Concentrations Of Paclitaxel Research Articles

Formulation-dependent differences in paclitaxel distribution to anatomical sites relevant to chemotherapy-induced peripheral neuropathy

IntroductionChemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event observed in patients receiving paclitaxel, associated with initial pathological changes in the peripheral nervous system, i.e., distal nerves and dorsal root ganglia (DRG). The prevalence of CIPN in patients receiving paclitaxel formulated i) in polyethylated castor oil with ethanol (CreEL-PTX), ii) as albumin-bound (nab-PTX), and iii) in XR17 micelles (micellar-PTX), is unexpectedly varying. We hypothesize that the discrepancy in CIPN prevalence could be governed by differences in the extent of paclitaxel distribution across blood-to-tissue barriers at the CIPN-sites, caused by the specific formulation.MethodsThe recently developed Combinatory Mapping Approach for CIPN was used to determine the unbound tissue-to-plasma concentration ratio Kp,uu,tissue, after a 4-h infusion of 4 mg/kg CreEL-PTX, 4 mg/kg nab-PTX or 1 mg/kg micellar-PTX in male and female Sprague Dawley rats. Kp,uu,tissue was determined in conventional (DRG, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN-sites.ResultsBased on our data, the Cremophor-free paclitaxel formulations were associated with a higher distribution of paclitaxel to CIPN-sites than CreEL-PTX, e.g., Kp,uu,DRG of 0.70 and 0.60 for nab-PTX and micellar-PTX, respectively, in comparison to 0.27 for CreEL-PTX (p < 0.01). In addition, the fraction of unbound paclitaxel in plasma was on average 1.6-fold higher in nab- and micellar PTX arms and equal to 0.061 and 0.065, respectively, compared to 0.039 for the CreEL-PTX treatment arm (p < 0.0001).DiscussionIn the case of similar unbound paclitaxel concentration in the plasma of patients and assumed species-independent extent of paclitaxel transport across the barriers, nab- and micellar-PTX formulations can lead to higher paclitaxel exposure at CIPN-sites in comparison to CreEL-PTX.

Enhanced in vivo Stability and Antitumor Efficacy of PEGylated Liposomes of Paclitaxel Palmitate Prodrug.

The clinical use of paclitaxel (PTX) in cancer treatment is limited by its poor water solubility, significant toxicity, and adverse effects. This study aimed to propose a straightforward and efficient approach to enhance PTX loading and stability, thereby offering insights for targeted therapy against tumors. We synthesized a paclitaxel palmitate (PTX-PA) prodrug by conjugating palmitic acid (PA) to PTX and encapsulating it into liposomal vehicles using a nano delivery system. Subsequently, we investigated the in vitro and in vivo performance as well as the underlying mechanisms of PTX-PA liposomes (PTX-PA-L). PTX had a remarkable antitumor effect in vivo and significantly decreased the myelosuppressive toxicity of PTX. Moreover, the introduction of PA increased the lipid solubility of PTX, forming a phospholipid bilayer as a membrane stabilizer, prolonging the circulation time of the drug and indirectly increasing the accumulation of liposomes at the tumor site. Our in vivo imaging experiments demonstrated that PTX-PA-L labeled with DiR has greater stability in vivo than blank liposomes and that PTX-PA-L can target drugs to the tumor site and efficiently release PTX to exert antitumor effects. In a mouse model, the concentration of PTX at the tumor site in the PTX-PA-L group was approximately twofold greater than that of Taxol. However, in a nude mouse model, the concentration of PTX at the tumor site in the PTX-PA-L group was only approximately 0.8-fold greater than that of Taxol. Furthermore, the originally observed favorable pharmacodynamics in normal mice were reversed following immunosuppression. This may be caused by differences in esterase distribution and immunity. This prodrug technology combined with liposomes is a simple and effective therapeutic strategy with promising developmental prospects in tumor-targeted therapy owing to its ability to convert PTX into a long-circulating nano drug with low toxicity, high pharmacodynamics, and good stability in vivo.

Extensive DNA Damage and Loss of Cell Viability Occur Synergistically With the Combination of Recombinant Methioninase and Paclitaxel on Pancreatic Cancer Cells which Report DNA-Damage Response in Real Time.

Methionine restriction selectively arrests cancer cells during the S-phase of the cell cycle. We hypothesized that DNA damage may occur in S-phase in cancer cells during methionine restriction. To determine if this occurs, we used MiaPaCa-2Tet-On 53BP1-green fluorescent protein (GFP) pancreatic cancer cells, which report GFP fluorescence in real time after DNA-damage response (DDR) in these cells. We also determined whether a chemotherapy drug in combination with methionine restriction increases the rate of DNA damage. MiaPaCa-2Tet-On 53BP1-GFP cells were used for in vitro experiments. The 25% and 50% inhibitory concentrations (IC25 and IC50, respectively) of recombinant methioninase (rMETase) and paclitaxel on MiaPaCa-2Tet-On 53BP1-GFP pancreatic cancer cells were determined. Cell viability and DDR with rMETase alone, paclitaxel alone, and their combination were measured in MiaPaCa-2Tet-On 53BP1-GFP cells. The IC25 of rMETase on MiaPaCa-2Tet-On 53BP1-GFP cells was 1.66 U/ml. The IC25 for paclitaxel on MiaPaCa-2Tet-On 53BP1-GFP cells was 3.31 nM. The combination of rMETase and paclitaxel synergistically reduced the viability of MiaPaCa-2Tet-On 53BP1-GFP cells. The IC50 of paclitacel on MiaPaCa-2Tet-On 53BP1-GFP cells was 5.1 nM. The IC50 of rMETase on MiaPaCa-2Tet-On 53BP1-GFP cells was 2.3 U/ml. The combination of rMETase (IC50) plus paclitaxel (IC50) on MiaPaCa-2Tet-On 53BP1-GFP cells also caused more DNA damage than either agent alone. The present study suggests the synergy of methionine restriction and chemotherapy is due, at least in part, to DNA damage of cancer cells.

Physicochemical Stability of Nab-Paclitaxel (Pazenir) Infusion Dispersions in Original Glass Vials and EVA Infusion Bags

Background/Objectives: The study objective was to determine the physicochemical stability of nab-paclitaxel (Pazenir) ready-to-use (RTU) dispersion for infusion in original glass vials and ready-to-administer (RTA) infusion dispersion in EVA infusion bags. Methods: Triplicate test dispersions were prepared and stored light protected for a maximum of 28 days either in the original glass vials (RTU) at 2–8 °C or in EVA infusion bags (RTA) at 2–8 °C and at 25 °C. Directly after reconstitution and on days 1, 3, 5, 7, 14, 21, and 28 samples were withdrawn and paclitaxel concentrations assayed by a stability-indicating HPLC method. In parallel, pH and osmolality were measured. In a second series, test dispersions were stored over a 14-day period and inspected daily for visible particles and colour changes. Samples were taken daily for particle size analysis. Integrity and particle size distribution of the nanoparticles were determined by dynamic light scattering (DLS) and albumin monomers, dimers, oligomers, or polymers by size-exclusion-chromatography (SEC). Results: Non-redispersible particles were observed in test dispersions on day 5 (RTA 25 °C), day 7 (RTA 2–8 °C), and day 11 (RTU 2–8 °C). DLS analysis revealed out-of-specification results for the polydispersity index from day 7 (RTA 25 °C) and day 12 (RTU, RTA refrigerated). Paclitaxel concentrations remained >95% of the initial concentrations for 7 days (RTU 2–8 °C, RTA 25 °C) and for 14 days (RTA 2–8 °C). All test dispersions met the specifications regarding the oligomeric status of albumin, pH, and osmolality over the investigation periods. Conclusions: Stability of nab-paclitaxel dispersions is limited by the release of water-insoluble paclitaxel from the nanoparticles and subsequent crystallisation and by formation of insoluble albumin aggregates. Based on our overall results, shelf life of refrigerated RTU and RTA nab-paclitaxel dispersions is limited to 7 days. Shelf life of RTA nab-paclitaxel dispersions stored at room temperature is limited to 4 days. Careful visual inspection of nab-paclitaxel dispersions after reconstitution and prior to administration is highly recommended to detect non-redispersible particles.

Clays-based geopolymers: a sustainable application as adsorbent of cytostatic drugs for water purification

The administration of cytostatic drugs in chemotherapy is steadily increasing, triggering thus a risk to the environment. Identifying powerful ways to effectively remove these hazardous pollutants from hospital and effluent wastewater before they discharge into the aquatic environment remains a critical and challenging task. Adsorption is among the most effective ways to treat contaminated water due to the wide availability and selectivity of the adsorbents besides the simplicity and the low start-up costs of the technique. In this work, a geopolymer, elaborated from an illito-kaolinitic clay (Douiret region of Tunisia) and industrial waste (silica fume and phosphogypsum), has been tested as promising decontamination of the cytostatic drugs paclitaxel (PCX) and irinotecan (IRI) from water samples. The foamed geopolymer was characterized using X-ray diffraction, Fourier transform infrared, scanning electron microscopy and thermogravimetric analysis before and after adsorption. Adsorption batch assays were performed using different concentrations of PCX and IRI, contact times and environmental conditions. The geopolymer had an excellent removal efficiency (almost 100% for PCX and 89% for IRI) using 20 mg of adsorbent and 2.5 mg/L of each drug concentration. The characterization results showed that cytostatic drugs were adsorbed to the geopolymer through physical interactions, pore filling, electrostatic attraction and hydrogen bonding. The specific surface area and pore volume of the geopolymer were 82.23 m2/g and 0.19 cm3/g, respectively. In addition to its cost-effective properties, the geopolymer demonstrated excellent efficiency in contaminated natural samples (including influent, effluent wastewater and surface water) denoting a great application for water purification.

A Simple Eco-Friendly HPLC-PDA Method for the Simultaneous Determination of Paclitaxel and Seliciclib in Plasma Samples for Assessing Their Pharmacodynamics and Pharmacokinetics in Combination Therapy for Uterine Sarcoma.

Background/Objectives: Uterine sarcoma, a rare cancer originating in the smooth muscle of the uterus, exhibits high rates of recurrence and metastasis. It represents one of the most challenging types of cancer due to its chemorefractory nature, showing little response to conventional chemotherapy methods and displaying a relative survival rate of 30-40%. A potentially promising approach for treating uterine sarcoma involves combination therapy with paclitaxel (PAC), a microtubule-targeting agent, and seliciclib (SEL), a cyclin-dependent kinase inhibitor. SEL has been identified as a drug that can enhance the effectiveness of PAC through synergistic effects. To further refine this treatment strategy, an efficient analytical tool capable of simultaneously measuring the concentrations of PAC and SEL in blood plasma is needed. This tool would make it easier to study the pharmacokinetic interactions of potential drugs and assist in monitoring therapy when administering this combination treatment. Regrettably, a method meeting these specific requirements has not been documented in the existing literature. Methods: This article introduces the first HPLC technique employing a PDA detector to concurrently measure PAC and SEL levels in plasma. The methodology underwent validation in accordance with the ICH standards for validating bioanalytical methods. Results: The method exhibited linearity in the concentrations ranging from 0.8 to 100 µg mL-1 for both PAC and SEL. The limits of quantification were determined and found to be 1.34 and 1.25 µg mL-1 for PAC and SEL, respectively. All the other validation criteria conformed to the ICH validation standards. The HPLC-PDA method was successfully employed to quantify both PAC and SEL in plasma samples with a high level of reliability (in terms of accuracy and precision). The eco-friendliness of the approach was verified using three thorough assessments. This technique serves as a valuable asset in establishing the correct dosage and administration schedule for the combined treatment involving PAC and SEL, ensuring the desired therapeutic effects and safety in managing uterine sarcoma. Conclusions: The proposed HPLC-PDA method is the first reliable and eco-friendly method developed to simultaneously determine PAC and SEL in high-throughput plasma samples in clinical laboratories.

Modulating the Self-Assembly of a Camptothecin Prodrug with Paclitaxel for Anticancer Combination Therapy: A Molecular Dynamics Approach.

Camptothecin (CPT) and paclitaxel (PTX), derived from natural products, are recognized for their significant efficacy in clinical cancer treatments. Despite its therapeutic advantages, CPT is challenged by issues of toxicity and solubility, necessitating its use in conjugation with other compounds for enhanced compatibility. This study delves into the coassembly mechanism of Evans blue-conjugated camptothecin (EB-CPT) with PTX, aiming to elucidate their synergistic potential in combination therapy applications, employing all-atom molecular dynamics simulations. The EB-CPT prodrug is reported to form a self-aggregated cluster. Our findings suggest that increasing the PTX concentration induces a dispersion of EB-CPT clusters, thereby disrupting their inherent self-assembly. This disruption is explained to be facilitated by the coassembly of EB-CPT and PTX. With increasing concentration of PTX, a lengthening of the coassembled structures is observed, supporting the experimental findings of tube-like coassembled structures at higher weight ratios of PTX. Hydrophobic interactions and π-π stacking are the primary forces responsible for the formation of both self- and coassembled structures. Interestingly, the structural analysis reveals that the CPT moiety of EB-CPT is less involved in assemblies due to steric hindrances. Instead, the interaction and coassembly processes are predominantly mediated by the EB derivative component of the prodrug. This research underscores the critical role of the solubilizing agent, EB derivative, in mediating the flexibility and interaction of CPT in combination therapy strategies, particularly with PTX, thus emphasizing the importance of conjugates for therapeutic developments. Furthermore, the molecular insights into the interaction sites and mechanisms facilitating coassembly between EB-CPT and PTX contribute valuable knowledge to the field, highlighting the potential of these nanomedicine combinations in advancing cancer treatment modalities.

α2β1 Integrin specific inhibitor BTT-3033 promotes paclitaxel-induced apoptosis in human ovarian cancer cells

Background and purpose: The new plan of using molecular targeted agents in combination with cytotoxic drugs may represent a promising strategy to increase the efficacy of chemotherapy. Hence, we examined whether α2β1 integrin-specific inhibitor, BTT-3033, could modulate the susceptibility of OVCAR3 and SKOV3 ovarian cancer cells to paclitaxel (PTX). Experimental approach: Ovarian cancer cell lines were treated with BTT-3033 and different concentrations of PTX. To determine the mechanisms involved in the PTX/BTT-3033 combination-induced cell death, cell viability, apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and caspase-3 activity were evaluated. Findings/Results: Both BTT-3033 (≥ 1 μM) and PTX (≥ 0.01 μM) suppressed the proliferation of OVCAR3 and SKOV3 cells in a concentration-related manner. Pretreatment with BTT-3033 (1 μM), followed by PTX-induced synergistic antiproliferative effects, decreased the IC50 values of PTX from 0.45 to 0.03 μM in OVCAR3 and 0.35 to 0.02 μM in SKOV3 cells. All of the coefficients of drug interaction for various PTX and BTT-3033 combinations were found to be less than 1. Moreover, PTX/BTT-3033 combination induced more apoptotic cells (from 4.2% to 87.0% in OVCAR3 and 2.4% to 88.5% in SKOV3) than PTX alone. Combination therapy also decreased MMP and increased the caspase-3 activity. Additionally, we found that the PTX/BTT-3033 combination enhanced ROS production in OVCAR3 and SKOV3 cells. Conclusion and implications: BTT-3033 has demonstrated the ability to enhance the susceptibility of ovarian cancer cells to PTX by inducing MMP loss, ROS production, and mitochondrial apoptosis, therefore this combination therapy might represent a promising strategy for ovarian cancer treatment.

CD133+/ABCC5+ cervical cancer cells exhibit cancer stem cell properties

ObjectiveThis study explores the correlation between Forkhead box M1 (FOXM1) and ATP-binding cassette subfamily C member 5 (ABCC5) in relation to paclitaxel resistance in cervical cancer. It aims to identify potential cervical cancer stem cell markers, offering fresh perspectives for developing therapeutic strategies to overcome paclitaxel chemoresistance in cervical cancer. MethodsPaclitaxel-resistant Hela cells (Hela/Taxol) were developed by intermittently exposing Hela cells to progressively increasing concentrations of paclitaxel. We assessed the biological properties of both Hela and Hela/Taxol cells using various assays: cell proliferation, clonogenic, cell cycle, apoptosis, scratch, and transwell. To determine which markers better represent tumor stem cells, we analyzed various known and potential stem cell markers in combination. Flow cytometry was employed to measure the proportion of positive markers in both parental and drug-resistant cell lines. Following statistical analysis to establish relative stability, CD133+ABCC5+ cells were sorted for further examination. Subsequent tests included sphere-forming assays and Western blot analysis to detect the presence of the stem cell-specific protein Sox2, aiding in the identification of viable cervical cancer stem cell markers. ResultsThe Hela/Taxol cell line exhibited significantly enhanced proliferation, migration, and invasion capabilities compared to the Hela cell line, alongside a marked reduction in apoptosis rates (P < 0.01). Notably, proportions of CD44+, CD24+CD44+, ABCC5+, CD24+CD44+ABCC5+, CD44+ABCC5+, CD24+CD44+FOXM1+, CD44+FOXM1+, CD133+ABCC5+, and CD133+FOXM1+ were significantly higher (P < 0.05). Furthermore, the size and number of spheres formed byCD133+ABCC5+ cells were greater in the sorted Hela/Taxol line (P < 0.01), with increased expression of the stem cell marker Sox2 (P < 0.001). ConclusionThe Hela/Taxol cells demonstrate increased tumoral stemness, suggesting that CD133+ABCC5+ may serve as a novel marker for cervical cancer stem cells.

Factors affecting peripheral neuropathy induced by nanoparticle albumin-bound paclitaxel in patients with pancreatic cancer.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major toxicity limiting the use of nab-paclitaxel (Nab-P) in treating patients with pancreatic cancer. The aim of this study was to identify the factors affecting CIPN using patient-reported outcome measures and the minimally invasive volumetric absorptive microsampling (VAMS) technique. The maximum concentrations of paclitaxel (Cmax) were measured from 81 VAMS samples collected from 44 participants with pancreatic cancer. The association between CIPN development and demographic, clinical and pharmacokinetic factors was determined using univariable and multivariable logistic regression. The association between CIPN severity and the factors was evaluated using Spearman's rank correlation. The impact of Cmax and the number of treatment cycles on the severity was assessed using multivariable linear regression. The development of CIPN was significantly associated with cumulative dose (odds ratio 1.005, 95% confidence interval [CI] 1.003-1.007), treatment cycles (3.47, 2.25-5.85), alkaline phosphate (0.992, 0.985-0.998) and age (1.092, 1.020-1.179), with an area under the receiver operating characteristic curve of 0.89 (95% CI 0.83-0.95). The severity of CIPN significantly worsened with increasing cumulative dose (coefficient 0.58, 95% CI 0.44-0.69), treatment cycles (0.57, 0.44-0.68) and age (0.18, 0.00-0.35). The severity of CIPN was predictable from treatment cycles (P = .0002) and Cmax (P = .01). The higher the cumulative dose of Nab-P, treatment cycles and age, the more frequently and severely do the patients experience CIPN. In predicting the severity of CIPN using Cmax, minimally invasive VAMS is a feasible alternative to venous blood sampling.

Optimizing Timing of Intraperitoneal Chemotherapy to Enhance Intravenous Carboplatin Concentration.

Despite advances in systemic chemotherapy, patients with gastric cancer (GC) and peritoneal metastases (PMs) continue to have poor prognoses. Intraperitoneal (IP) administration of Paclitaxel (PTX) combined with systemic chemotherapy shows promise in treating PMs from GC. However, methods of drug administration need to be optimized to maximize efficacy. In this study, we utilized a mouse model with PMs derived from a human GC cell line, administering PTX either IP or intravenously (IV), and Carboplatin (CBDCA) IV 0, 1, and 4 days after PTX administration. The PMs were resected 30 min later, and concentrations of PTX and CBDCA in resected tumors were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results indicated that PTX concentrations were higher with IP administration than with IV administration, with significant differences observed on days 0 and 1. CBDCA concentrations 4 days post-IP PTX administration were higher than with simultaneous IV PTX administration. These findings suggest that IP PTX administration enhances CBDCA concentration in peritoneal tumors. Therefore, sequential IV administration of anti-cancer drugs appears more effective than simultaneous administration with IP PTX, a strategy that may improve prognoses for patients with PMs.

A multi-component paclitaxel −loaded β-elemene nanoemulsion by transferrin modification enhances anti-non-small-cell lung cancer treatment

A multi-component paclitaxel (PTX) −loaded β-elemene nanoemulsion by transferrin modification (Tf-PE-MEs) was developed to enhance non-small-cell lung cancer (NSCLC) treatment. After transferrin modification, the particle size of Tf-PE-MEs was (14.87 ± 1.84) nm, and the zeta potential was (−10.19 ± 0.870) mV, respectively. In vitro experiments showed that Tf-PE-MEs induced massive apoptosis in A549 cells, indicating that it had significant cytotoxicity to A549 cells. Through transferrin modification, Tf-PE-MEs accumulated at the tumor site efficiently with overexpressed transferrin receptor (TfR) on the surface of A549 cells. This will allow increasing PTX and β-elemene concentration in the target cells, enhancing the therapeutic effect. Compared to PTX alone, Tf-PE-MEs displayed good anti-tumor efficacy and diminished systemic toxicity in vivo studies. With favourable therapeutic potential, this study provides a new strategy for the combined anticancer treatment of non-small cell lung cancer.

The Rapid Detection of Paclitaxel-Induced Changes in Cervical Cancer Cells Using an Ultrasensitive Biosensor

Background: Paclitaxel is a widely used cancer treatment drug that has a significant inhibitory effect on cervical cancer cells (HeLa cells). This study aims to investigate the effects of paclitaxel on HeLa cells and evaluate the application of terahertz (THz) spectroscopy and surface plasmon resonance (SPR) biosensors in this process. Methods: We utilized an SPR biosensor in conjunction with THz spectroscopy to measure the terahertz absorbance spectra of HeLa cells exposed to various concentrations of paclitaxel. The minimum number of cells used for detection was 15.25 × 105. At the same time, cell proliferation levels were assessed through proliferation assays and compared with the terahertz spectroscopy data. Results: The experimental results indicated that with the increasing concentration of paclitaxel, the terahertz absorbance spectra of HeLa cells exhibited a blue shift, and cell proliferation was significantly inhibited. The results of the proliferation assays were consistent with the terahertz spectroscopy data, validating the effectiveness of this method. Conclusion: This study demonstrates that the combination of THz spectroscopy and SPR biosensors is a promising technology that can provide a simple, rapid, and low-cost method for studying chemistry–biology relationships, especially in the field of drug evaluation.

Population pharmacokinetic and exposure-toxicity analyses of nab-paclitaxel after pegylated recombinant human granulocyte colony-stimulating factor administration in patients with metastatic breast cancer.

This study aimed to establish a population pharmacokinetic (PK) model to evaluate the dynamic relationship between the concentrations of total and unbound paclitaxel, and the exposure-response analysis of albumin-bound paclitaxel (nab-paclitaxel) after pegylated recombinant human granulocyte colony-stimulating factor (PEG-G-CSF) administration in patients with metastatic breast cancer. A total of 653 concentrations corresponding to total paclitaxel and 334 concentrations corresponding to unbound paclitaxel were analyzed in 24 subjects who randomized received a single 260 mg/m2 dose of two nab-paclitaxel formulations with a 21-35-day washout period. PEG-G-CSF was administered to all the patients in each cycle to prevent neutropenia. The exposure-response relationships were evaluated using the exposure to total, albumin-coated, and unbound paclitaxel, as well as the reduction in neutrophil count. The exposure data were analyzed using nonlinear mixed-effect modeling. A linear regression model was used to test the statistical significance of the correlation between percentage of reduction in neutrophil count and exposure. The PK characteristics of total paclitaxel were described using a three-compartment model with first-order elimination, and a mechanism-based model incorporating linear release of nab-paclitaxel and the saturated binding of unbound paclitaxel to plasma components was established. The release ratio of paclitaxel from nab-paclitaxel was estimated to be 4.60% and the maximum unbound fraction (2.76%) was reached at the end of the infusion. The study found that a longer duration of total paclitaxel concentration > 0.19 µmol/L was significantly correlated with a reduction in neutrophil count (r2 = 0.23, P = 0.00062). Specifically, a duration of > 8.6h was a predictor of a decreased neutrophil count. The decrease in neutrophils induced by nab-paclitaxel was significantly correlated with the duration above a total paclitaxel concentration of 0.19 µmol/L despite the use of PEG-G-CSF.

A signal-on electrochemiluminescence (ECL) sensor based on luminol@carbon nanotubes and CdTe-ZnS@hydroxyapatite for the detection of paclitaxel

A signal-on solid-state electrochemiluminescence (ECL) sensor based on luminol@carbon nanotubes (luminol@CNTs) and CdTe-ZnS@hydroxyapatite (CdTe-ZnS@HAP) was constructed for the detection of paclitaxel (PTX). In this sensing platform, luminol was used as the main luminophore and CdTe-ZnS was used as a co-reaction accelerator. CNTs and HAP were acted as carriers to adsorb more luminophores and co-reaction promoters. In addition, due to the enhanced effect of PTX on the ECL intensity of the luminol-O2 system, PTX was introduced as the final detection target. Under the optimal experimental conditions, the ECL intensity change values (ΔI) of the sensor showed a good linear relationship with the logarithm of PTX concentration in the range of 3 × 10-12 − 3 × 10-7 molL-1, and the limit of detection was 1 × 10-12 mol L-1(S/N = 3). This method was successfully applied to the determination of trace PTX concentration in serum.

Establishment of a novel small bowel adenocarcinoma cell line using patient‑derived xenografts, which produces CEA and CA19‑9.

Small bowel adenocarcinoma (SBA) is a rare tumor with a poor prognosis. Due to its rarity, the research infrastructure for SBA, including cell lines, is inadequate. The present study established a novel SBA cell line, SiCry-15X, using patient-derived xenografts of SBA. The following criteria were defined for establishment: Long-term culturability, tumorigenicity and similarity with the original tumor. The biological characteristics of the cell line, its sensitivity to anticancer drugs and its ability to produce tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were evaluated. SiCry-15X cells adhered and grew as a monolayer, with a population doubling time of 37 h. Polymerase chain reaction results confirmed the human origin of the cell line, and short tandem repeat analysis revealed that the cells were genetically identical to the original tumor. The 50% inhibitory concentrations of 5-fluorouracil, paclitaxel, irinotecan, oxaliplatin and cisplatin for SiCry-15X were 104.05, 0.24, 63.3, 146.55 and 49.29 µM, respectively. CEA and CA19-9 concentrations in the culture media were markedly elevated. In addition, CEA and CA19-9 levels in the serum of cell-derived xenograft model mice were elevated. Moreover, CEA and CA19-9 were produced by SiCry-15X cells and distributed throughout the blood. Furthermore, increases in serum CEA and CA19-9 of cell-derived xenograft model mice were consistent with the clinical course of the disease. The newly established SBA cell line, SiCry-15X, could be an effective tool for conducting further studies on SBA.

Exosome-Mediated Transfer of ALDH2 in Nasopharyngeal Carcinoma Cells Confers Increased Resistance to Paclitaxel Treatment.

Nasopharyngeal carcinoma (NPC) is an aggressive and highly metastatic malignant tumor. Despite recent therapeutic advances, resistance to Taxol (the generic name of paclitaxel) therapy remains a major challenge in clinical management. Therefore, it is imperative to explore the potential mechanisms of paclitaxel resistance in NPC. This study aimed to investigate the expression of aldehyde dehydrogenase 2 (ALDH2) in NPC cells and its critical role in paclitaxel resistance. Paclitaxel-resistant cell line CNE1/Taxol (CNE1-TR), a drug-resistant cell line, was established by exposing the CNE1 nasopharyngeal carcinoma cell line to progressively increasing concentrations of paclitaxel. Furthermore, we investigated the role of ALDH2 in paclitaxel resistance and the function of exosomes using cell culture, Western blotting, reverse transcription-polymerase chain reaction (RT-PCR), Cell Counting Kit-8 (CCK-8), and nanoparticle tracking analysis. The results showed that in the presence of paclitaxel, the CNE1-TR cells manifested higher survival rate and half-maximal inhibitory concentration (IC50) value compared to the parental cell line, indicating strong resistance to paclitaxel. CNE1-TR cells had significantly upregulated mRNA and protein levels of ALDH2. In addition, exosome analysis showed that CNE1-TR cells were able to deliver ALDH2 via exosomes, increasing paclitaxel resistance in the recipient cells. We observed that the ALDH2 expression levels and paclitaxel resistance in CNE1-TR cells were effectively reduced by blocking the release of exosomes. ALDH2 is not only a key molecular marker indicative of therapeutic efficacy, but also a potential therapeutic target for developing novel anticancer strategies. By blocking the exosomal transport of ALDH2 or directly inhibiting its activity, it may be possible to overcome paclitaxel resistance, thus improving the success rate of clinical treatment.

Enhancing the effectiveness of paclitaxel with stigmasterol bioactive compounds for cancer treatment

This study examines the anticancer activity of stigmasterol bioactive compounds combined with paclitaxel. Drug resistance and high toxicity in chemotherapy present a challenge in treating cancer. However, no study has reported the combination therapy of SS with PTX up to now. We evaluated the potential effects of stigmasterol (SS) combined with Paclitaxel (PTX) on cell viability and apoptosis in liver cancer (HepG2) and normal liver (AML 12) cells. The SS showed the highest cytotoxic effects on HepG2 cells (IC50= 117.75 µg/ml) compared to PTX (IC50= 294.59 µg/ml); however, SS and PTX did not affect normal cells, and SS caused higher apoptotic activity in the sub-G1 phase in HepG2 cells after being treated with SS alone compared to other treatments. In combination therapy for both cells, PTX: SS significantly increased cell viability (IC50 of 464.44 and 1056.44 µg/ml for HepG2 and AML 12, respectively) that differed from the drug alone and the compound, confirming that the PTX combined with SS did not enhance cytotoxic performance against HepG2 cell lines. However, this study found that PTX: SS could reduce the side effects arising from the treatment with PTX. This research indicates that SS is a potential anticancer agent for liver cancer. Furthermore, the current study introduces a novel synergistic therapy that can target various cell lines or enhance the concentration of both SS and PTX to investigate the delivery technologies of both compounds.

The phenomenon of drug-coating embolism during lower extremity endovascular interventions with paclitaxel-coated balloon.

There is a risk of distal embolization lower extremity endovascular interventions. Possibly a drug-coating embolism caused by coating detachment from intravascular devices. This review focuses on providing updated information on distal embolism in endovascular revascularization of lower extremity arteries, including the use of drug-coated balloons. Drug-coating embolism is a special case of distal embolization during recanalization of the arteries of the lower extremities. Preclinical studies have demonstrated embolization of drug-coated balloons during angioplasty of lower extremity arteries. However, the clinical role of drug-coating embolism is not completely clear. A 2020 meta-analysis found an increased risk of major lower extremity amputation after drug-coated balloon angioplasty in patients with critical limb ischemia. But long-term research is emerging to support the safety of using these devices. Perhaps a more thorough assessment of the quality of life and the degree of compensation of lower limb ischemia with an intraoperative assessment of the frequency of peripheral embolizations using ultrasound emboli detection, as well as microcirculation with transcutaneous oximetry and laser Doppler flowmetry of the operated lower limb will allow a more detailed study of the phenomenon of drug-coating embolism and its impact on long-term clinical outcomes. According to the results of preclinical studies, the use of paclitaxel-coated balloons leads to an increase in the concentration of paclitaxel in distal skeletal muscles. However, paclitaxel concentration in skeletal muscle was significantly higher in first-generation DCBs. The non-target effects of drug-coating balloon are not fully understood and require further study. Understanding the phenomenon of drug-coating embolism can help physicians to better assess the patient risk and to minimize complications.

Quantitative assessment of paclitaxel in Taxus wallichiana zucc. bark using HPTLC densitometry: Insights for germplasm selection and toxicological studies

Taxus wallichiana Zucc. [Synonym: Taxus baccata subsp. Wallichiana (Zucc.) Pilg.] or Himalayan Yew belonging to the evergreen gymnosperm family Taxaceae, grows in temperate regions and has been used in traditional medicines to treat cancer, bronchial disorders, colds, cough, etc. The plant is known to contain paclitaxel (PTX), a key bioactive component with anticancer properties. High-performance thin layer chromatography (HPTLC) was used in the present study to estimate paclitaxel from the bark of T. wallichiana obtained from 15 different geographical locations in the eastern and western Himalayas of India. HPTLC method was determined to be a reliable and efficient technique for the quantification of paclitaxel, offering rapid outcomes.The bark materials of T. wallichiana chemotype obtained from Sikkim (Samanden) contained the highest concentration of paclitaxel, followed by West Bengal (Sandakphu), Arunachal Pradesh (Dibang Valley), and respectively. The present study also examined the cytotoxicity and genotoxicity of the aqueous bark extract of the TW1 chemotype at various doses on the meristematic cells derived from the roots of Allium cepa L.. The bark extracts demonstrate considerable cytotoxic and mitotic properties. This study could be useful to the pharmaceutical industry for selecting elite (high paclitaxel-producing) chemotypes of T. wallichiana. The toxicological evaluation of the T. wallichiana chemotypes (using Allium cepa test) could also help to determine the genotoxic properties of the bark extract.