ABSTRACT
BACKGROUND: The intravesical instillation of the paclitaxel-hyaluronan conjugate ONCOFID-P-B™ in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder carcinoma in situ (CIS; NCT04798703 phase I study), induced 75 and 40% of complete response (CR) after 12 weeks of intensive phase and 12 months of maintenance phase, respectively. The aim of this study was to provide a detailed description of the tumor microenvironment (TME) of ONCOFID-P-B™-treated BCG-unresponsive bladder CIS patients enrolled in the NCT04798703 phase I study, in order to identify predictive biomarkers of response. METHODS: The composition and spatial interactions of tumor-infiltrating immune cells and the expression of the most relevant hyaluronic acid (HA) receptors on cancer cells, were analyzed in biopsies from the 20 patients enrolled in the NCT04798703 phase I study collected before starting ONCOFID-P-B™ therapy (baseline), and after the intensive and the maintenance phases. Clinical data were correlated with cell densities, cell distribution and cell interactions. Associations between immune populations or HA receptors expression and outcome were analyzed using univariate Cox regression and log-rank analysis. RESULTS: In baseline biopsies, patients achieving CR after the intensive phase had a lower density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL), but also fewer interactions between CTL and macrophages or T-regulatory cells, as compared to non-responders (NR). NR expressed higher levels of the HA receptors CD44v6, ICAM-1 and RHAMM. The intra-tumoral macrophage density was positively correlated with the expression of the pro-metastatic and aggressive variant CD44v6, and the combined score of intra-tumoral macrophage density and CD44v6 expression had an AUC of 0.85 (95% CI 0.68-1.00) for patient response prediction. CONCLUSIONS: The clinical response to ONCOFID-P-B™ in bladder CIS likely relies on several components of the TME, and the combined evaluation of intra-tumoral macrophages density and CD44v6 expression is a potentially new predictive biomarker for patient response. Overall, our data allow to advance a potential rationale for combinatorial treatments targeting the immune infiltrate such as immune checkpoint inhibitors, to make bladder CIS more responsive to ONCOFID-P-B™ treatment.
Subject(s)
Carcinoma in Situ , Hyaluronic Acid/analogs & derivatives , Paclitaxel/analogs & derivatives , Urinary Bladder Neoplasms , Humans , Urinary Bladder/pathology , Hyaluronic Acid/therapeutic use , BCG Vaccine/therapeutic use , Tumor Microenvironment , Paclitaxel/therapeutic use , Urinary Bladder Neoplasms/pathology , Carcinoma in Situ/drug therapy , Carcinoma in Situ/pathology , Adjuvants, Immunologic/therapeutic use , Neoplasm Recurrence, Local/drug therapyABSTRACT
Background: NK105 is a paclitaxel (PTX)-incorporating "core-shell-type" polymeric micellar nanoparticle formulation composed of block copolymers (polyethylene glycol and a polyamino acid). The efficacy and safety of NK105 and paclitaxel in advanced or recurrent breast cancer have never been compared at equivalent dose levels. Patients and Methods: Patients were randomly assigned to either NK105 or PTX in a 1:1 ratio. The study drug was administered on Day 1, 8, and 15 of a 28-day cycle with 80 mg/m2. The primary endpoint was overall response rate (ORR), secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events. Results: A total of 123 patients (NK105, n=62; PTX, n=61) received one of the two drugs. There was no significant difference in ORR, the median PFS, or OS (NK105 group: 41.9%, 9.1, and 27.5 months, respectively; PTX group: 45.9%, 7.8, and 32.4 months, respectively). Neutropenia occurred more frequently in the NK105 group, but most patients did not require granulocyte-colony stimulating factor or dose-reduction. The median time to onset of peripheral sensory neuropathy (PSN) in the NK105 group was significantly longer than that in the PTX group (p=0.001), and PSN (≥ grade 3) was not observed in the NK105 group. Conclusion: Weekly NK105 administration was well-tolerated. Efficacy was similar in both groups. The PSN profile was better in the NK105 group.
Subject(s)
Breast Neoplasms , Peripheral Nervous System Diseases , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms/drug therapy , Colony-Stimulating Factors/therapeutic use , Female , Humans , Paclitaxel/analogs & derivatives , Paclitaxel/therapeutic use , Peripheral Nervous System Diseases/chemically induced , Polyethylene Glycols/therapeutic use , PolymersABSTRACT
Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Bile Acids and Salts/chemistry , Bile Acids and Salts/pharmacology , Paclitaxel/chemistry , Paclitaxel/pharmacology , Animals , Antineoplastic Agents, Phytogenic/chemical synthesis , Apoptosis/drug effects , Bile Acids and Salts/chemical synthesis , Cell Line , Cell Survival/drug effects , Colonic Neoplasms/drug therapy , Deoxycholic Acid/analogs & derivatives , Deoxycholic Acid/chemical synthesis , Deoxycholic Acid/chemistry , Deoxycholic Acid/pharmacology , Humans , Leukemia/drug therapy , Mice , Paclitaxel/analogs & derivatives , Paclitaxel/chemical synthesisABSTRACT
Breast cancer is one of the most common types of cancer in female patients with high morbidity and mortality. Multi-drug chemotherapy has significant advantages in the treatment of malignant tumors, especially in reducing drug toxicity, increasing drug sensitivity and reducing drug resistance. The objective of this research is to fabricate lipid nanoemulsions (LNs) for the co-delivery of PTX and docosahexaenoic acid (DHA) with folic acid (FA) decorating (PTX/DHA-FA-LNs), and investigate the anti-tumor activity of the PTX/DHA-FA-LNs against breast cancer both in vitro and in vivo. PTX/DHA-FA-LNs showed a steady release of PTX and DHA from the drug delivery system (DDS) without any burst effect. Furthermore, the PTX/DHA-FA-LNs exhibited a dose-dependent cytotoxicity and a higher rate of apoptosis as compared with the other groups in MCF-7 cells. The cellular uptake study revealed that this LNs were more readily uptaken by MCF-7 cells and M2 macrophages in vitro. Additionally, the targeted effect of PTX/DHA-FA-LNs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. The anti-tumor efficiency results showed that PTX/DHA-FA-LNs significant inhibited tumor volume growth, prolonged survival time, and reduced toxicity when compared with the other groups. These results indicated that DHA increases the sensitivity of tumor cells and tumor-associated macrophages (ATM2) to PTX, and synergistic effects of folate modification in breast cancer treatment, thus PTX/DHA-FA-LNs may be a promising nanocarrier for breast cancer treatment.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Drug Carriers/chemistry , Nanoparticles/chemistry , Paclitaxel/analogs & derivatives , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Liberation , Emulsions/chemistry , Female , Folic Acid/chemistry , Humans , MCF-7 Cells , Mice , Mice, Inbred BALB C , Mice, Nude , Paclitaxel/administration & dosage , Paclitaxel/pharmacology , RAW 264.7 Cells , Tumor-Associated Macrophages/drug effects , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: This study reports the safety and efficacy of Oncofid-P-B, a novel compound under development by Fidia Farmaceutici S.p.A. with specific binding to CD44 receptor, in patients with CIS unresponsive or intolerant to BCG. MATERIALS AND METHODS: This is a phase 1 open-label, single arm, multicenter European study to assess safety, tolerability and efficacy of Oncofid-P-B administered in 20 patients with CIS ± Ta-T1, unresponsive or intolerant to BCG, unwilling or unfit for cystectomy. Oncofid-P-B was administered by intravesical instillation for 12 consecutive weeks (intensive phase) followed, in CR patients, by 12 monthly instillations (maintenance phase). The primary objective was the overall safety profile. Secondary objectives included: i) any evidence of antitumor activity, ii) patient's compliance, iii) systemic absorption. The CR was defined as a negative cystoscopy, negative biopsy of the urothelium and negative cytology. RESULTS: At the end of the intensive phase, 15 of the 20 enrolled patients (75%), achieved the CR. Patients still in CR after 3, 6, 9 and 12 months of maintenance phase were 13 (65%), 12 (60%), 9 (45%) and 8 (40%), respectively. Only seven (5 mild and 2 moderate) drug-related AEs were reported in three patients. No drug related serious AEs and no drug related withdrawals have been reported. In all plasma samples, the drug concentratiosn was below the LLOQ (1ng/ml). CONCLUSIONS: Oncofid-P-B is very safe, well tolerated and highly effective (75% CR) when administered weekly for up to 12 consecutive weeks (75% CR), with 40% CR still after 15 months from treatment start.
Subject(s)
Carcinoma in Situ/drug therapy , Hyaluronic Acid/analogs & derivatives , Paclitaxel/analogs & derivatives , Urinary Bladder Neoplasms/drug therapy , Adjuvants, Immunologic , Aged , Aged, 80 and over , BCG Vaccine , Europe , Female , Humans , Hyaluronic Acid/adverse effects , Hyaluronic Acid/therapeutic use , Male , Middle Aged , Paclitaxel/adverse effects , Paclitaxel/therapeutic use , Prospective Studies , Time Factors , Treatment OutcomeABSTRACT
Drug-polymer conjugates that can self-assemble into nanoparticles are promising drug delivery systems that improve the drug bioavailability and allow their controlled release. However, despite the possibility of reaching high drug loadings, the efficiency of the drug release, mediated by cleavage of the drug-polymer linker, is a key parameter to obtain significant anticancer activity. To overcome the limitations of experimental characterizations and to gain a better understanding of such systems, we conducted a coarse-grained molecular dynamics simulation study on four representative drug-polymer conjugates obtained by the "drug-initiated" method and studied their supramolecular organization upon self-assembly. The prodrugs were composed of either a gemcitabine or a paclitaxel anticancer drug, either a propanoate or a diglycolate linker, and a polyisoprene chain. Our simulations gave crucial information concerning the spatial organization of the different components (e.g., drug, linker, polymer, etc.) into the nanoparticles and revealed that the linkers are not fully accessible to the solvent. Notably, some cleavage sites were either poorly hydrated or partially solvated. These observations might account for the low efficiency of drug release from the nanoparticles, particularly when the linker is too short and/or not hydrophilic/solvated enough. We believe that our theoretical study could be adapted to other types of polymer prodrugs and could guide the design of new polymer prodrug nanoparticles with improved drug release efficiency.
Subject(s)
Deoxycytidine/analogs & derivatives , Drug Carriers/chemistry , Nanoparticles/chemistry , Paclitaxel/analogs & derivatives , Polymers/chemistry , Prodrugs/chemistry , Deoxycytidine/chemistry , Drug Liberation , Hydrophobic and Hydrophilic Interactions , Molecular Dynamics Simulation , GemcitabineABSTRACT
Whether alterations in the microtubule cytoskeleton affect the ability of endothelial cells (ECs) to sprout and form branching networks of tubes was investigated in this study. Bioassays of human EC tubulogenesis, where both sprouting behavior and lumen formation can be rigorously evaluated, were used to demonstrate that addition of the microtubule-stabilizing drugs, paclitaxel, docetaxel, ixabepilone, and epothilone B, completely interferes with EC tip cells and sprouting behavior, while allowing for EC lumen formation. In bioassays mimicking vasculogenesis using single or aggregated ECs, these drugs induce ring-like lumens from single cells or cyst-like spherical lumens from multicellular aggregates with no evidence of EC sprouting behavior. Remarkably, treatment of these cultures with a low dose of the microtubule-destabilizing drug, vinblastine, led to an identical result, with complete blockade of EC sprouting, but allowing for EC lumen formation. Administration of paclitaxel in vivo markedly interfered with angiogenic sprouting behavior in developing mouse retina, providing corroboration. These findings reveal novel biological activities for pharmacologic agents that are widely utilized in multidrug chemotherapeutic regimens for the treatment of human malignant cancers. Overall, this work demonstrates that manipulation of microtubule stability selectively interferes with the ability of ECs to sprout, a necessary step to initiate and form branched capillary tube networks.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Neovascularization, Pathologic/drug therapy , Paclitaxel/pharmacology , Animals , Blood Vessels/drug effects , Blood Vessels/growth & development , Cells, Cultured , Docetaxel/pharmacology , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/physiology , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Endothelium, Vascular/growth & development , Epothilones/pharmacology , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/physiology , Humans , Mice , Mice, Inbred C57BL , Morphogenesis/drug effects , Neovascularization, Pathologic/pathology , Neovascularization, Physiologic/drug effects , Paclitaxel/analogs & derivativesABSTRACT
The current clinical performance of chemotherapy is far from satisfactory, greatly limited by insufficient delivery efficacy and serious systemic side effects. Dimeric prodrug systems are emerging as valuable strategies for boosting the antitumor outcome. Here, dimeric paclitaxel prodrugs were synthesized with different bridged linkers, and the formed prodrug nanoparticles possessed excellent colloidal stability and ultrahigh drug content. The diselenide bond containing paclitaxel prodrugs could respond to a redox-heterogeneous intracellular microenvironment for on-demand drug release and subsequently show a selective cytotoxicity toward tumor cells against normal cells. Furthermore, the optimal carrier materials were screened out according to their contribution on stability, endocytosis, cytotoxicity, biodistribution, and antitumor efficacy. Compared with DSPE-PEG, human serum albumin, and Fe-tannic acid-based complex, F127 anchored dimeric paclitaxel nanoformulations exhibited preferential tumor accumulation and potent anticancer effect. Our present work provides deep insight into the development of advanced nanoformulations with comprehensive advantages for enhancing cancer therapy.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Disulfides/therapeutic use , Nanoparticles/therapeutic use , Neoplasms/drug therapy , Paclitaxel/therapeutic use , Prodrugs/therapeutic use , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacokinetics , Cell Line, Tumor , Cell Proliferation/drug effects , Disulfides/chemistry , Disulfides/pharmacokinetics , Drug Liberation , Drug Therapy , Female , Humans , Mice , Mice, Inbred BALB C , NIH 3T3 Cells , Nanoparticles/chemistry , Neoplasms/pathology , Oxidation-Reduction , Paclitaxel/analogs & derivatives , Paclitaxel/pharmacokinetics , Prodrugs/chemistry , Prodrugs/pharmacokineticsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima (Roxb.) Wight et Arn is a medicinal plant mainly distributed in southwest China. It is used in folk medicine for the treatment of tumors and is synergistic with chemotherapies. In our previous study, 11α-O-2-methybutyryl-12ß-O-tigloyl-tenacigenin B (MT2), a main steroid aglycone isolated from the total aglycones of M. tenacissima, significantly enhanced the in vivo antitumor effect of paclitaxel in mice bearing human tumor xenografts, showing its potential as a chemosensitizer. However, the pharmacokinetic characteristics, plasma protein binding rate, and metabolic profile of MT2 remain unclear. AIM OF THE STUDY: To elucidate the pharmacokinetic characteristics, plasma protein binding rate, and metabolic profile of MT2 in rats. MATERIALS AND METHODS: MT2 in rat plasma and phosphate-buffered saline was quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method, while the MT2 metabolites in rat liver microsomes were analyzed using UPLC-triple time-of-flight MS/MS. RESULTS: For intravenously administered MT2, the maximum plasma concentration and the area under the plasma concentration-time curve indicated dose dependency, while the elimination half-life time, the mean residence time, apparent volume of distribution and total apparent clearance values remained relatively unchanged in both the 5 mg/kg and 10 mg/kg groups. For orally administered MT2, the bioavailability was 1.08-1.11%. In rat plasma, MT2 exhibited a protein binding rate of 93.84-94.96%. In rat liver microsomes, MT2 was metabolized by oxidation alone or in combination with demethylation, and five MT2 metabolites were identified. CONCLUSION: MT2 has low oral bioavailability and a high plasma protein binding rate in rats. After administration, MT2 is transformed into oxidative metabolites in the liver. To achieve a high blood concentration of MT2, it should be administered intravenously. These findings would serve as a reference for further MT2-based pharmacological study and drug development.
Subject(s)
Biological Products/pharmacokinetics , Blood Proteins/metabolism , Marsdenia/chemistry , Plant Extracts/pharmacokinetics , Administration, Oral , Adsorption , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Biological Availability , Biological Products/metabolism , Blood Proteins/chemistry , Chromatography, Liquid , Drugs, Chinese Herbal , Half-Life , Injections, Intravenous , Male , Microsomes, Liver/metabolism , Molecular Structure , Paclitaxel/analogs & derivatives , Paclitaxel/chemistry , Phytotherapy , Plant Extracts/chemistry , Rats , Rats, Sprague-Dawley , Tandem Mass SpectrometryABSTRACT
The C-22,23-epoxy taccalonolides are microtubule stabilizers that bind covalently to ß-tubulin with a high degree of specificity. We semisynthesized and performed biochemical and cellular evaluations on 20 taccalonolide analogues designed to improve target engagement. Most notably, modification of C-6 on the taccalonolide backbone with the C-13 N-acyl-ß-phenylisoserine side chain of paclitaxel provided compounds with 10-fold improved potency for biochemical tubulin polymerization as compared to that of the unmodified epoxy taccalonolide AJ. Covalent docking demonstrated that the C-13 paclitaxel side chain occupied a binding pocket adjacent to the core taccalonolide pocket near the M-loop of ß-tubulin. Although paclitaxel-taccalonolide hybrids demonstrated improved in vitro biochemical potency, they retained features of the taccalonolide chemotype, including a lag in tubulin polymerization and high degree of cellular persistence after drug washout associated with covalent binding. Together, these data demonstrate that C-6 modifications can improve the target engagement of this covalent class of microtubule drugs without substantively changing their mechanism of action.
Subject(s)
Paclitaxel/analogs & derivatives , Steroids/pharmacology , Tubulin Modulators/pharmacology , HeLa Cells , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , TubulinABSTRACT
Background and Introduction: Peripheral neuropathy is one of the most common dose-limiting side effects of solvent-based paclitaxel. Paclitaxel poliglumex (PPX) and NK105 were developed to overcome the paclitaxel induced peripheral neuropathy. However, the incidence of peripheral neuropathy induced by PPX and NK105 was reported higher than solvent-based paclitaxel, but evidence remains inconsistent. METHODS: The article was reported in accordance with PRISMA Guidelines (Registration number: CRD42021245313). We conducted a meta-analysis to compare the incidence and severity of peripheral neuropathy between solvent-based paclitaxel, PPX and NK105 mono-chemotherapy. RESULTS: Results revealed that no significant difference exists between the incidence of all grade peripheral neuropathy among the solvent-based paclitaxel, PPX and NK105 treated groups. While, the incidence of high grade peripheral neuropathy induced by NK105 was lower than two other groups. Moreover, the overall survival was not improved in PPX compared with other groups. However, NK105 demonstrated significant longer overall survival in patients with cancer. CONCLUSION: Current evidence suggests more attention should be paid to the paclitaxel poliglumex re-formulation.
Subject(s)
Antineoplastic Agents, Phytogenic , Peripheral Nervous System Diseases , Antineoplastic Agents, Phytogenic/adverse effects , Humans , Paclitaxel/adverse effects , Paclitaxel/analogs & derivatives , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/drug therapy , Polyglutamic Acid/analogs & derivatives , SolventsABSTRACT
Breast cancer is one of the most prevalent and reoccurring cancers and the second most common reason of death in women. Despite advancements in therapeutic strategies for breast cancer, early tumor recurrence and metastasis in patients indicate resistance to chemotherapeutic medicines, such as paclitaxel due to the abnormal expression of ER and EGF2 in breast cancer cells. Therefore, the development of alternatives to paclitaxel is urgently needed to overcome challenges involving drug resistance. An increasing number of studies has revealed miRNAs as novel natural alternative substances that play a crucial role in regulating several physiological processes and have a close, adverse association with several diseases, including breast cancer. Due to the therapeutic potential of miRNA and paclitaxel in cancer research, the current review focuses on the differential roles of various miRNAs in breast cancer development and treatment. miRNA delivery to a specific target site, the development of paclitaxel and miRNA formulations, and nanotechnological strategies for the delivery of nanopaclitaxel in the management of breast cancer are discussed. These strategies involve improving the cellular uptake and bioavailability and reducing the toxicity of free paclitaxel to achieve accumulation tumor site. Furthermore, a molecular docking study was performed to ascertain the enhanced anticancer activity of the nanoformulation of ANG1005 and Abraxane. An in silico analysis revealed that ANG1005 and Abraxane nanoformulations have superior and significantly enhanced interactions with the proteins α-tubulin and Bcl-2. Therefore, ANG1005 and Abraxane may be more suitable in the therapeutic management of breast cancer than the existing free paclitaxel. miRNAs can revert abnormal gene expression to normalcy; since miRNAs serve as tumor suppressors. Therefore, restoration of particular miRNAs levels as a replacement therapy may be an effective endocrine potential strategy for treating ER positive/ negative breast cancers.
Subject(s)
Breast Neoplasms/drug therapy , Drug Delivery Systems , MicroRNAs/genetics , Nanoparticles/administration & dosage , Nanotechnology/methods , Paclitaxel/analogs & derivatives , Peptides/administration & dosage , Receptors, Estrogen/metabolism , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/chemistry , Breast Neoplasms/pathology , Computer Simulation , Disease Management , Drug Resistance, Neoplasm , Female , Gene Expression Regulation, Neoplastic , Humans , Molecular Docking Simulation , Nanoparticles/chemistry , Paclitaxel/administration & dosage , Paclitaxel/chemistry , Peptides/chemistryABSTRACT
It is known that 7-epitaxol has much stronger cytotoxicity than taxol does. However, the content of 7-epitaxol in yew is much less than taxol, which makes it more costly to obtain. We describe here a method to effectively convert taxol to 7-epitaxol. The key condition for reaction needs NaHCO3 in solvent acetonitrile (ACN). The conversion rate can be over 82%.
Subject(s)
Antifungal Agents/chemical synthesis , Paclitaxel/chemical synthesis , Sodium Bicarbonate/chemistry , Acetonitriles/chemistry , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Microbial Sensitivity Tests , Molecular Conformation , Paclitaxel/analogs & derivatives , Paclitaxel/chemistry , Paclitaxel/pharmacology , Saccharomyces cerevisiae/drug effectsABSTRACT
A novel 2-fluorodeoxyglucose conjugated derivative of paclitaxel was efficiently synthesized using a linker between 2'-OH of paclitaxel and C1-hydroxyl group of 2-fluorodeoxyglucose. In preparation of the prodrug, allyl carbonates were selected as the protective group and the efficient one-step removal of allyloxycarbonyl groups at the end of the synthesis using palladium chemistry gave the target molecule in good yield. The prodrug not only improved the pharmaceutical properties of paclitaxel, such as solubility and stability, but also demonstrated enhanced cytotoxicity and selectivity for cancer cells and less toxicity toward normal HUVEC cells.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Paclitaxel/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Carbohydrate Conformation , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Hep G2 Cells , Human Umbilical Vein Endothelial Cells/drug effects , Humans , K562 Cells , MCF-7 Cells , Paclitaxel/analogs & derivatives , Paclitaxel/chemistry , Solubility , Structure-Activity RelationshipABSTRACT
A Pseudomonas CoA ligase (BadA) biocatalyzed aroyl CoA thioesters used by a downstream N-benzoyltransferase (NDTNBT) in a cascade reaction made aroyl analogs of the anticancer drug paclitaxel. BadA kept the high-cost aroyl CoA substrates at saturation for the downstream NDTNBT by recycling CoA when it was added as the limiting reactant. A deacylated taxane substrate N-debenzoyl-2'-deoxypaclitaxel was converted to its benzoylated product at a higher yield, compared to the converted yield in assays in which the BadA ligase chemistry was omitted, and benzoyl CoA was added as a cosubstrate. The resulting benzoylated product 2'-deoxypaclitaxel was made at 196% over the theoretical yield of product that could be made from the CoA added at 50 µM, and the cosubstrates benzoic acid (100 µM), and N-debenzoyl-2'-deoxypaclitaxel (500 µM) added in excess. In addition, a 2-O-benzoyltransferase (mTBT) was incubated with BadA, aroyl acids, CoA, a 2-O-debenzoylated taxane substrate, and cofactors under the CoA-recycling conditions established for the NDTNBT/BadA cascade. The mTBT/BadA combination also made various 2-O-aroylated products that could potentially function as next-generation baccatin III compounds. These ligase/benzoyltransferase cascade reactions show the feasibility of recycling aroyl CoA thioesters in vitro to make bioactive acyl analogs of paclitaxel precursors.
Subject(s)
Alkaloids/chemistry , Antineoplastic Agents/chemistry , Coenzyme A Ligases/metabolism , Paclitaxel/analogs & derivatives , Taxoids/chemistry , Benzoic Acid/chemistry , Biocatalysis , Bridged-Ring Compounds , Carboxylic Acids/chemistry , Catalysis , Escherichia coli , Kinetics , Paclitaxel/chemistry , Rhodopseudomonas/enzymology , Substrate SpecificityABSTRACT
PURPOSE: ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown. PATIENTS AND METHODS: A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis was conducted (n = 72 BCBM; n = 28 leptomeningeal carcinomatosis subset). ANG1005 was administered intravenously at 600 mg/m2 every 3 weeks. Tumor assessment was based on central nervous system (CNS) RECIST 1.1 for intracranial, and RECIST 1.1 for extracranial response. The primary endpoint was determination of intracranial objective response rate (iORR). RESULTS: Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS-directed therapies was 2.8 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology facility [IRF] review). In the leptomeningeal carcinomatosis subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI, 5.4-9.4). CONCLUSIONS: Even though the study preset rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in all patients including symptom improvement and prolonged overall survival compared to historical control for the subset of patients with leptomeningeal carcinomatosis (n = 28).
Subject(s)
Brain Neoplasms/drug therapy , Breast Neoplasms/drug therapy , Meningeal Carcinomatosis/drug therapy , Neoplasm Recurrence, Local/drug therapy , Paclitaxel/analogs & derivatives , Peptides/therapeutic use , Adult , Aged , Brain Neoplasms/secondary , Breast Neoplasms/pathology , Female , Follow-Up Studies , Humans , Meningeal Carcinomatosis/pathology , Middle Aged , Neoplasm Recurrence, Local/pathology , Paclitaxel/therapeutic use , PrognosisABSTRACT
With the aim of finding an extracellular biocatalyst that can efficiently remove the C-7 xylose group from 10-deacetyl-7-xylosltaxol, a Dictyoglomus turgidum ß-xylosidase was cloned and expressed in Escherichia coli BL21 (DE3). The molecular mass of purified Dt-Xyl3 was approximately 84â¯kDa. The recombinant Dt-Xyl3 was most active at pH 5.0 and 75⯰C, retaining 88% activity at 65⯰C for 1â¯h, and displaying excellent stability over pH 4.0-7.5 for 24â¯h. In terms of kinetic parameters, the Km and Vmax values for pNPX were 0.8316â¯mM and 5.0178⯵mol/mL·min, respectively. Moreover, Dt-Xyl3 was activated by Mn2+ and Ba2+ and inhibited by Cu2+, Ni+ and Al3+. In particular, it displayed high tolerance to salts with 60.8% activity in 20% (w/v) NaCl. Ethanol and methanol at 5-15% showed little effect on the enzymatic activity. Dt-Xyl3 demonstrated multifunctional activities followed by pNPX, pNPAraf and pNPG and had a high selectivity for cleaving the outer xylose moieties of 10-deacetyl-7-xylosltaxol with Kcat/Km 110.87â¯s-1/mM, which produced 10-deacetyl-taxol to semi-synthesize paclitaxel. Under the optimized conditions (60⯰C, pH 4.5, enzyme dosage of 0.5 U/mL), 1â¯g of 10-deacetyl-7-xylosltaxol was transformed to its corresponding aglycone 10-deacetyl-taxol within 30â¯min, with a molar conversion of 98%. This is the first report that Dictyoglomus turgidum can produce extracellular GH3 ß-xylosidase with highly specific activity for 10-deacetyl-7-xylosltaxol biotransformation, thus leading to the application of ß-xylosidase Dt-Xyl3 as a biocatalyst in biopharmaceutics.
Subject(s)
Bacteria/enzymology , Paclitaxel/analogs & derivatives , Xylosidases/metabolism , Biotransformation , Cloning, Molecular , Kinetics , Paclitaxel/metabolism , Substrate Specificity , Xylosidases/geneticsABSTRACT
Paclitaxel spirulina nanoparticles were said to have promising anticancer activity against gastric cancer. Nanoparticles of paclitaxel-spirulina were prepared for treating gastric cancer using precipitation technique. The synergistic anticancer efficiency againstMKN45 cells retains when the paclitaxel and spirulina were encapsulated into nanoparticles. To increase the site specific delivery, intra-tumoral administration was carried in the in vivo evaluation. There was an increase in overall survival in an MKN45-transplanted mice model and notable improvement in anti-tumour efficacy when paclitaxel-spirulina nanoparticles were delivered through intra-tumoral administration. The further investigation of overall anticancer mechanism of these nanoparticles is made as a major part in this research. Hence, the conjecture of this research is that, the paclitaxel-spirulina encapsulated nanoparticles could be an effective chemotherapeutic formulation for gastric cancer.
Subject(s)
Stomach Neoplasms/pathology , In Vitro Techniques/instrumentation , Paclitaxel/analogs & derivatives , Spirulina , Nanoparticles/classification , Organization and Administration , Efficiency , MethodsABSTRACT
Conjugation of therapeutics to human serum albumin (HSA) using bromomaleimides represents a promising platform for half-life extension. We show here that the Cys-34 crevice substantially reduces the rate of serum stabilising maleimide hydrolysis in these conjugates, necessitating reagent optimisation. This improved reagent design is applied to the construction of an HSA-paclitaxel conjugate, preventing drug loss during maleimide hydrolysis.
Subject(s)
Antineoplastic Agents/chemistry , Maleimides/chemistry , Paclitaxel/analogs & derivatives , Serum Albumin, Human/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cysteine/chemistry , Drug Stability , Humans , Hydrolysis , Maleimides/toxicity , Paclitaxel/toxicity , Serum Albumin, Human/toxicityABSTRACT
LESSONS LEARNED: Induction chemotherapy with Genexol-PM and cisplatin demonstrated modest tumor response in locally advanced head and neck squamous cell carcinoma.Considering favorable toxicity profiles and promising survival data, further studies on this regimen are warranted in patients with head and neck squamous cell carcinoma. BACKGROUND: Genexol-PM is a polymeric micellar formulation of paclitaxel without Cremophor EL. We investigated the efficacy and safety of Genexol-PM plus cisplatin as induction chemotherapy (IC) in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). METHODS: Patients received Genexol-PM (230 mg/m2) and cisplatin (60 mg/m2) every 3 weeks as IC. After three cycles of IC, definitive treatment of either concurrent chemoradiotherapy (CCRT) with weekly cisplatin (30 mg/m2) or surgery was performed. The primary endpoint was overall response rate (ORR) after IC. RESULTS: Of 52 patients enrolled, 47 completed three cycles of IC, and the ORR was 55.8% (95% confidence interval, 42.3-69.3). Although there was one treatment-related death, toxicity profiles to Genexol-PM and cisplatin were generally favorable, and the most common grade 3 or 4 toxicities were neutropenia (15.4%), anorexia (7.7%), and general weakness (7.7%). Fifty-one patients received definitive treatment (CCRT [n = 44] or radical surgery [n = 7]). The rate of complete response following CCRT was 81.8% (36/44). After a median follow-up of 39 months, estimates of progression-free survival (PFS) and overall survival (OS) at 3 years were 54.3% and 71.3%, respectively. CONCLUSION: IC with Genexol-PM and cisplatin demonstrated modest tumor response with well-tolerated toxicity profiles for patients with LA-HNSCC.