lncRNA PVT1 silencing inhibits gastric cancer cells' progression via enhancing chemosensitivity to paclitaxel.

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide because of its high morbidity and the absence of effective therapies. Even though paclitaxel is a powerful anticancer chemotherapy drug, recent studies have indicated its ineffectiveness against GC cells. Long non-coding RNA (lncRNA) PVT1 has a high expression in GC cells and increases the progression of tumors via inducing drug resistance. In the present study, the effects of the siRNA-mediated lncRNA PVT1 gene silencing along with paclitaxel treatment on the rate of apoptosis, growth, and migration of AGS GC cells were investigated. AGS cells were cultured and then transfected with siRNA PVT1 using electroporation. The MTT test was used to examine the effect of treatments on the viability of cultured cells. Furthermore, the flow cytometry method was used to evaluate the impact of treatments on the cell cycle process and apoptosis induction in GC cells. Finally, the mRNA expression of target genes was assessed using the qRT-PCR method. The results showed that lncRNA PVT1 gene suppression, along with paclitaxel treatment, reduces the viability of cancer cells and significantly increases the apoptosis rate of cancer cells and the number of cells arrested in the G2/M phase compared to the control group. Based on the results of qRT-PCR, combined treatment significantly decreased the expression of MMP3, MMP9, MDR1, MRP1, Bcl-2, k-Ras, and c-Myc genes and increased the expression of the Bax gene compared to the control group. The results of our study showed that lncRNA PVT1 gene targeting, together with paclitaxel treatment, induces apoptosis, inhibits growth, alleviates drug resistance, and reduces the migratory capability of GC cells. Therefore, there is a need for further investigations to evaluate the feasibility and effectiveness of this approach in vivo in animal models.

Preparation and characterization of mesoporous HA coating with paclitaxel loaded lignin nanospheres on titanium surface.

Background: Primary malignant bone tumor is a disease that can lead to death. The usually applied clinical treatment strategy is surgical resection of the primary tumor. However, tumor cells are difficult to clean up, easy to make the tumor recurrence, and the bone defect caused by surgical resection also hindered the postoperative recovery. Materials and methods: Herein, in this work, mesoporous hydroxyapatite (HA) coating with petal-structure was prepared on titanium (Ti) implant surfaces by micro-arc oxidation (MAO) to accelerate the bone growth, and then paclitaxel (PTX) loaded lignin nanospheres were deposited into the HA coatings to get a sustained release for killing residual tumor cells. Results: The results showed that many gaps and holes of micro-scale were formed in the petal-structured HA coatings, they worked as traps for the PTX loaded nanospheres to enhance the deposited amount and immobilization stability, playing good role of drug loading platform. The encapsulation of PTX by lignin ensured a lower release rate and a higher sustaining release time when compared with the PTX without encapsulation. In addition, the HA coating with PTX loaded lignin nanospheres showed higher killing effect to tumor cells than to osteoblast. Conclusion: The mesoporous HA coating with paclitaxel loaded lignin nanospheres endowed the titanium surface with good biological property and tumor cell-killing effect, so the obtained Ti-based material had a highly hopeful application as the localized implant for therapy of primary malignant bone tumor.

Attenuation of p38 MAPK/NF-κB/TRPV1/CGRP is involved in the antinociceptive effect of hesperidin methyl chalcone and taxifolin in paclitaxel-induced peripheral neuropathy.

Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is a disabling side effect of PTX, which adversely affects the life quality of cancer patients. Flavonoids such as hesperidin methyl chalcone (HMC) and taxifolin (TAX) can alleviate neuropathic pain via their anti-inflammatory, antioxidant, neuroprotective, and antinociceptive properties. The current study aimed to assess the efficacy of HMC and TAX in preventing PIPN individually or in combination. Pretreatment with HMC and TAX mitigated PTX-induced mechanical allodynia and hyperalgesia, cold allodynia, and thermal hyperalgesia as well as restore the normal histological architecture. Remarkably, neuropathic pain was relieved by suppression of nerve growth factor (NGF), p38 mitogen-activated protein kinase (p38 MAPK), and transient receptor potential vanilloid type-1 (TRPV1), which ultimately lead to reduced calcitonin gene-related peptide (CGRP). Furthermore, both HMC or TAX enhanced nuclear factor erythroid 2-related factor 2 (Nrf2), leading to elevated glutathione (GSH) and total antioxidant capacity (TAC) along with lowered malondialdehyde (MDA), which in turn, downregulated nuclear factor kappa B P65 (NF-κB P65) and its phosphorylated form and eventually reduced tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) then lowered the apoptotic indices. Promisingly, the combination of both agents was superior to each drug alone through targeting more diverse signaling pathways and achieving synergistic and comprehensive therapeutic effects. In conclusion, pretreatment with HMC and TAX separately or in combination alleviated PIPN via modulating NGF/p38 MAPK/NF-κB P65/TRPV1/CGRP pathway.

Non­obstructive mesenteric ischaemia during drug therapy for maxillary cancer: A case report.

Non-occlusive mesenteric ischaemia (NOMI) refers to irreversible intestinal ischaemia and necrosis in the absence of organic obstruction to the mesenteric blood vessels. In cases of delayed diagnosis, the prognosis is poor and the mortality rate is 58-70%, being the highest among patients with acute mesenteric ischaemia. The risk factors for this disease include heart disease, sepsis, and administration of catecholamines and digitalis; however, there are few reports of its onset during drug therapy for malignant tumours. The present study reported the case of an 85-year-old man who developed NOMI during drug therapy for maxillary cancer. The patient was diagnosed with right maxillary carcinoma, for which paclitaxel, carboplatin and cetuximab (PCE) therapy was administered. Four days after starting the second course of PCE therapy, the patient visited the emergency department of our hospital with chief complaints of melena and abdominal pain. Contrast-enhanced computed tomography revealed ischaemia from the transverse to the descending colon, leading to a diagnosis of NOMI. Colectomy and colostomy were performed during the emergency surgery on the same day. Although the patient's general condition improved, he was transferred to a recuperation facility for palliative care.

Strategies in Taxol development. A review.

Taxol is a compound with a rigid, tetracyclic structure of diterpene, which is characterized by significant antitumor properties. Firstly, Taxol has been isolated by extraction from the bark of the yew tree. However, the low level of availability obligated the researchers' world to uncover alternative techniques of Taxol obtainment. In the last few years, many synthetic and semi-synthetic methodologies have been elaborated. Nowadays, many novel biotechnological approaches using cell suspension cultures and biotransformation are initiated and expanded. These processes are very beneficial. The reason is that both the final product and the yield of the process have high levels. Such approaches are very distinctive and they help achieve significant quantities of natural compounds, which often exist in small amounts in plants. Moreover, a very important aspect of Taxol development is nanotechnology. The use of this method has many benefits - the retention time is protracted and the concentration of a drug in tumor tissue is raised. This is due to the specific targeting of nanomolecules. What is essential for patients is that systemic side effects are reduced and the healthy biological systems and tissues do not damage. Also, the paper presents new directions with the application of Artificial Intelligence methods. Every year, new concepts are created for obtaining Taxol and developing methods to significantly increase its bioavailability.

Exclusion of ranitidine from premedication regimen during paclitaxel treatment: A retrospective single-center analysis.

INTRODUCTION: To minimize the risk of hypersensitivity reactions (HSRs) caused by paclitaxel infusion, premedication with corticosteroid, H1-antagonist and H2 antagonist (ranitidine) was standard of care. Discontinuation of ranitidine in 2020 led to adjustments in premedication regimens and a new regimen without ranitidine was implemented in our center. This study aimed to compare the incidence of HSRs during paclitaxel treatment of a standard premedication regimen including ranitidine with a new premedication regimen without ranitidine and with a titrated infusion rate during the first two administrations. METHODS: Retrospective data analysis was performed on two cohorts of adult patients with solid tumors who started treatment with paclitaxel and received a premedication regimen with and without ranitidine over the years 2021 and 2023 respectively (before and after ranitidine withdrawal). Univariable and multivariable logistic regression models were used to investigate any associations with H2 antagonist treatment adjusting for confounding variables. RESULTS: A total of 319 patients were included. 158 patients received the standard premedication regimen with ranitidine compared to 161 patients who did not received ranitidine. HSRs were observed in 10 of 1101 administrations of paclitaxel (0,90%) in ranitidine group compared to 2 of 899 (0,22%) in the ranitidine-free cohort (p = 0.048). Analysis incidence per patient also found results with statistically significant differences: 5.7% (9 of 158 patients) in the ranitidine cohort compared to 1.2% (2 of 161 patients) in the ranitidine-free cohort (p = 0.029). CONCLUSIONS: The results of the study show the effectiveness of a premedication regimen including only dexchlorpherinamine and dexamethasone, along with a titrated infusion rate during the first two administrations, in reducing the incidence of paclitaxed-induced HSRs.

The correlation between vitamin D and the occurrence of peripheral neuropathy induced by paclitaxel chemotherapy.

Introduction: Paclitaxel, a widely used chemotherapeutic agent for various cancers, induces peripheral neuropathy (PIPN) in approximately 80% of patients, severely affecting their quality of life. The role of vitamin D in pain perception has gained attention, but its correlation with PIPN remains unclear. Methods: This study included 129 cancer patients who received adjuvant paclitaxel chemotherapy from January to June 2023. Neuropathic pain was assessed using the Douleur Neuropathique 4 Questions (DN4) questionnaire, and serum levels of vitamin D and glutathione (GSH) were measured to explore the correlation between vitamin D levels and neuropathic pain induced by paclitaxel chemotherapy. Results: The results showed a negative correlation between vitamin D deficiency and the occurrence of neuropathic pain (Spearman correlation coefficient of -0.324, P < 0.001). The receiver operating characteristic (ROC) curve analysis revealed that the area under the vitamin D curve for neuropathic pain was 0.681. Furthermore, after paclitaxel chemotherapy, there was a significant decrease in GSH levels in the serum of patients, with a more pronounced decline in the vitamin D-deficient group. Discussion: The findings of this study indicate that higher levels of vitamin D are negatively associated with the occurrence of paclitaxel-induced neuropathic pain, suggesting that vitamin D might protect against oxidative stress. This discovery is significant for clinical treatment as it may help physicians better understand the mechanisms of pain during paclitaxel therapy and provide new strategies for the prevention and treatment of such pain. It also suggests that modulating vitamin D levels could reduce the neurotoxicity of paclitaxel, thereby improving patients' quality of life and treatment compliance.

Prodrugs of paclitaxel improve in situ photo-vaccination.

Photodynamic therapy (PDT) effectively kills cancer cells and initiates immune responses that promote anticancer effects locally and systemically. Primarily developed for local and regional cancers, the potential of PDT for systemic antitumor effects [in situ photo-vaccination (ISPV)] remains underexplored. This study investigates: (1) the comparative effectiveness of paclitaxel (PTX) prodrug [Pc-(L-PTX)2] for PDT and site-specific PTX effects versus its pseudo-prodrug [Pc-(NCL-PTX)2] for PDT combined with checkpoint inhibitors; (2) mechanisms driving systemic antitumor effects; and (3) the prophylactic impact on preventing cancer recurrence. A bilateral tumor model was established in BALB/c mice through subcutaneous injection of CT26 cells. Mice received the PTX prodrug (0.5 µmole kg-1, i.v.), and tumors were treated with a 690-nm laser (75 mW cm-2 for 30 min, drug-light interval 0.5 h, light does 135 J cm-1), followed by anti-CTLA-4 (100 µg dose-1, i.p.) on days 1, 4, and 7. Notable enhancement in both local and systemic antitumor effectiveness was observed with [Pc-(L-PTX)2] compared to [Pc-(NCL-PTX)2] with checkpoint inhibitor. Immune cell depletion and immunohistochemistry confirmed neutrophils and CD8+ T cells are effectors for systemic antitumor effects. Treatment-induced immune memory resisted newly rechallenged CT26, showcasing prophylactic benefits. ISPV with a PTX prodrug and anti-CTLA-4 is a promising approach for treating metastatic cancers and preventing recurrence.

Using QI to develop a sustainable method for titrating taxane infusions to reduce hypersensitivity reactions.

OBJECTIVE: To develop a sustainable three-step method for titrating first and second taxane exposures through integration of best practices in patient and environmental safety; and to evaluate the impact on immediate hypersensitivity rates. METHODS: A quality improvement study was initiated at a large, NCI-designated comprehensive cancer center in the U.S. to determine a sustainable method of slow, upward titration for reducing taxane-related hypersensitivity reactions. Multidisciplinary collaboration led to the incorporation of best practices for safe preparation and administration of high risk, hazardous drugs. Retrospective data from the electronic health records of 690 patients who received 1221 taxane doses were analyzed. Non-titrated infusions were compared with infusions titrated using a method initially tested for efficacy; and infusions titrated using a method revised for greater compliance with safety standards. Two-sided Fisher's exact tests at a 0.1 level of significance were used to detect differences in the rate of HSR between the three groups. RESULTS: A method of taxane titration that incorporated standardized, preprogrammed infusion rates and tubing primed with inert IV fluid showed a significant reduction in HSR incidence in comparison to non-titrated infusions (6% v. 19%, P = 0.001) and a similar decrease in the rate of HSR (6%) to the initial method previously studied (7%) (P = 0.659) which was not sustainable due to patient and environmental safety concerns. CONCLUSIONS: A three-step titration method using standardized, preprogrammed infusion rates and tubing primed with inert IV fluid reduced taxane-related HSRs and was adopted as sustainable practice in ambulatory cancer care.

Liposomal Nanoformulation-encapsulated Paclitaxel for Reducing Chemotherapy Side Effects in Lung Cancer Treatments: Recent Advances and Future Outlooks.

Paclitaxel is one notable chemotherapy drug that is used to treat a number of cancers, including lung cancer. Nevertheless, it has drawbacks such as toxicity, low solubility in water, and the emergence of multidrug resistance (MDR). This article reviews the use of liposomal formulations to improve paclitaxel administration and efficacy for lung cancer therapy. Paclitaxel's pharmacological characteristics can be improved by liposomes through increased solubility, extended circulation, passive tumor targeting through leaky vasculature, and decreased side effects. Recent developments in paclitaxel liposomal formulations, including as cationic liposomes, conventional liposomes, targeted liposomes with particular ligands, and liposome-loaded microorganisms, are outlined in this article. In comparison to free paclitaxel, these nanoformulations exhibit enhanced cytotoxicity, cellular uptake, apoptosis, tumor growth suppression, and anticancer effects in lung cancer cell lines and animal models. One efficient way to get around the drawbacks of paclitaxel is to alter its size, makeup, and surface characteristics. This will let the medication accumulate and penetrate tumors more easily, avoid multidrug resistance, and cause less systemic toxicity. The article explores clinical studies showcasing the safety and therapeutic efficacy of liposomal paclitaxel for individuals afflicted with lung cancer. In its entirety, the document provides an in-depth examination of the potential enhancement in paclitaxel's dispersion and anti-tumor impacts through the utilization of liposomal technology when addressing diverse manifestations of lung cancer.

Synergistic ferroptosis in triple-negative breast cancer cells: Paclitaxel in combination with Erastin induced oxidative stress and Ferroportin-1 modulation in MDA-MB-231 cells.

Ferroptosis is an important regulated cell death mechanism characterized by iron-dependent lipid peroxidation and oxidative stress. In this study, we examined the ferroptosis-inducing effect of the combined use of Paclitaxel, a microtubule-stabilizing agent, and Erastin, a ferroptosis inducer, in breast cancer cells. In this context, the combination of the compounds in question was applied to the cells and the presence of a synergistic effect was determined by calculating the combination index. Glutathione (GSH) levels and glutathione peroxidase (GPX) activity were determined by commercial assay kits, and the effect of the compounds on lipid peroxidation was determined by measurement of malondialdehyde (MDA) levels. Additionally, the effect of combination treatment on ferroptotic protein expression was determined by western blot. Our findings revealed that the combination treatment caused a significant change in mitochondrial function by causing an increase in the depolarized/viable cell population. Additionally, there was a significant increase in intracellular reactive oxygen species (ROS) levels compared to single applications of the compounds. The significant increase observed in malondialdehyde (MDA) levels revealed that the combination treatment increased lipid peroxidation. Moreover, intracellular GSH levels and glutathione peroxidase (GPX) activity significantly decreased by Paclitaxel-Erastin combination. The expression of ferroptosis-regulating proteins was significantly downregulated. The findings showed that the Paclitaxel-Erastin combination synergistically contributed to the accumulation of lipid reactive oxygen species and induced the ferroptotic cell death pathway in breast cancer cells.

A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer.

BACKGROUND: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH-, high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH- to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC. METHODS: Patients diagnosed with stage IV pancreatic cancer randomized 1:1 to gemcitabine and nab-paclitaxel only (SOC, control) or to SOC with concomitant P-AscH-, 75 g three times weekly (ASC, investigational). The primary outcome was overall survival with secondary objectives of determining progression-free survival and adverse event incidence. Quality of life and patient reported outcomes for common oncologic symptoms were captured as an exploratory objective. Thirty-six participants were randomized; of this 34 received their assigned study treatment. All analyses were based on data frozen on December 11, 2023. RESULTS: Intravenous P-AscH- increased serum ascorbate levels from micromolar to millimolar levels. P-AscH- added to the gemcitabine + nab-paclitaxel (ASC) increased overall survival to 16 months compared to 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90 % CI 0.23, 0.92; p = 0.030). Median progression free survival was 6.2 (ASC) vs. 3.9 months (SOC) (HR = 0.43; 90 % CI 0.20, 0.92; p = 0.029). Adding P-AscH- did not negatively impact quality of life or increase the frequency or severity of adverse events. CONCLUSIONS: P-AscH- infusions of 75 g three times weekly in patients with metastatic pancreatic cancer prolongs overall and progression free survival without detriment to quality of life or added toxicity (ClinicalTrials.gov number NCT02905578).

Dexamethasone is non-inferior to antihistamine plus dexamethasone premedication in preventing ramucirumab plus nab-paclitaxel infusion-related reactions in gastric cancer: a multicenter retrospective study.

PURPOSE: Ramucirumab (RAM) is recommended as premedication with H1-receptor antagonists (H1RA) to prevent infusion-related reactions (IRRs). However, RAM is a human antibody with a low incidence of IRRs. We evaluated the noninferiority of non-H1RA (dexamethasone [DEX] alone) premedication to H1RA (plus DEX) premedication in terms of IRRs in patients with gastric cancer receiving RAM plus nanoparticle albumin-bound paclitaxel (nab-PTX). METHODS: This was a noninferiority, multicenter, retrospective trial conducted in three Japanese centers to assess the incidence of IRRs in patients receiving RAM plus nab-PTX for gastric cancer between 2018 and 2023. Patients with gastric cancer receiving RAM plus nab-PTX were divided into groups with and without H1RA premedication. The incidence of IRRs was compared between the two groups. RESULTS: Ninety patients were evaluated, with non-H1RA and H1RA premedications in 43 and 47 cases, respectively. After the first dose of RAM, IRRs were not observed in either group. IRRs during the overall doses were 0% for non-H1RA premedication and 2.1% for H1RA premedication (90% confidence interval (CI): -5.6%-1.3% for each comparison). The upper limit of the 90% CI (1.3%) did not exceed the noninferiority margin (Δ) of + 10% and therefore met the noninferiority criteria. CONCLUSION: RAM plus nab-PTX for gastric cancer with DEX premedication may be possible without H1RA premedication.

Predictors of immediate and delayed cutaneous hypersensitivity reactions to paclitaxel.

Paclitaxel is one of the first-line treatments for breast, ovarian, and lung cancers. However, its use is limited by the high frequency of hypersensitivity reactions. In this retrospective chart review at Memorial Sloan Kettering Cancer Center, we assess clinical factors associated with immediate and delayed hypersensitivity reactions to paclitaxel and characterize delayed hypersensitivity reactions to paclitaxel in patients with breast cancer. 12,274 patients were treated with paclitaxel. 6,165 had breast cancer and 1,233 were seen by a dermatologist. 734 patients (11.9%) developed an immediate hypersensitivity reaction. Age (p < 0.001), race (p < 0.001), and prior history of allergy (p = 0.05) were associated with immediate hypersensitivity reactions. 147 patients (4.0%) had a rash of interest. The most common phenotypes were maculopapular (52%) and urticaria (36%). Race (p < 0.001) and history of allergy (p < 0.001) were associated with development of a cutaneous reaction. Patients with an immediate hypersensitivity reaction were more likely to have developed a delayed cutaneous reaction (OR = 1.80). Risk factors for development of immediate hypersensitivity reactions in this study were younger age, race, and history of allergy. Patients who developed an immediate hypersensitivity reaction were more likely to develop a delayed hypersensitivity reaction. Risk factors for development of the rash included Asian race and history of allergy. Identification of risk factors is critical to guide care coordination. Awareness of these clinical factors which are associated with development of a rash could guide providers in choosing treatment with paclitaxel or nab-paclitaxel. If the cutaneous reactions are bothersome to the patient, the transition of treatment from paclitaxel to nab-paclitaxel may be warranted, or a consideration of re-challenge or desensitization may be discussed.

Enhanced Synergistic Efficacy Against Breast Cancer Cells Promoted by Co-Encapsulation of Piplartine and Paclitaxel in Acetalated Dextran Nanoparticles.

Malignant breast tumors constitute the most frequent cancer diagnosis among women. Notwithstanding the progress in treatments, this condition persists as a major public health issue. Paclitaxel (PTX) is a first-line classical chemotherapeutic drug used as a single active pharmaceutical ingredient (API) or in combination therapy for breast cancer (BC) treatment. Adverse effects, poor water solubility, and inevitable susceptibility to drug resistance seriously limit its therapeutic efficacy in the clinic. Piplartine (PPT), an alkaloid extracted from Piper longum L., has been shown to inhibit cancer cell proliferation in several cell lines due to its pro-oxidant activity. However, PPT has low water solubility and bioavailability in vivo, and new strategies should be developed to optimize its use as a chemotherapeutic agent. In this context, the present study aimed to synthesize a series of acetalated dextran nanoparticles (Ac-Dex NPs) encapsulating PPT and PTX to overcome the limitations of PPT and PTX, maximizing their therapeutic efficacy and achieving prolonged and targeted codelivery of these anticancer compounds into BC cells. Biodegradable, pH-responsive, and biocompatible Ac-Dex NPs with diameters of 100-200 nm and spherical morphologies were formulated using a single emulsion method. Selected Ac-Dex NPs containing only PPT or PTX as well as those coloaded with PPT and PTX achieved excellent drug-loading capabilities (PPT, ca. 11-33%; PTX, ca. 2-14%) and high encapsulation efficiencies (PPT, ∼57-98%; PTX, ∼80-97%). Under physiological conditions (pH 7.4), these NPs exhibited excellent colloidal stability and were capable of protecting drug release, while under acidic conditions (pH 5.5) they showed structural collapse, releasing the therapeutics in an extended manner. Cytotoxicity results demonstrated that the encapsulation in Ac-Dex NPs had a positive effect on the activities of both PPT and PTX against the MCF-7 human breast cancer cell line after 48 h of treatment, as well as toward MDA-MB-231 triple-negative BC cells. PPT/PTX@Ac-Dex NPs were significantly more cytotoxic (IC50/PPT = 0.25-1.77 µM and IC50/PTX = 0.07-0.75 µM) and selective (SI = 2.9-6.7) against MCF-7 cells than all the control therapeutic agents: free PPT (IC50 = 4.57 µM; SI = 1.2), free PTX (IC50 = 0.97 µM; SI = 1.0), the single-drug-loaded Ac-Dex NPs, and the physical mixture of both free drugs. All combinations of PPT and PTX resulted in pronounced synergistic antiproliferative effects in MCF-7 cells, with an optimal molar ratio of PPT to PTX of 2.3:1. PPT/PTX-2@Ac-Dex NPs notably promoted apoptosis, cell cycle arrest at the G2/M, accumulation of intracellular reactive oxygen species (ROS), and combined effects from both PPT and PTX on the microtubule network of MCF-7 cells. Overall, the combination of PTX and PPT in pH-responsive Ac-Dex NPs may offer great potential to improve the therapeutic efficacy, overcome the limitations, and provide effective simultaneous delivery of these therapeutics for BC treatment.

Glycolytic pathway analysis and gene expression profiles of combination of aloe vera and paclitaxel on non-small cell lung cancer and breast cancer.

The purpose of this study is to enhance the effectiveness of known anticancer medications using natural compounds. The study investigated the impact of combining AVE with PAX on non-small cell lung cancer (A549) and breast cancer (MCF7). In this study, A549 and MCF7 cells were treated with PAX (5 µM), AVE (24 µg/mL), and a combination of PAX and AVE (5 µM + 24 µg/mL). The glucose consumption rates of the cells were determined by extracellular acidification rate (ECAR) thanks to the SeaHorse XFe24 instrument. In addition, gene expression profiles were determined by performing Total RNA sequencing with the Novaseq 6000 instrument. Finally, the expressions of GAPDH, BAX, and BCL-2 genes involved in the apoptotic pathway were detected by RT-qPCR. The combined application of PAX and AVE reduced the ECAR value in both cell lines. According to the RT-qPCR results, the expression level of the apoptotic gene BAX increased in both cell lines (p < 0.05). Total RNA sequencing revealed that the combination effects of PAX and AVE play a role in the ribosome mechanism, thereby affecting the protein translation system in MCF7 while apoptosis and cell cycle have come to the forefront in A549.

Stable Porous Organic Cage Nanocapsules for pH-Responsive Anticancer Drug Delivery for Precise Tumor Therapy.

The search for drug nanocarriers with stimuli-responsive properties and high payloads for targeted drug delivery and precision medicine is currently a focal point of biomedical research, but this endeavor still encounters various challenges. Herein, a porous organic cage (POC) is applied to paclitaxel (PTX) drug delivery for cancer therapy for the first time. Specifically, water-soluble, stable, and biocompatible POC-based nanocapsules (PTX@POC@RH40) with PTX encapsulation efficiency over 98% can be synthesized by simply grafting nonionic surfactant (Polyoxyl 40 hydrogenated castor oil, RH40) on the POC surface. These PTX@POC@RH40 nanocapsules demonstrate remarkable stability for more than a week without aggregation and exhibit pH-responsive behavior under acidic conditions (pH 5.5) and display sustained release behavior at both pH 7.4 and pH 5.5. Intravenous administration of PTX@POC@RH40 led to a 3.5-fold increase in PTX bioavailability compared with the free PTX group in rats. Moreover, in vivo mouse model experiments involving 4T1 subcutaneous breast cancer tumors revealed that PTX@POC@RH40 exhibited enhanced anticancer efficacy with minimal toxicity compared with free PTX. These findings underscore the potential of POCs as promising nanocarriers for stimuli-responsive drug delivery in therapeutic applications.

Fabrication and evaluation of chitosan-coated nanostructured lipid carriers for co-delivery of paclitaxel and PD-L1 siRNA.

This study aimed to develop a nanostructured lipid carrier (NLC) capable of co-delivering paclitaxel (PTX) and programmed death-ligand 1 (PD-L1) small interfering RNA (siRNA) to enhance PTX bioavailability and bolster immunity through PD-L1 knockdown. We prepared a PTX-loaded NLC (P-NLC) and coated it with positively charged chitosan (Chi) to create P-NLC-Chi, which was subsequently conjugated to siRNA (P-NLC-Chi-siRNA). The P-NLC-Chi formulation was optimized using the Box-Behnken design. P-NLC-Chi measured 123.8 ±â€¯0.52 nm (zeta potential, 22.71 ±â€¯0.49 mV). By verifying the gel retardation assay and observing changes in the zeta potential, the optimal binding ratio of NLC to PD-L1 siRNA was identified as 50:1. The P-NLC-Chi-siRNA particle size was 181.97 ±â€¯0.67 nm, with a zeta potential of 18.66 ±â€¯0.23 mV. siRNA stability was observed in serum over a 24-h period. Enhanced cytotoxicity and intracellular uptake of the complex were evident in breast cancer cells and breast cancer-resistant cells (MCF-7 and MCF-7/ADR cells, respectively). Evaluation of P-glycoprotein-mediated efflux demonstrated that NLC mitigated drug efflux in MCF-7/ADR cells. Subcutaneous injection of P-NLC-Chi-siRNA into tumor-bearing BALB/c nude mice injected with MCF-7/ADR cells revealed a reduction in tumor size. In vitro and in vivo experiments indicated a significant reduction in PD-L1 mRNA expression levels. Additionally, an in vivo study revealed tumor-specific CD4 + and CD8 + T cell responses within the tumor tissue following the injection of P-NLC-Chi-siRNA. Our findings suggest that Chi-coated NLC for the co-delivery of PTX and PD-L1 siRNA has great potential as an innovative delivery system for chemoimmunotherapy.

[Electroacupuncture with different frequencies for paclitaxel-induced peripheral neuropathy: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy of electroacupuncture (EA) at frequencies of 2 Hz, 100 Hz, and 2 Hz/100 Hz for chemotherapy-induced peripheral neuropathy (CIPN). METHODS: One hundred and sixty female breast cancer patients with CIPN induced by paclitaxel were randomly divided into a 2 Hz EA group (40 cases, 1 case dropped out), a 100 Hz EA group (40 cases, 2 cases dropped out), a 2 Hz/100 Hz EA group (40 cases, 3 cases dropped out), and a medication group (40 cases, 2 cases dropped out). The three EA groups received acupuncture at bilateral Quchi (LI 11), Waiguan (TE 5), Hegu (LI 4), Zusanli (ST 36), and Yanglingquan (GB 34). Electrodes of the HANS-200E acupoint nerve stimulator were connected to the same side Hegu (LI 4) and Waiguan (TE 5), and Zusanli (ST 36) and Sanyinjiao (SP 6), with EA stimulation frequencies of 2 Hz, 100 Hz, and 2 Hz/100 Hz, respectively. Each session lasted 30 min, once every other day, three times a week. The medication group received oral mecobalamin tablets, 0.5 mg per dose, three times a day. All groups were treated for four weeks. The functional assessment of cancer therapy/gynaecologic oncology group-neurotoxicity (FACT/GOG-Ntx), peripheral neurotoxicity grading based on the National Cancer Institute-common terminology criteria for adverse events Version 5.0 (NCI-CTCAE V5.0), and peripheral neuropathy pain visual analogue scale (VAS) scores were observed before and after treatment, and at follow-up after 4 weeks of treatment completion, and clinical efficacy was evaluated after theatment. RESULTS: Compared before treatment, FACT/GOG-Ntx scores in all groups were decreased after treatment and during follow-up (P<0.01). The score reduction between before and after treatment in the three EA groups was greater than the medication group (P<0.01, P<0.05), with the 2 Hz and 2 Hz/100 Hz EA groups showing a greater reduction than the 100 Hz EA group (P<0.05). The reduction of FACT/GOG-Ntx score between before treatment and follow-up in the 2 Hz and 2 Hz/100 Hz EA groups was greater than the medication group (P<0.01). Peripheral neurotoxicity grading in the three EA groups were improved after treatment (P<0.01). Compared before treatment, the peripheral neurotoxicity grading in the 2 Hz and 2 Hz/100 Hz EA groups was improved at follow-up (P<0.01, P<0.05). The VAS scores for peripheral neuropathy pain in the three EA groups were decreased after treatment (P<0.01, P<0.05). At follow-up, VAS scores in the 2 Hz, 2 Hz/100 Hz, and medication groups were decreased (P<0.01, P<0.05), with a greater reduction in the 2 Hz/100 Hz EA group than the medication group after treatment and follow-up (P<0.01, P<0.05). The overall effective rates for the 2 Hz, 100 Hz, 2 Hz/100 Hz, and medication groups were 79.5% (31/39), 68.4% (26/38), 81.1% (30/37), and 47.4% (18/38), respectively, with the 2 Hz and 2 Hz/100 Hz groups showing higher effective rates than the medication group (P<0.05). CONCLUSION: EA is effective in treating paclitaxel-induced CIPN. While there is no overall difference in efficacy among the different frequencies, 2 Hz and 2 Hz/100 Hz EA showing potential advantages. For patients with concurrent peripheral neuropathy pain, 2 Hz/100 Hz electroacupuncture is recommended.

Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma.

BACKGROUND: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have demonstrated activity in the post-platinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 50% of patients with aUC can tolerate platinum-containing treatment, treatments combining first-line ICIs with non-platinum drugs are urgently needed. Therefore, we assessed the safety and efficacy of the anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first-line therapy in aUC (NCT04603846). METHODS: This was a multi-center, single-arm, phase Ib study that enrolled patients with treatment-naive aUC. Patients received Socazolimab (5 mg/kg) and nab-paclitaxel (260 mg/m2) Q3w. The primary endpoint was safety and tolerability of the combination regimen. Second endpoints were the objective response rate (ORR) and progression-free survival. RESULTS: Between September, 2020 and September, 2021, 20 patients with urothelial carcinoma were enrolled, arising from renal pelvis (5), bladder (8), and ureter (7). After a median follow-up of 17 months, the median number of treatment cycles was 12. No patients had dose limiting toxicity. All patients had treatment-related adverse events (TRAEs), most of which were grade 1 or 2. The common TRAEs (≥20%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesis, and anorexia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (30.0%), increased ALT (10.0%), and increased γGT (5.0%). Two patients (10%) discontinued treatment because of grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4-5 TRAEs were observed. Among the 17 patients who had received at least one tumor assessment, ORR was 58.8% (95% CI, 32.9%-81.6%) and the median progression-free survival was 8.3 months (95% CI, 5.2-19.5). The median duration of response was 13.3 months (95% CI, 2.0-20.1), and the overall survival was 19.5 months (95% CI, 11.2-not reached). CONCLUSION: Socazolimab combined with nab-paclitaxel has shown good safety and promising antitumor activity as first-line therapy in patients with advanced urothelial carcinoma.