素难治性前列腺癌患者行多西他赛联合泼尼松3周方案化疗.患者69～82岁,平均75岁.入选标准：全雄激素阻断治疗失败,排除抗雄激素撤除综合症,并至少经过1次抗雄药物撤退以外的二线内分泌治疗无效.治疗方案：化疗第一天用多西他赛75 mg/m2,泼尼松5 mg,2次/d;从化疗第二天起泼尼松5 mg,2次/d,连续应用,21 d为1疗程.观察终点为血PSA、可测量病灶和疼痛的变化.结果 13例入组患者中1例失访,11例可评价疗效,PSA有效率为54%（6/11）,有效患者PSA从治疗前的23.6 ng/ml、515.5 ng/ml、150.0 ng/ml、16.4 ng/ml、152.7 ng/ml、12.3 ng/ml,下降到治疗后最低2.4 ng/ml、139.9 ng/ml、42.3 ng/ml、6.7 ng/ml、67.5 ng/ml、5.7 ng/ml.有效持续时间4个月、3个月、8个月、3个月、2个月、2个月.可测量病灶2例为稳定.骨痛改善率为50%（3/6）.12例可评价不良反应,主要不良反应为骨髓抑制,Ⅲ度白细胞减少占50%.12例中位随访194 d.死亡5例,已死亡患者从诊断激素非依赖性前列腺癌起中位生存期36个月.结论 多西他赛联合泼尼松3周方案治疗激素难治性前列腺癌有一定疗效,毒性可耐受.     

培美曲塞二钠(PMD)对比多西紫杉醇单药二线治疗晚期非小细胞肺癌的临床观察

目的探讨培美曲塞二钠(pemetrexed disodium,PMD)对比多西他赛(DOC)单药二线治疗晚期非小细胞肺癌(NSCLC)的临床疗效和毒副反应。方法选择经病理学或细胞学确诊一线治疗失败的NSCLC患者69例,分为2组,PMD组24例患者采用单药PMD治疗,DOC组采用单药DOC治疗,化疗2个周期后评价疗效及观察毒副反应。结果 2组的有效率、疾病控制率、中位生存期、1年生存率比较无统计学意义(P>0.05);PMD组的血液学毒性(粒细胞减少)明显低于DOC组(P>0.05),其他消化道反应、乏力、脱发等无差异(P>0.05)。结论 PMD对比DOC单药二线治疗晚期NSCLC临床疗效相似,PMD的血液学毒性反应相对明显降低,故更适于治疗二线晚期NSCLC患者。