cabazitaxel and Neoplasms

The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. The taxanes share the characteristics of extensive hepatic metabolism and biliary excretion, the need for dose adaptation in patients with liver dysfunction, and a substantial pharmacokinetic variability even after taking into account known covariates. Data from clinical studies suggest that optimal scheduling of the taxanes is dependent not only on the specific taxane compound, but also on the tumor type and line of treatment. Still, the optimal dosing regimen (weekly vs 3 weekly) and optimal dose of the taxanes are controversial, as is the value of pharmacological personalization of taxane dosing. In this article, an overview is given on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamics and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most active and safe regimen, the recommended initial dose and the issue of therapeutic drug dosing.

Topics: Albumins; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Liver; Neoplasms; Paclitaxel; Taxoids; Treatment Outcome; Tubulin Modulators

Paclitaxel and docetaxel were two epoch-making anticancer drugs and have been successfully used in chemotherapy for a variety of cancer types. In the year 2010, a new taxane, cabazitaxel, was approved by FDA for use in combination with prednisone for the treatment of metastatic hormone-refractory prostate cancer. Albumin-bound paclitaxel (nab™-paclitaxel; abraxane) nanodroplet formulation was another notable invention (FDA approval 2005 for refractory, metastatic, or relapsed breast cancer). Abraxane in combination with gemcitabine for the treatment of pancreatic cancer was approved by FDA in 2013. Accordingly, there have been a huge number of patent applications dealing with taxane anticancer agents in the last 5 years. Thus, it is a good time to review the progress in this area and find the next wave for new developments.. This review covers the patent literature from the year 2010 to early 2015 on various aspects of taxane-based chemotherapies and drug developments.. Three FDA-approved taxane anticancer drugs will continue to expand their therapeutic applications, especially through drug combinations and new formulations. Inspired by the success of abraxane, new nano-formulations are emerging. Highly potent new-generation taxanes will play a key role in the development of efficacious tumor-targeted drug delivery systems.

Topics: Animals; Antineoplastic Agents; Docetaxel; Drug Delivery Systems; Drug Design; Female; Humans; Male; Nanostructures; Neoplasms; Paclitaxel; Patents as Topic; Taxoids

Taxane-type anticancer drugs, including paclitaxel and its semi-synthetic derivatives docetaxel and cabazitaxel, are widely applied to chemotherapy of malignancy like breast cancer, ovarian cancer, non-small cell lung cancer and prostate cancer. However, their clinical applications are generally limited by scarce natural resources, various side effects and multidrug resistance. Therefore, it is significant to develop paclitaxel-mimics with simplified structure, fewer side effects and improved pharmaceutical properties. Based on our investigation on chemistry of paclitaxel, the current review summarized the most recent advances in the design, synthesis and biological activities of paclitaxel-mimics, which could be appealing to researchers in the field of medicinal chemistry and oncology. Meanwhile, smart design, interesting synthesis and potential bioactivities of these novel compounds may also provide valuable reference for the wider scientific communities.

Topics: Animals; Antineoplastic Agents, Phytogenic; Docetaxel; Drug Resistance, Multiple; Humans; Mice; Molecular Structure; Neoplasms; Paclitaxel; Taxoids

The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. Despite years of research, the optimal dosing regimen (weekly vs 3-weekly) and optimal dose is still controversial, as is the value of pharmacological personalization of taxane dosing.. This review provides an overview of the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamics and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most active and safe regimen (paclitaxel, docetaxel, nab-paclitaxel), the recommended initial dose (cabazitaxel) and pharmacological dosing individualization.. Taxanes share the characteristics of extensive hepatic metabolism and biliary excretion, the need for dose adaptation in patients with liver dysfunction, and substantial pharmacokinetic variability even after taking into account known covariates. Data from clinical studies suggest that optimal scheduling of the taxanes is dependent not only on the specific taxane compound, but also on the tumor type and line of treatment. Finally, treating oncologists should be aware of the substantial risk for drug-drug interactions that is a direct consequence of the complex hepatic metabolism of the taxanes.

Topics: Albumins; Animals; Antineoplastic Agents; Docetaxel; Dose-Response Relationship, Drug; Drug Interactions; Humans; Liver; Neoplasms; Paclitaxel; Taxoids

First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with docetaxel. In conclusion, the demonstrated activity of cabazitaxel in tumors with innate or acquired resistance to docetaxel, CNS tumors, and pediatric tumors made this agent a candidate for further clinical evaluation in a broader range of patient populations compared with first-generation taxanes.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Molecular Conformation; Neoplasms; Taxoids

Cabazitaxel is a new taxane characterized by convenient administration, a favorable pharmacokinetic and safety profile and a decreased propensity for P-glycoprotein (Pgp)-mediated drug resistance. In preclinical studies cabazitaxel inhibited cell growth in a wide range of human cancer cell lines, including tumor models expressing Pgp. Phase I clinical trials established that the cabazitaxel side effect profile is similar to that reported for taxanes, with neutropenia and neuropathy being the most commonly reported toxicities. Further clinical studies have revealed that cabazitaxel is clinically active in women with taxaneresistant metastatic breast cancer and in men with metastatic castration-resistant prostate cancer previously treated with docetaxel. The TROPIC phase III trial concluded that, compared to mitoxantrone/prednisone, the combination cabazitaxel/prednisone conferred a statistically significantly longer overall survival in patients after treatment with a docetaxel-containing regimen, providing the basis for its FDA approval in 2010.

Topics: Animals; Antineoplastic Agents; Female; Humans; Male; Neoplasms; Taxoids

Taxane-gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of three to six patients received cabazitaxel (15-20 mg/m) before (part 1a) or after (part 1b) gemcitabine (700-1000 mg/m) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n=12), five patients received 20 mg/m cabazitaxel plus 1000 mg/m gemcitabine (20/1000), five received 15/900, two received 15/700. In part 1b, all six patients received the lowest dose (700/15). At all doses, two or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n=4), grade 4 neutropenia (n=2), grade 4 thrombocytopenia (n=2), and grade 3 aspartate transaminase increase (n=1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade nonhematologic events were fatigue (66.7%), decreased appetite (50.0%), and diarrhea (44.4%). The most frequent grade 3-4 hematologic abnormalities were neutropenia (83.3%), leukopenia (77.8%), and lymphopenia (72.2%). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable partial responses were observed in three patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25% from single-agent doses, preclude further investigation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Taxoids

This study assessed the cardiovascular safety of cabazitaxel, based on thorough evaluation of QT and non-QT variables, and the relationship between pharmacokinetic and pharmacodynamic electrocardiographic (ECG) profiles and the occurrence of Grade ≥3 cardiovascular adverse events.. Patients with advanced solid tumors were treated with cabazitaxel 25 mg/m(2) every 3 weeks. Digital ECG recordings were obtained during Cycle 1 over 24 h after dosing. The primary end point was effect of cabazitaxel on QT interval corrected by the Fridericia formula (QTcF). Secondary end points were additional ECG parameters (QT, PR and QRS intervals, and heart rate), plasma pharmacokinetics of cabazitaxel and overall clinical safety.. The pharmacodynamic (ECG) population included 94 patients. In 63 patients with a full 24-h ECG evaluation, the maximum upper bound of 90 % confidence interval (CI) for mean QTcF change from baseline was 7.46 ms (mean 4.8 ms), occurring at 1 h 30 min post-infusion. The slope of QTcF change from baseline versus cabazitaxel concentration was slightly negative (-0.012 [95 % CI -0.017; -0.008], equivalent to a 1.2 ms decrease per 100 ng/mL increase in cabazitaxel concentration). For non-QT variables, no effect was noted. No Grade ≥3 cardiac adverse events were observed; Grade ≥3 hypotension and lymphocele occurred in two patients and one patient, respectively.. These results suggest that cabazitaxel has no clinically significant cardiovascular adverse effects in patients with advanced solid tumors.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart; Heart Rate; Humans; Male; Middle Aged; Neoplasms; Prospective Studies; Taxoids

Cabazitaxel is a second-generation taxane with in vivo activity against taxane-sensitive and -resistant tumor cell lines and tumor xenografts. Cabazitaxel/cisplatin have therapeutic synergism in tumor-bearing mice, providing a rationale for assessing this combination in patients with solid tumors.. The primary objectives of this study were to determine dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a cabazitaxel/cisplatin combined regimen (Part 1) and to assess antitumor activity at the MTD (Part 2). Safety and pharmacokinetics (PK) were also examined.. Twenty-five patients with advanced solid tumors were enrolled (10 in Part 1; 15 in Part 2). In Part 1, two dose levels were evaluated; the MTD for cabazitaxel/cisplatin (given Q3W) was 15/75 mg/m(2). DLTs occurring during Cycle 1 at the maximum administered dose (20/75 mg/m(2); acute renal failure and febrile neutropenia) and the MTD (febrile neutropenia and hypersensitivity despite pre-medication) were as expected for taxane/platinum combinations. For the 18 patients treated at the MTD, the most frequent possibly related non-hematologic treatment-emergent adverse events (Grade ≥ 3) were nausea (16.7%), fatigue, acute renal failure and decreased appetite (each 11.1%). Neutropenia was the most frequent treatment-emergent Grade ≥ 3 hematologic laboratory abnormality at the MTD (77.8%). The best overall response at the MTD was stable disease, observed in 66.7% of patients. PK results of the combination did not appear to differ from single-agent administration for each agent.. Combination treatment with cabazitaxel/cisplatin had a manageable safety profile; no PK interactions were evident. The recommended Phase II dose for this combination is cabazitaxel/cisplatin 15/75 mg/m(2) administered every 3 weeks. Antitumor activity findings suggest that further evaluation of this combination in disease-specific trials is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Response Evaluation Criteria in Solid Tumors; Taxoids

Cabazitaxel is primarily metabolized by CYP3A. This study evaluated the impact of moderate/strong CYP3A inhibitors [aprepitant (Study Part 2); ketoconazole (Study Part 3)] or strong CYP3A inducers [rifampin (Study Part 4)] on the pharmacokinetics of cabazitaxel.. Adult patients received IV cabazitaxel/cisplatin 15/75 mg/m(2) on Day 1 of 3-week cycles (5/75 mg/m(2) in Cycles 1 and 2 of Part 3 to allow a safety margin to the cabazitaxel MTD). Patients received repeated oral doses of aprepitant, ketoconazole or rifampin before/during Cycle 2. Cabazitaxel clearance was the primary endpoint; clearance and area under the plasma concentration-time curve (AUC) were normalized to body surface area and dose, respectively.. The PK population included 13 (Part 2), 23 (Part 3) and 21 patients (Part 4). Repeated aprepitant administration did not affect cabazitaxel clearance [geometric mean ratio (GMR) 0.98; 90 % confidence interval (CI) 0.80-1.19]. Repeated ketoconazole administration resulted in 20 % decrease in cabazitaxel clearance (GMR 0.80; 90 % CI 0.55-1.15), associated with 25 % increase in AUC (GMR 1.25; 90 % CI 0.86-1.81). Repeated rifampin administration resulted in 21 % increase in cabazitaxel clearance (GMR 1.21; 90 % CI 0.95-1.53), associated with 17 % decrease in AUC (GMR 0.83; 90 % CI 0.65-1.05). The GMR of AUC0-24 with rifampin administration was 1.09 (90 % CI 0.9-1.33), suggesting that rifampin had a low impact during the initial phases of cabazitaxel elimination. Safety findings were consistent with previous results.. Cabazitaxel pharmacokinetics are modified by drugs strongly affecting CYP3A. Co-administration of cabazitaxel with strong CYP3A inhibitors or inducers should be avoided.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Area Under Curve; Cisplatin; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inducers; Drug Interactions; Female; Humans; Ketoconazole; Male; Middle Aged; Morpholines; Neoplasms; Rifampin; Taxoids

Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives.. Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5-12 mg/m² doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose.. Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m², which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in C(max) and AUC(0-t) were dose proportional for the 6-12 mg/m² doses.. The MTD of weekly cabazitaxel was 12 mg/m² and the recommended weekly dose was 10 mg/m². The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens.. The study was registered with ClinicalTrials.gov as NCT01755390.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Combined Modality Therapy; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Taxoids; Treatment Outcome

Although the taxanes paclitaxel and docetaxel are among the most active agents for the treatment of a wide range of cancers, tumours often develop resistance to these treatments. Cabazitaxel is a novel taxane active in both preclinical models of chemotherapy-sensitive and -resistant human tumours and patients with advanced prostate cancer that progressed following docetaxel treatment.. To establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel.. Cabazitaxel was administered every 3 weeks to patients with advanced solid tumours. The design allowed intrapatient dose escalation. The primary objective was to determine the MTD. Secondary objectives were to describe the safety profile, establish an appropriate dose, determine the pharmacokinetic (PK) profile of cabazitaxel, and assess antitumour activity.. Twenty-one patients were recruited. The MTD was reached at 30 mg/m(2), at which three of five patients experienced haematologic DLTs during the first cycle. DLTs during subsequent cycles were mainly haematologic and reported at 25 and 30 mg/m(2) dosing levels. Nail disorders and severe alopecia were not reported, and neurotoxicity, fluid retention and hypersensitivity were mild and infrequent. Cabazitaxel demonstrated linear PK, a triphasic elimination profile, with a long half-life and high clearance. Of the 19 patients evaluable for response, one unconfirmed partial response and six occurrences of stable disease were reported.. The 25mg/m(2) dose of cabazitaxel was recommended for use in future clinical studies. In this study, cabazitaxel had an acceptable tolerability profile and activity in cervical, colorectal, endometrial and lung cancers.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Taxoids

To develop a population pharmacokinetic (PK) model for cabazitaxel in patients with advanced solid tumors and examine the influence of demographic and baseline parameters.. One hundred and seventy patients who received cabazitaxel (10-30 mg/m(2), 1-h IV infusion) every 7 or 21 days in five Phase I-III studies were analyzed by non-linear mixed-effect modeling (NONMEM VI). Model evaluation comprised non-parametric bootstrap and visual predictive checks.. Cabazitaxel PK was best described by a linear three-compartment model with: first-order elimination; interindividual variability on clearance (CL), central volume of distribution (V1), and all intercompartmental rate constants except K21; interoccasion variability in CL and V1; proportional residual error of 27.8%. Cabazitaxel CL was related to body surface area (BSA) and tumor type (breast cancer; finding confounded by study). Typical CL for a non-breast cancer patient with a BSA of 1.84 m(2) was 48.5 L/h, with V1 26.0 L, steady-state volume of distribution 4,870 L and alpha, beta, and gamma half-lives of 4.4 min, 1.6, and 95 h, respectively. Sex, height, weight, age, Caucasian race, renal/hepatic function, and cytochrome P450 inducer use did not significantly further explain the PK of cabazitaxel. Bootstrap and posterior predictive checks confirmed the adequacy of the model.. Cabazitaxel PK appears unaffected by most baseline patient factors, and the influence of BSA on CL is addressed in practice by BSA-dependent doses. This analysis suggests consistent cabazitaxel PK and exposure across most solid tumor types, although the potential influence of breast cancer on CL requires further confirmation.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Antineoplastic Agents, Phytogenic; Bayes Theorem; Body Surface Area; Cytochrome P-450 Enzyme System; Data Interpretation, Statistical; Drug Resistance, Neoplasm; Enzyme Induction; Female; Half-Life; Humans; In Situ Hybridization; Linear Models; Male; Middle Aged; Neoplasms; Nonlinear Dynamics; Racial Groups; Taxoids

To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity.. Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course.. Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses.. The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Neutropenia; Taxoids

The clinical success of anticancer therapy is usually limited by drug resistance and the metastatic dissemination of cancer cells. Mitochondria are essential generators of cellular energy and play a crucial role in sustaining cell survival and metastatic escape. Selective drug strategies targeting mitochondria are able to rewire mitochondrial metabolism and may provide an alternative paradigm to treat many aggressive cancers with high efficiency and low toxicity. Here, we present a pseudo-stealthy mitochondria-targeted pro-nanotaxane and test it against recurrent and metastatic tumor xenografts. The nanoparticle encapsulates a mitochondria-targetable pro-taxane agent, which can be converted into the chemically unmodified cabazitaxel drug, with further surface cloaking with a low-density lipophilic triphenylphosphonium cation. The resultant nanotaxane could be effectively taken up by cells and consequently specifically localized to the mitochondria. The

Topics: Animals; Cell Line, Tumor; Drug Delivery Systems; Humans; Mitochondria; Nanoparticles; Neoplasms; Organelle Biogenesis

Topics: A549 Cells; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; HeLa Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Paclitaxel; Polyesters; Polymers; Prodrugs; Taxoids

New strategies to fabricate nanomedicines with high translational capacity are urgently desired. Herein, a new class of self-assembled drug cocktails that addresses the multiple challenges of manufacturing clinically useful cancer nanomedicines was reported.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dasatinib; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; Mice; Nanomedicine; Neoplasms; Taxoids

Drug resistance remains a major challenge in achieving cures in cancer patients. Cabazitaxel has shown the ability to overcome drug resistance induced by paclitaxel and docetaxel; however, substantially high toxicity has been observed in patients receiving this agent, which compromises its efficacy. We have previously demonstrated that a polymeric platform (termed cabazitaxel-NPs) encapsulating the oligolactide-cabazitaxel conjugate exhibits desired antitumor efficacy and improved in vivo tolerability. However, we found that upon cabazitaxel treatment, cancer cells adapted to activate Akt signaling, which potentially discounts the drug efficacy. We therefore hypothesized that combing cabazitaxel nanotherapeutics with a pan-Akt inhibitor MK-2206 would synergistically sensitize the resistant cancer. In this study, we confirmed that nanoparticle formulation reduced the systemic toxicity, with higher tolerance than solution-based free cabazitaxel agent in animals. Interestingly, the activation of Akt signaling in the resistant cancer was reversed by the addition of MK-2206. In particular, the collaboration of these two ingredients was demonstrated to maximize the efficacy in vitro and in a xenograft model bearing paclitaxel-resistant tumors. Mechanistically, Akt inhibition increased the microtubule-stabilizing effect of cabazitaxel nanomedicine. Collectively, this report introduced a binary platform composed of cytotoxic nanotherapeutics and inhibitors with certain targets to combat multidrug resistance, and such a combined regimen has the potential for the clinical treatment of patients with resistant cancer.

Topics: Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Nanomedicine; Neoplasms; Proto-Oncogene Proteins c-akt; Taxoids

The present study investigated the feasibility of improving the tumor‑targeting efficacy and decreasing the toxicity of liposomal cabazitaxel (Cab) with aptamer modification. The process involved preparing aptamer (TLS1c)‑modified liposomes and studying the behavior of the liposomes in vitro and in vivo. TLS1c as an aptamer, which has high specificity for BNL 1ME A.7R.1 (MEAR) cells, was conjugated with Cab liposomes (Cab/lipo) to enhance MEAR tumor tissue targeting. Confocal laser scanning microscopy and flow cytometry analyses demonstrated that the fluorescence of the liposomes modified with the aptamer was notably stronger compared with that of the unmodified liposomes. Furthermore, the biodistribution data of the modified liposomes tested in tumor‑bearing mice revealed high specificity of biotinylated TLS1c‑modified Cab/lipo (BioTL‑Cab/lipo) for tumor tissues. Furthermore, the modified liposomes demonstrated decreased cytotoxicity and simultaneously retained potent inhibition against tumor growth. It is likely that the specific binding of the aptamer (TLS1c) to the targeted cells (MEAR) facilitates the binding of the liposomes to the targeted cells. Therefore, BioTL‑Cab/lipo may be considered as a promising delivery system to improve cell targeting and reduce drug toxicity in the treatment of cancer.

Topics: Animals; Antineoplastic Agents; Aptamers, Nucleotide; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Hep G2 Cells; Humans; Liposomes; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Taxoids; Tissue Distribution

We previously developed cabazitaxel (CTX)-loaded human serum albumin nanoparticles (NPs-CTX) via a self-assembly method, and these NPs showed efficacy in prostate cancer therapy. Many studies have shown that the levels of folic acid (FA) receptor on the surface of various tumor cells are high. Therefore, FA-modified NPs-CTX may have enhanced antitumor effects compared with unmodified NPs-CTX.. NPs-CTX were first prepared via self-assembly, and FA was conjugated on the surface of NPs-CTX through the -NH. Both NPs-CTX and FA-NPs-CTX exhibited good stability and morphology. Drug release from the NPs was not affected by FA conjugation. Compared with CTX dissolved in a mixture of Tween 80 and 13% ethanol (w/w) at a ratio of 1:4 (v/v) (Tween-CTX), the two nanoformulations had lower lytic activity against normal red blood cells. However, FA-NPs-CTX showed greater inhibition of tumor cells with overexpressed FR, compared with NPs-CTX, in the cytotoxicity experiments. Moreover, the cellular uptake of FA-NPs-CTX was enhanced through FR-mediated endocytosis in HeLa cells in vitro and HeLa xenograft tumors in vivo. Although Tween-CTX exhibited tumor growth inhibition similar to FA-NPs-CTX in vivo, this inhibition also caused adverse side effects; the median lethal dose (LD50) of Tween-CTX to mice was 5.68 mg/kg, while FA-NPs-CTX-treated mice survived at doses exceeding 400 mg/kg.. The results showed that FA-NPs-CTX caused inhibition of tumor growth in a manner similar to that of Tween-CTX; however, the safety and tolerability of CTX were greatly improved by FA conjugation compared with those of Tween-CTX. In summary, FA-NPs-CTX have great potential in CTX delivery, and this formulation is a promising candidate for the treatment of cancers with high FR levels.

Topics: A549 Cells; Animals; Cell Death; Cell Line, Tumor; Drug Delivery Systems; Drug Liberation; Endocytosis; Female; Folate Receptor 2; Folic Acid; HeLa Cells; Hemolysis; Humans; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Serum Albumin, Human; Taxoids; Tissue Distribution; Xenograft Model Antitumor Assays

In this work, a nano-in-micro carrier was constructed by loading polymer-lipid hybrid nanoparticles (NPs) into porous and hollow yeast cell wall microparticles (YPs) for macrophage-targeted oral delivery of cabazitaxel (CTX). The YPs, primarily composed of natural β-1,3-d-glucan, can be recognized by the apical membrane receptor, dectin-1, which has a high expression on macrophages and intestinal M cells. By combining electrostatic force-driven self-deposition with solvent hydration/lyophilization methods, the positively charged NPs loaded with CTX or fluorescence probes were efficiently packaged into YPs, as verified by scanning electron microscope (SEM), atomic force mircoscope (AFM), and confocal laser scanning microscopy (CLSM) images. NP-loaded YPs (NYPs) showed a slower in vitro drug release and higher drug stability compared with NPs in a simulated gastrointestinal environment. Biodistribution experiments confirmed a widespread distribution and extended retention time of NYPs in the intestinal tract after oral administration. Importantly, a large amount of NYPs were primarily accumulated and transported in the intestinal Peyer's patches as visualized in distribution and absorption site studies, implying that NYPs were mainly absorbed through the lymphatic pathway. In vitro cell evaluation further demonstrated that NYPs were rapidly and efficiently taken up by macrophages via receptor dectin-1-mediated endocytosis using a mouse macrophage RAW 264.7 cell line. As expected, in the study of in vivo pharmacokinetics, the oral bioavailability of CTX was improved to 32.1% when loaded in NYPs, which is approximately 5.7 times higher than that of the CTX solution, indicating the NYPs are efficient for oral targeted delivery. Hence, this nano-in-micro carrier is believed to become a hopeful alternative strategy for increasing the oral absorption of small molecule drugs.

Topics: Administration, Oral; Animals; Antineoplastic Agents; beta-Glucans; Biological Availability; Cell Wall; Delayed-Action Preparations; Drug Carriers; Drug Liberation; Drug Screening Assays, Antitumor; Intestinal Absorption; Macrophages; Male; Mice; Models, Animal; Nanoparticles; Neoplasms; Particle Size; Proteoglycans; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Saccharomyces cerevisiae; Taxoids; Tissue Distribution

Topics: Administration, Intravenous; Animals; Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Drug Carriers; Drug Stability; Female; Guinea Pigs; Humans; Lethal Dose 50; Male; Mice; Mice, Nude; Microspheres; Neoplasms; Particle Size; Phosphatidylethanolamines; Polyethylene Glycols; Rats; Taxoids; Xenograft Model Antitumor Assays

The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these cabazitaxel derivatives, docosahexaenoic acid-derived compound

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Delivery Systems; Drug-Related Side Effects and Adverse Reactions; Humans; Materials Testing; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Nanomedicine; Neoplasms; Polymerization; Polymers; Prodrugs; Rats; Rats, Sprague-Dawley; Taxoids; Xenograft Model Antitumor Assays

A novel formulation for cabazitaxel loaded HSA nanoparticle (Cbz-NPs) with non-crosslinking agent participation was reported in this study.. A simple method through unfolding of HSA self-assembling nanoparticle for cabazitaxel (Cbz) overcomes the drawbacks of Cbz with high toxicity, poor solubility and low tissue specificity, and avoids side effects of polysorbate 80 which is commonly used for dissolving Cbz.. The optimum condition was obtained by Response surface methodology (RSM). The NPs were analyzed by differential scanning calorimetry (DSC) and drug release in vitro was also determined. Furthermore, cytotoxicity, cellular uptake were assessed.. The experimental encapsulation efficacy (EE) is 52.95%, which is close to the predicted value of 62.44%, indicating the correct prediction, and the nanoscale-sized particles enhanced permeability and retention (EPR) effect. Differential scanning calorimetry (DSC) demonstrates an amorphous state of cabazitaxel-NPs, and a sustained release was found in vitro drug release. Human prostate cancer lines PC3 and Human Lung Cancer line A549 were employed for cytotoxicity study by the MTT test. Single solvent with polysorbate 80 showed serious cytotoxicity with the cell viability of only 80% while no toxicity was found in drug-free nanoparticles. Fluorescence intensity of FITC-HSA nanoparticles encapsulating Cbz increased with the incubation time. The cellular localizatiton of cabazitaxel-NPs was observed by confocal microscopy.. Cbz-NPs may be considered as a viable opportunity for anticancer drug delivery.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Carriers; Humans; Nanoparticles; Neoplasms; Particle Size; Serum Albumin; Taxoids

Supramolecular constructed pseudo block copolymer micelles based on β-cyclodextrin terminated 4 and 7 armed star poly(N-vinylpyrrolidone) and adamantane terminated linear poly(ε-caprolactone) were prepared. The size, morphology, stability and protein adsorption were experimentally examined. The micelles with 7 armed PVP chains as the micellar exterior showed the lowest amount of protein adsorption and the best stability in media. When cabazitaxel, a new taxane, was loaded into the micelles, 14.4% drug loading content and 85% encapsulation efficacy were achieved. In vitro cytotoxicity studies demonstrated that the cabazitaxel-loaded micelles show significant cytotoxicity against drug-resistant A2780/T cell lines. Biodistribution studies showed that the micelles can almost double the content of cargo in tumor sites compared with the free cargo. In vivo antitumor activity examinations indicated that cabazitaxel-loaded micelles show superior antitumor activity over free paclitaxel and free cabazitaxel.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Survival; Drug Carriers; Humans; Kaplan-Meier Estimate; Mice; Micelles; Microscopy, Confocal; Neoplasms; Polyesters; Polymers; Spectroscopy, Fourier Transform Infrared; Taxoids; Tissue Distribution; Transplantation, Heterologous

Topics: Antineoplastic Agents; Docetaxel; Humans; Neoplasms; Paclitaxel; Taxoids

Taxanes are important chemotherapeutic agents with proven efficacy in human cancers, but their use is limited by resistance development. We report here the preclinical characteristics of cabazitaxel (XRP6258), a semisynthetic taxane developed to overcome taxane resistance.. Cabazitaxel effects on purified tubulin and on taxane-sensitive or chemotherapy-resistant tumor cells were evaluated in vitro. Antitumor activity and pharmacokinetics of intravenously administered cabazitaxel were assessed in tumor-bearing mice.. In vitro, cabazitaxel stabilized microtubules as effectively as docetaxel but was 10-fold more potent than docetaxel in chemotherapy-resistant tumor cells (IC50 ranges: cabazitaxel, 0.013-0.414 μmol/L; docetaxel, 0.17-4.01 μmol/L). The active concentrations of cabazitaxel in these cell lines were achieved easily and maintained for up to 96 hours in the tumors of mice bearing MA16/C tumors treated with cabazitaxel at 40 mg/kg. Cabazitaxel exhibited antitumor efficacy in a broad spectrum of murine and human tumors (melanoma B16, colon C51, C38, HCT 116, and HT-29, mammary MA17/A and MA16/C, pancreas P03 and MIA PaCa-2, prostate DU 145, lung A549 and NCI-H460, gastric N87, head and neck SR475, and kidney Caki-1). Of particular note, cabazitaxel was active in tumors poorly sensitive or innately resistant to docetaxel (Lewis lung, pancreas P02, colon HCT-8, gastric GXF-209, mammary UISO BCA-1) or with acquired docetaxel resistance (melanoma B16/TXT).. Cabazitaxel is as active as docetaxel in docetaxel-sensitive tumor models but is more potent than docetaxel in tumor models with innate or acquired resistance to taxanes and other chemotherapies. These studies were the basis for subsequent clinical evaluation.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Humans; Melanoma, Experimental; Mice; Microtubule Proteins; Neoplasms; Protein Stability; Taxoids

While first-generation taxanes are valuable treatment options for many solid tumors, they are limited by an inability to cross the blood-brain barrier (BBB) and by limited efficacy in pediatric patients. Following promising preclinical data for the next-generation taxane cabazitaxel, including activity in tumor models fully sensitive, poorly sensitive or insensitive to docetaxel, and its ability to cross the BBB, further preclinical studies of cabazitaxel relevant to these two clinical indications were performed.. Cabazitaxel brain distribution was assessed in mice, rats and dogs. Cabazitaxel antitumor activity was assessed in mice bearing intracranial human glioblastoma (SF295; U251) xenografts, and subcutaneous cell line-derived human pediatric sarcoma (rhabdomyosarcoma RH-30; Ewing's sarcoma TC-71 and SK-ES-1) or patient-derived pediatric sarcoma (osteosarcoma DM77 and DM113; Ewing's sarcoma DM101) xenografts. The activity of cabazitaxel-cisplatin combination was evaluated in BALB/C mice bearing the syngeneic murine colon adenocarcinoma, C51.. Cabazitaxel penetrated rapidly in the brain, with a similar brain-blood radioactivity exposure relationship across different animal species. In intracranial human glioblastoma models, cabazitaxel demonstrated superior activity to docetaxel both at early (before BBB disruption) and at advanced stages, consistent with enhanced brain penetration. Compared with similar dose levels of docetaxel, cabazitaxel induced significantly greater tumor growth inhibition across six pediatric tumor models and more tumor regressions in five of the six models. Therapeutic synergism was observed between cisplatin and cabazitaxel, regardless of administration sequence.. These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Brain; Brain Neoplasms; Child, Preschool; Cisplatin; Dogs; Drug Synergism; Female; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasm Staging; Neoplasms; Neoplasms, Experimental; Rats; Rats, Sprague-Dawley; Species Specificity; Taxoids; Tissue Distribution; Xenograft Model Antitumor Assays; Young Adult