Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

A cabazitaxel liposome for increased solubility, enhanced antitumor effect and reduced systemic toxicity

The potential side effects of cabazitaxel(CBZ)in the field of cancer treatment have become a great limitation to its further clinical application.Liposomal delivery is a well-established approach to increase the therapeutic index of hydrophobic drugs.In this study,a PEGmodified liposome was developed for efficiently encapsulating CBZ,thus enhancing its specific tumor inhibition effect and reducing the systemic toxicity.It was found that the loading efficiency of CBZ into the liposome could be improved with the increase of lipophilic materials,as it could be over 80%under the weight ratio of 20:1(total lipid:CBZ).The diameter of CBZ loaded liposome(CBZ@Lipo)was^100 nm.And the liposome suspending in aqueous medium was stable at 4°C for at least one month,according to the change of its size distribution.The killing ability of CBZ@Lipo to cancer cells was significantly lower comparing to that of CBZ solution,which could be attributed to the slow release of CBZ from the liposomes.However,CBZ@Lipo could induce an obvious apoptosis of the cancer cells at low concentration.Furthermore,CBZ@Lipo exhibited an expressively enhanced tumor growth inhibition effect comparing to CBZ solution.More importantly,CBZ@Lipo showed an obviously higher biosafety proved by lower hemolysis probability,stable body weight of mice during the whole experiment and no obvious lesion in histology analysis.Our work provided a useful reference of the formulation of CBZ,which had potential for greater clinical application.

Cabazitaxel in castration resistant prostate cancer with brain metastases: 3 case reports

Prostate cancer is the most common non-cutaneous malignancy for men. The skeleton is the most common metastatic site but, following an improvement in survival, metastases in uncommon sites are being found more frequently in clinical practice, especially brain metastases. Despite the new drugs now available for metastatic castration resistant prostate cancer, no clinical evidence exists about their effectiveness on brain metastases. We describe the clinical history of 3 patients treated with cabazitaxel plus whole brain radiotherapy. These case reports demonstrate that cabazitaxel is highly active and well tolerated in brain metastases.

Prostate-specific antigen doubling time and response to cabazitaxel in a hormone-resistant metastatic prostate cancer patient

We report a case of metastatic castration-resistant prostate cancer, who received prior treatment with docetaxel and was then given cabazitaxel as salvage therapy. The patient was monitored by prostate-specific antigen doubling time and prostate-specific antigen absolute value. The prostate-specific antigen doubling time was found to be a good response predictor in the patient.

ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10(ABCC1O) are not primary resistance factors for cabazitaxel

Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.

A novel cabazitaxel liposomes modified with ginsenoside Rk1 for cancer targeted therapy

Objective:In this study,we aim to enhance the anti-prostate cancer efficacy of cabazitaxel(CTX)and reduce its immunosuppression and systemic toxicity by developing CTX-loaded liposomes modified with ginsenoside Rk1(Rk1/CTX-Lip).Methods:Physical and chemical properties of Rk1/CTX-Lip were investigated.We evaluated the biological functions of Rk1/CTXLip,both in vitro and in vivo.A subcutaneous prostate cancer(RM-1)-bearing mouse model was established to study the efficacy of Rk1/CTX-Lip inhibition in tumors.Simultaneously,a Candida albicans infection model was established in tumor-bearing mice to study the infection-relieving efficacy of Rk1/CTX-Lip.Finally,biocompatibility and in vivo safety of Rk1/CTX-Lip were evaluated.Results:We successfully prepared Rk1/CTX-Lip,achieving high CTX encapsulation efficiency(97.24±0.75)%and physical stability.Rk1/CTX-Lip demonstrated evasion of macrophage phagocytosis,effective tumor tissue targeting,and a significant reduction(>50%)in average tumor volume compared with Chol/CTX-Lip.Moreover,it relieved the concurrent infection burden and effectively regulated immune organs and cells,demonstrating superior biocompatibility.Conclusion:Rk1/CTX-Lip presents a promising new therapy for prostate cancer and holds potential for relieving concurrent fungal infections in cancer patients with low immunity.

治疗晚期前列腺癌新药——cabazitaxel

Cabazitaxel是一种用于治疗晚期前列腺痛的新药，由赛诺菲-安万特公司研制，2010年6月获美国FDA批准上市。该药是紫杉烷类化合物……1，分子式C45H57NO14C3H60，相对分子质量为894．01，结构式见图1。笔者将从药理学、药动学、临床试验和不良反应等方面对该药进行介绍。

还原响应性卡巴他赛交联前药胶束的制备及评价

通过在卡巴他赛(CTX)的C-2位接枝可交联硫辛酸(LA)制备改构药物CTX-LA,以硫辛酸接枝的两亲性嵌段共聚物聚乙二醇-聚乳酸-硫辛酸(mPEG-PLA-(LA)4)为辅料,采用固体分散-薄膜水化法制备了包载CTX的载药胶束(CTX-loaded CCMs)。通过纳米粒度分析仪、紫外-可见分光光度计、透射电子显微镜(TEM)、傅里叶变换红外光谱(FT-IR)、核磁共振氢谱(1HNMR)、X射线衍射(XRD)等对载药胶束的粒径分布、包封率、载药量、稳定性进行测试,并对体外药物释放行为、体外细胞毒性、急性毒性和抗肿瘤效果进行考察。结果表明:载药胶束平均粒径为(26.09±0.18)nm,包封率为(97.43±2.34)%,载药量为8.94%。该胶束稳定性极好,具有明显的缓释效果和还原响应性,可显著降低CTX的急性毒性,药物耐受剂量较CTX市售制剂(Jevtana)提高2倍以上,且抗肿瘤效果显著提升,对A549肺腺癌生长抑制率高达99.06%。

Current taxane formulations and emerging cabazitaxel delivery systems

Cabazitaxel is a second-generation taxane with promising anti-tumor activity and is approved for treating hormone-refractory metastatic prostate cancer previously treated with docetaxel. Although first-generation taxanes （i.e. paclitaxel and docetaxel） have sparked broad interest in a variety of drug delivery vehicles, fewer have yet been developed for cabazitaxel. This review summarizes several clinical-stage approaches for taxane formulation and recent efforts to develop novel cabazitaxel delivery systems.

聚乙二醇修饰的树状大分子负载卡巴他赛的制备工艺优化及抗肿瘤活性研究

目的 制备一种高效递送卡巴他赛(CTX)的聚乙二醇(PEG)修饰树状大分子递送胶束(mPEG-PAMAM),优化处方和制备工艺。方法 聚酰胺-胺树状大分子(PAMAM)与PEG发生迈克尔加成反应得到mPEG-PAMAM胶束,经纳米沉淀法进行药物装载,通过红外光谱、核磁共振氢谱鉴定合成材料的结构;通过透射电镜和激光粒度仪观察载药胶束的外貌形态并测定其粒径、电位;高效液相色谱法测定其载药量、包封率等;通过MTT等实验考察其细胞毒性,共聚焦显微镜探究其细胞摄取情况;在动物水平上注射RM-1前列腺癌细胞构建小鼠肿瘤模型,探究其整体抑瘤能力。结果 mPEG-PAMAM@CTX胶束呈较规则的球形,平均粒径(162.8±0.7)nm,载药量6.58%,包封率61.12%,48 h内药物累计释放量达到86.8%;mPEG-PAMAM@CTX具有良好的细胞摄取,能有效地杀伤肿瘤细胞;在体内动物模型中,CTX经体内循环,主要富集在肿瘤部位,表明CTX能够通过mPEG-PAMAM胶束高效递送到RM-1肿瘤组织,且肿瘤抑制率为68.97%。结论 本研究制备的mPEG-PAMAM@CTX胶束能够有效提高CTX溶解度,增强肿瘤抑制效果,为难溶性药物递送的开发提供新的思路。

Anti-cancer liposomal chemophototherapy using bilayer-localized photosensitizer and cabazitaxel

Photodynamic therapy(PDT)is a non-invasive tumor ablation modality that can be enhanced in combination with concurrent chemotherapy.Previously,we demonstrated that liposomes containing a bilayer-anchored photosensitizer(porphyrin-phospholipid;PoP)can be loaded with drugs in their aqueous core to improve drug delivery and tumor ablation upon target tissue irradiation with red-light.In the present work,we demonstrate that this concept can be extended to drugs loaded within the hydrophobic bilayer of liposomes.Cabazitaxel(CTX)is a potent second generation taxane anti-cancer drug that was loaded in the bilayer of liposomes also containing 0.1 molar%PoP,generating CTX-loaded PoP liposomes(CTX-PoP-Lip).CTX-PoP-Lip showed unilamellar vesicle morphology,and exhibited integrity in storage and serum,while maintaining drug stability under laser irradiation.In vitro cell killing evaluation showed that red-light laser irradiation induced cytotoxicity in cells incubated with CTX-PoP-Lip,compared to control treatments.In vivo pharmacokinetic analysis revealed that following intravenous administration to mice,CTX and PoP exhibited somewhat altered circulation profiles,suggesting that the CTX may have exchanged with serum factors in blood.Nevertheless,when a single treatment of CTX-PoP-Lip with laser irradiation was administered to mice bearing human MIA Paca-2 tumors,tumors were effectively ablated whereas the equivalent chemotherapy and PDT monotherapies were ineffective.These results demonstrate the versatility of liposome delivery systems for achieving tumor ablation with chemophototherapy.

Acid-sensitive PEGylated cabazitaxel prodrugs for antitumor therapy

Although the antitumor drug cabazitaxel shows great therapeutic potential,its high toxicity and poor water solubility limit its utility.However,the use of stimuli-responsive prodrugs is a promising strategy for overcoming these limitations.Herein,we report the synthesis of two highly water soluble,acidsensitive PEGylated acyclic-ketal-linked cabazitaxel prodrugs(PKCs)with improved antitumor efficacy.In an acidic tumor microenvironment,the PKCs hydrolyzed rapidly to release the native drug,whereas they were stable in the normal physiological environment.Compared with cabazitaxel injection,the PKCs had much higher maximum tolerated doses:and in an MDA-MB-231 subcutaneous xenograft nude mouse model,the PKCs showed better antitumor efficacy and safety than cabazitaxel injection.The prodrug strategy reported herein could be useful for the development of other water soluble,acidsensitive prodrugs with improved efficacy.

抗前列腺癌新药——Cabazitaxel

Cabazitaxel（商品名JEVTANA）是一种新型紫杉烷类化疗药物。由紫杉类植物的提取物合成。其化学名为（2α，5β，7β，10β，13α）-4-乙酰氧基-13-（{（2R，3S）-3-[（叔丁氧羰基）氨基]-2-羟-3-苯丙酰基}氧）-1-羟-7，10-二甲氧基9-氧-5，20-环氧-11-烯-2-苯甲酸酯·丙烷-2-酮（1：1）。

挤出法制备卡巴他赛脂质体的工艺优化

目的对挤出法制备卡巴他赛脂质体的挤出工艺进行优化。方法以产品的平均粒径(MD)和多分散指数(PDI)为评价指标,采用正交设计法和部分正交析因法来筛选最优工艺参数。结果最优挤出工艺参数为:核孔膜组合200 nm+80 nm(单层或双层),挤出次数组合3+3或3+2,挤出温度10~23℃,挤出时间控制在18 h内,挤出压力0.5~1.2 MPa。结论采用最优挤出工艺参数可以成功制得平均粒径值和多分散指数值均符合规定标准且储存稳定性良好的卡巴他赛脂质体产品。

卡巴他赛脂质微球注射液容器内残氧量对制剂稳定性影响

目的考察卡巴他赛脂质微球(cabazitaxel lipid microsphere,CTX-LM)注射液容器内残氧量对制剂稳定性的影响,并讨论制剂中药物的降解机制。方法在加速条件下,测定药物含量,制剂粒径、p H值、残氧量、全氧化值等指标。结果残存氧对卡巴他赛固体原料药无降解作用,40、60和80℃加速10 d的含量质量分数分别为99.8%、99.8%和99.9%,残氧量无明显变化;高温条件下卡巴他赛水溶液药物含量质量分数降低至40.4%,但与残存氧无关。对于卡巴他赛脂质微球注射液,高温下低氧组制剂氧化程度小于高氧组,且化学稳定性更好,降解活化能分别为62.6 k J·mol-1和56.1 k J·mol-1。其机制为磷脂的不饱和脂肪酸侧链经残存氧氧化断裂,产生酸性氧化产物使体系p H值下降,加剧了卡巴他赛在弱酸条件的水解,且残存氧越多、温度越高时,药物降解越显著。结论控制容器内残氧量有助于提高卡巴他赛脂质微球注射液的稳定性。

卡巴他赛注射液在比格犬体内的药代动力学

目的:建立LC-MS/MS法测定卡巴他赛在比格犬血浆中的浓度,并将该方法应用于卡巴他赛注射液在比格犬体内的药动学研究。方法:以卡马西平为内标,血浆样品经甲醇沉淀蛋白,富集生物样品中的卡巴他赛,然后进行LC-MS/MS检测。色谱柱采用Agilent EC C_(18)柱(50 mm×4.6 mm,2.7μm),柱温为30℃,以甲醇-水(95∶5)为流动相,流速为0.5 ml·min^(-1),进样量为5μl,采用电喷雾电离源(ESI),正离子多反应监测(MRM)扫描分析,卡巴他赛和内标的离子选择通道分别为m/z858.4→577.4,m/z 237.1→194.1;比格犬单剂量静脉静滴卡巴他赛注射液20 mg·h^(-1),于不同时间点取血测定血浆中药物的含量并利用DAS 2.0软件计算其药动学参数。结果:卡巴他赛在10.0~1 000.0 ng·ml^(-1)范围内线性关系良好,平均回收率均大于93.53%,日内与日间精密度(RSD)均小于7.4%。比格犬静脉注射卡巴他赛后AUC(0-t)为(155 181.93±11 593.33)ng·ml^(-1)·min^(-1),AUC(0-∞)为(167 528.12±16 671.46)ng·ml^(-1)·min^(-1),t_(max)为60 min,C_(max)为(688.37±52.06)ng·ml^(-1)。结论:该法快速、精确、简便,可用于比格犬血浆中卡巴他赛的测定及药动学研究。

Chemotherapy and its evolving role in the management of advanced prostate cancer

Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.

顶空气相色谱法测定卡巴他赛中有机溶剂的残留量

目的 建立顶空气相色谱法测定卡巴他赛中甲醇、乙醇、丙酮、二氯甲烷和正己烷共5种有机溶剂的残留量。方法采用顶空气相色谱法,氢火焰离子化检测器;载气为氮气,流速为2.0 m L·min-1;色谱柱为DB-624毛细管柱（30 m×530μm,3μm）;采用柱温50℃保持7 min,以50℃·min-1的速率升温至220℃,保持3 min;进样口温度为200℃,检测器温度为250℃;分流进样,分流比为5∶1;顶空平衡温度为100℃,顶空平衡时间为20 min;顶空定量环体积为1 m L。以外标法用峰面积计算残留溶剂的含量。结果 甲醇、乙醇、丙酮、二氯甲烷和正己烷的线性关系良好（r=0.997 8～0.999 5）,平均回收率为94.0%～99.1%,检测限分别为0.67、0.64、0.23、0.94和0.03 mg·L-1。结论 本方法可用于卡巴他赛中残留溶剂的检查。

Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer

Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer （mCRPC）. The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents （sipuleuceI-T, cabazitaxel and abiraterone） with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.