Paclitaxel Solution Research Articles

Sialic Acid-Modified nanomedicines modulate neutrophils for dual therapy of cancer and sepsis: Addressing neglected sepsis comorbidities during cancer treatment.

Advanced cancer patients face a high risk of sepsis due to immune suppression and infection susceptibility. To tackle this challenge, we developed an innovative animal model that simulates the clinical scenario of late-stage cancer complicated by sepsis and designed a sialic acid (SA)-modified paclitaxel (PTX) liposome (PTX-SAL). This formulation specifically targets overactivated peripheral blood neutrophils (PBNs) by binding to L-selectin on their surface. It effectively eliminates hyperactive neutrophils and blocks their migration, thus reducing infiltration into tumor and inflammation sites. In sepsis and melanoma mouse models, PTX-SAL demonstrated superior therapeutic efficacy and a favorable safety profile. Notably, in the late-stage tumor model with sepsis, PTX-SAL significantly improved survival rates, with a 72-hour survival rate of 66.7%. In stark contrast, the PTX solution (PTX-S) group exhibited accelerated mortality, with all animals succumbing within 24 h, highlighting the detrimental effects of PTX-S's non-selective cytotoxicity on immune cells. These findings underscore the superior long-term safety and therapeutic advantage of nanomedicines like PTX-SAL over conventional drug formulations. In summary, SA-modified nanomedicines offer a dual benefit by targeting and eliminating inflammatory neutrophils, addressing both tumor progression and sepsis, and significantly reducing mortality in preclinical models. This innovative strategy fills a critical gap in the treatment of advanced cancer complicated by sepsis.

Mesenchymal stem cell-delivered paclitaxel nanoparticles exhibit enhanced efficacy against a syngeneic orthotopic mouse model of pancreatic cancer

Pancreatic cancer is considered the deadliest among various solid tumors, with a five-year survival rate of 13 %. One of the major challenges in the management of advanced pancreatic cancer is the inefficient delivery of chemotherapeutics to the tumor site. Even though nanocarriers have been developed to improve tumoral delivery of chemotherapeutics, less than 1 % of the drugs reach tumors, rendering inadequate concentration for effective inhibition of tumors. As a potential alternative, mesenchymal stem cells (MSCs) can effectively deliver their cargo to tumor sites because of their resistance to chemotherapeutics and inherent tumor tropism. In this study, we used MSCs for the delivery of dibenzocyclooctyne (DBCO)-functionalized paclitaxel (PTX)-loaded poly(lactide-co-glycolide)-b-poly (ethylene glycol) (PLGA) nanoparticles. MSCs were modified to generate artificial azide groups on their surface, allowing nanoparticle loading via endocytosis and surface conjugation via click chemistry. This dual drug loading strategy significantly improves the PTX-loading capacity of azide-expressed MSCs (MSC-Az, 55.4 pg/cell) compared to unmodified MSCs (28.1 pg/cell). The in vitro studies revealed that PTX-loaded MSC-Az, nano-MSCs, exhibited cytotoxic effects against pancreatic cancer without altering their inherent phenotype, differentiation abilities, and tumor tropism. In an orthotopic pancreatic tumor model, nano-MSCs demonstrated significant inhibition of tumor growth (p < 0.05) and improved survival (p < 0.0001) compared to PTX solution, PTX nanocarriers, and Abraxane. Thus, nano-MSCs could be an effective delivery system for targeted pancreatic cancer chemotherapy and other solid tumors.

PEGylated pH-Responsive Liposomes for Enhancing the Intracellular Uptake and Cytotoxicity of Paclitaxel in MCF-7 Breast Cancer Cells.

This study aimed to develop paclitaxel (PTX)-loaded PEGylated (PEG)-pH-sensitive (SpH) liposomes to enhance drug delivery efficiency and cytotoxicity against MCF-7 breast cancer cells. PTX-loaded PEG-SpH liposomes were prepared using the thin film hydration method. ATR-FTIR compatibility studies revealed no significant interactions among liposome formulation components. TEM images confirmed spherical morphology, stability, and an ideal size range (180-200nm) for improved blood circulation. At pH 5.5, liposomes exhibited increased size and positive zeta potential, indicating pH-sensitive properties due to CHEMS response to the acidic tumor microenvironment. Conversely, at pH 7.4, liposomes showed a slightly larger size (199.25 ± 1.64nm) and a more negative zeta potential (-36.94 ± 0.32mV), suggesting successful PEG-SpH surface modification, enhancing stability, and reducing aggregation. PTX-loaded PEG-SpH liposomes demonstrated high encapsulation efficiency (84.57 ± 0.92% w/w) and drug loading capacity (4.12 ± 0.26% w/w). In-vitro drug release studies revealed accelerated first-order PTX release at pH 5.5 and a controlled zero-order release at pH 7.4. Cellular uptake studies on MCF-7 cells demonstrated enhanced PTX uptake, attributed to mPEG-PCL incorporation prolonging circulation time and CHEMS facilitating PTX release in the tumor microenvironment. Furthermore, PTX-loaded PEG-SpH liposomes exhibited significantly improved cytotoxicity with an IC50 value of 1.107µM after 72-h incubation, approximately 90% lower than plain PTX solution. Stability studies confirmed the robustness of the liposomal formulation under various storage conditions. These findings highlight the potential of PEGylated pH-responsive liposomes as effective nanocarriers for enhancing PTX therapy against breast cancer.

Injectable, Adhesive Albumin Nanoparticle-Incorporated Hydrogel for Sustained Localized Drug Delivery and Efficient Tumor Treatment.

Injectable hydrogels are receiving increasing attention as local depots for sustained anticancer drug delivery. However, most current hydrogel-based carriers lack tissue-adhesive ability, a property that is important for the immobilization of drug-loaded systems at tumor sites to increase local drug concentration. In this study, we developed a paclitaxel (PTX)-loaded injectable hydrogel with firm tissue adhesion for localized tumor therapy. PTX-loaded bovine serum albumin (BSA) nanoparticles (PTX@BN) were prepared, and the drug-loaded hydrogel was then fabricated by cross-linking PTX@BN with o-phthalaldehyde (OPA)-terminated 4-armed poly(ethylene glycol) (4aPEG-OPA) via a condensation reaction between OPA and the amines in BSA. The hydrogel showed firm adhesion to various organs and tumor tissues ex vivo due to the condensation reaction of unreacted OPA groups and amines in the tissues. The PTX-loaded nanocomposite hydrogels sustained PTX release over 30 days following the Korsmeyer-Peppas model and exhibited notable inhibition activities against mouse C26 colon and 4T1 breast cancer cells in vitro. Following peritumoral injection into mice with C26 or 4T1 tumors, the PTX@BN-loaded hydrogel significantly enhanced the antitumor efficacy and prolonged animal survival time compared to free PTX solutions with low systemic toxicity. Therefore, the adhesive, PTX-loaded nanocomposite hydrogels have the potential for efficient localized tumor therapy.

Preliminary Insights into JWH182: a Synthetic Cannabinoid’s Neuroprotective Role Against Paclitaxel-Induced Neuronal Toxicity

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN), a frequently encountered consequence of neurotoxic chemotherapy, affects approximately 30 to 40% of patients. Taxanes are associated with an exceptionally high incidence of peripheral neuropathy, with Paclitaxel (PTX) accounting for approximately 70,8% of CIPN cases. Patient’s symptoms are severe, compelling oncologists to consider dosage reduction or even complete abandonment of the treatment plan. Several recent studies have shown the potential efficacy of either synthetic, endogenous or phytocannabinoids in alleviating CIPN symptoms. In case of in vitro studies, neural protection can be assessed by measuring the axon length of the cultured neurons. Therefore, our study aimed to investigate whether the synthetic cannabinoid JWH182 could emerge as a promising new candidate for managing Paclitaxel-induced peripheral neuropathy, in case of an in vitro neural model. METHODS: Primary neuronal cultures were obtained from mouse-derived dorsal root ganglia (DRG) explants. The harvested ganglia were subjected to a series of enzymatic and mechanical dissociating processes, followed by a density-gradient centrifugation to isolate neurons, which were then seeded in Poly-D-Lysine coated 6-well plates and incubated for 24h. Thereafter, cells were exposed to an equal parts solution of 20 uM JWH182 and 1uM PTX. As a means of comparison, the neurons from the positive control group were exclusively exposed to a 1uM PTX solution, whereas the negative control group was left untreated. Photographs of the neurons were taken before the treatment and subsequently at 6, 24, 48 and 72 hours, with a particular focus on observing changes in axon length and cell viability. RESULTS: Unlike our positive control group, which displayed noticeable adverse effects on axon length, the sample treated with both PTX and JWH182 presented more promising outcomes. To be precise, there was a less important reduction in axon length at all time points following drug administration. In the meantime, the negative control exhibited no changes, maintaining a typical morphology and rate of axonal growth. CONCLUSION: These findings suggest that the synthetic cannabinoid JWH182 confers a protective effect on DRG neurons treated with Paclitaxel. As a result, this compound holds the potential to emerge as a novel treatment option for managing Paclitaxel-induced peripheral neuropathy. This could lead to the alleviation of symptoms in oncological patients, thereby enhancing their quality of life and their overall disease prognosis. Ultimately, these initial results lay the foundation for subsequent in vitro and in vivo experiments, aimed at validating our hypothesis.

The Quantification of Paclitaxel and Its Two Major Metabolites in Biological Samples by HPLC-MS/MS and Its Application in a Pharmacokinetic and Tumor Distribution Study in Xenograft Nude Mouse.

A rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the quantification of Paclitaxel (PTX), 6α-hydroxypaclitaxel (6α-OHP), and p-3'-hydroxypaclitaxel (3'-OHP) in mouse plasma and tumor tissue. The analytes were separated using a C18 column (50 × 2.1 mm, 1.8 μm), and a triple-quadrupole mass spectrometry device equipped with an electrospray ionization (ESI) source was applied for their detection. PTX, 6α-OHP, and 3'-OHP were extracted from the biological samples with the solid-phase extraction cartridge. The method was fully validated according to the FDA's guidance. The method was linear over the concentration ranges of 0.5~1000.0 ng/mL for PTX and 0.25~500.0 ng/mL for 6α-OHP and 3'-OHP. The precision, accuracy, extraction recovery, and matrix effects were within acceptable limits. The present method was successfully applied to the study of the pharmacokinetics and distribution of PTX, 6α-OHP, and 3'-OHP in the tumors of post xenograft nude mice intravenously injected with PTX solution.

Exploring the intrinsic micro-/nanoparticle size on their in vivo fate after lung delivery.

Micro-/nanocarriers due to their significant advantages are widely investigated in pulmonary drug delivery. However, different size carriers have varied drug release rate, concealing the effect of particle size on the fate of drugs in vivo. Therefore, by keeping drug release rate comparable, the objective of this study is to elucidate the influence of particle size itself on drug in vivo fate after intratracheal instillation to mice. Here, using paclitaxel (PTX) as a drug model, 100nm, 300nm, 800nm, and 2500nm poly(lactide-co-glycolide) (PLGA) particles with the same release rate were prepared. It was demonstrated that the in vivo fate of particles after lung delivery was size-dependent. Consistent with most reports of model particles with neglected release kinetics, the mucus penetration capacity in airtifical mucus decreased with increasing particle size and there is no significant difference between 800nm and 2500nm particles. The in vivo airway distribution experiments confirmed the results of the in vitro mucus penetration study, that is, the smaller the particles, the more distributed in the airway. Both in vitro and in vivo macrophage uptake results confirmed that the larger particles were more readily taken up by macrophages. In contrast, the uptake of smaller particles in A549 cells was higher than that of larger particles. Some new findings were disclosed in lung retention, lung absorption and lung targeting. Different from previous reports, this study demonstrated that particles with smaller size had longer lung retention, AUC(0-t) in bronchoalveolar lavage fluid (BALF) of 100nm particles was 1.6, 1.9, 2.5 times higher than that of 300nm, 800nm, and 2500nm particles and 11.7 times of the PTX solution group. The same trend was observed in lung tissue absorption, the AUC(0-t) in the lavaged lung of 100nm particles was 1.8, 2.2, 2.8, 8.6 times higher than that of 300nm, 800nm, 2500nm particles and PTX solution groups, respectively. The lung targeting efficiency was particles size independent. In conclusion, the in vivo fate of particles with the same release kinetics after intratracheal instillation is size-dependent, smaller size particles are conducive for lung retention and lung absorption. Overall, our study provided scientific guidance for the rational design of particle based pulmonary drug delivery system.

The Basic Study of Liposome in Temperature-Sensitive Gel at Body Temperature for Treatment of Peritoneal Dissemination

Peritoneal dissemination is a disease that is difficult to treat surgically because it is widely scattered and proliferates in the abdominal cavity. It is a challenge that even if the drug is administered directly into the abdominal cavity, it rapidly disappears from the abdominal cavity, and the therapeutic effect is not optimal, as expected. In this study, for a liposomal paclitaxel in temperature-sensitive gel that is a suspension before administration and a gel after intraperitoneal administration, the antitumor effect of this formulation was evaluated. Temperature-sensitive gels were prepared using methylcellulose, sodium citrate, and macrogol 4000 and mixed with liposomal paclitaxel. Liposomal paclitaxel containing temperature-sensitive gel in the body was administered into the peritoneal cavity of a mouse model of peritoneal dissemination; the number of cells was significantly reduced compared to a paclitaxel solution of liposomal paclitaxel. These results showed that the liposome in temperature-sensitive gel inhibited cell proliferation in the abdominal cavity. This formulation can be administered easily at room temperature, and it gels and remains in the abdominal cavity for a long period, resulting in a more substantial effect than the existing drug.

Glycosylated paclitaxel mixed nanomicelles: Increasing drug brain accumulation and enhancing its in vitro antitumoral activity in glioblastoma cell lines

Glioblastoma multiforme (GBM) is the most common, most aggressive and lethal of brain cancers. Patients with GBM exhibit a survival between 12 and 15 months. Unfortunately, intravenous chemotherapy for GBM is very limited due to the poor penetration of the drugs through the blood brain barrier. In this framework, we expand the potential of a nanoformulation based in mixed micelles of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®) and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) loaded with paclitaxel (PTX). The nanoformulation was surface-decorated with glucose moieties as an attempt to optimize its anticancer performance and the PTX accumulation in the central nervous system. Soluplus® glycosylation was produced using a ring-opening reaction assisted by microwave. Hence, a multifunctional nanocarrier employing Soluplus(Glu) and TPGS (5:1 wt ratio) loaded with PTX (4 mg/mL) was investigated. Its micellar size before lyophilization, after lyophilization, drug loading content and encapsulation efficiency were 119.3 ± 41.8 nm, 140.0 ± 70.2 nm, 6.16 ± 0.06% and 98.5%, respectively. The colloidal dispersions were also characterized in terms of morphology and in vitro PTX release. Glycosylated PTX-loaded system demonstrated an enhanced (∼4.5-fold) in vitro anti-glioma efficacy than its glucose-free counterpart in U251 human glioblastoma cells. Further, in vivo assays revealed that our nanoformulation improved PTX pharmacokinetic parameters after i.v. administration. Interestingly, brain drug accumulation was improved (>8-fold) for the polymeric micelles in comparison with the PTX solution in Wistar rats. Overall, our micellar system represents a feasible nanotechnological platform for the potential improvement of glioma chemotherapy.

Oral and Lymphatic Delivery of Paclitaxel via Lipid Nanocapsules

Paclitaxel (Ptx) is a potent anticancer drug, especially in breast and ovarian cancers. However, orally administered Ptx presents a major therapeutic challenge because of its low bioavailability. In addition, an adjuvant consisting of Cremophor？？ EL and dehydrated alcohol is used in current clinical formulations of Ptx, which causes serious side effects. The side effects of Cremophor？？ EL include hypersensitivity reactions, nephrotoxicity, and neurotoxicity. Therefore, this study prepared lipid nanocapsules (LNCs) containing Ptx to reduce its toxicity and improve bioavailability. The LNCs were characterized using droplet size distribution, zeta potential, drug encapsulation efficiency, stability, differential scanning calorimetry, field emission-transmission electron microscopy, and in vitro release tests. The reference (Ptx) solution and LNCs containing Ptx were orally administered (12 mg/kg) to rats. The plasma and the mesenteric and axillary lymph nodes were obtained, and the concentrations of Ptx in these tissues were measured to compare and evaluate the pharmacokinetics and lymphatic delivery of Ptx. The mean droplet size, zeta potential, and encapsulation efficiency of the optimized Ptx-LNCs were approximately 87.6±6.2 nm, -4.0±0.4 mV, and 90.5±7.8%, respectively. The in vitro release profiles of the prepared Ptx-LNCs were affected by the pH of the dissolution media. Based on in vivo studies, the bioavailability of orally administered Ptx in LNCs was significantly (p<0.05) improved by approximately 2-fold compared to the reference solution. The prepared Ptx-LNCs also showed significantly (p<0.05) higher lymphatic targeting efficiencies than the reference solution. Based on these results, we conclude that the prepared Ptx-LNCs could be a good candidate as an effective oral formulation of Ptx.

A photothermal/chemotherapy injectable paclitaxel gel with irradiation stability

The aim of this study is to construct an injectable gel with stable phototherapy and chemotherapy. Res-PTX@IR780 gel with phototherapy and chemotherapy property was prepared by introduction of photosensitizer IR780 and antioxidant resveratrol (Res) into the polyethylene glycol (PEG) solution of paclitaxel (PTX). The results showed that PTX, PTX@IR780 and Res-PTX@IR780 could form gels and the gels were injectable. ATR-FTIR results indicated not only components of the gels but also the formation of hydrogen bonding during the gelation. The results of UV showed instability of IR780 solution and stability improvement of Res-IR780 solution under infrared radiation (IR) irradiation. Photothermal tests showed that Res-PTX@IR780 displayed better photothermal conversion and photothermal stability under multiple irradiations than PTX@IR780. The results of in vivo exploration in mice showed that the skin site injected with Res-PTX@IR780 gel heated up from 35 ℃ to 64 ℃, and the temperature difference was up to 30 ℃. Res-PTX@IR780 gel is very promising as a combination agent of photothermal therapy and chemotherapy for the in situ treatment of tumors due to good photothermal conversion and photothermal stability under multiple irradiations.

Development and optimization of paclitaxel loaded Eudragit/PLGA nanoparticles by simplex lattice mixture design: Exploration of improved hemocompatibility and in vivo kinetics

Anemia is the most common hematological abnormality of chemotherapy, which is responsible for poor clinical outcomes. To overcome this complication, the present study was aimed for developing a Eudragit/polylactic-co-glycolic acid (PLGA) based nanoparticulate system for a model drug paclitaxel (PTX). The study was planned using a simplex lattice mixture design. PTX nanoparticles (PTXNp) were evaluated in vitro for physicochemical properties, hemolytic effects and cytotoxic effects. Further, the nanoparticles were subjected to in vivo screening using rats for hemocompatibility, pharmacokinetic profile, and biodistribution to the vital organs. The PTXNps were 65.77–214.73 nm in size, showed more than 60% sustained drug release in 360 h and caused less than 8% hemolysis. The parameters like red blood cell count, activated partial thromboplastin time (aPTT), prothrombin time (PT) and C3 complement were similar to the negative control. Cytotoxicity results suggested that all the PTXNp demonstrated drug concentration-dependent cytotoxicity. The in vivo pharmacokinetic study concluded that PTXNp formulations had significantly higher blood AUC (93.194.55–163,071.15 h*ng/mL), longer half-lives (5.80–6.35 h) and extended mean residence times (6.05–8.54 h) in comparison to PTX solution (p < 0.05). Overall, the study provides a nanoparticulate drug delivery system to deliver PTX safely and effectively along with reducing the associated hematological adverse effects.

Establishing a protocol for the compatibilities of closed-system transfer devices with multiple chemotherapy drugs under simulated clinical conditions.

Closed-system drug transfer devices (CSTDs) are used to prevent occupational exposure to hazardous drugs in health care providers. They are considered Class II medical devices by the US FDA and are cleared but not approved before marketing. While compatibility tests are conducted by CSTD manufacturers, the procuring institution needs to consider performing its own studies before buying these devices. Herein we tested the compatibility of the components of the Needleless® DualGuard CSTD system (vial access clips, vial access spikes, and administration adaptors) with 10 antineoplastic drugs, under simulated clinical conditions, including compounding and administration, and examined drug potency maintenance, plasticizer migration, and device functionality. All drugs maintained potency within 5%. Diisononyl phthalate leakage was observed from the administration adaptors for paclitaxel and concentrated etoposide solution. In addition, white particles were discovered in CSTDs storing busulfan solution and small cracks were observed on devices which stored melphalan. Thus, it was concluded that even in simulated clinical conditions, instead of extreme conditions, there are still concerns regarding the efficacy and safety of CSTD components. The methodology may be used to implement and detect possible interactions between antineoplastic agents and CSTD components before procurement.

Therapeutic Efficacy and Biodistribution of Paclitaxel-Bound Amphiphilic Cyclodextrin Nanoparticles: Analyses in 3D Tumor Culture and Tumor-Bearing Animals In Vivo.

The uniqueness of paclitaxel’s antimitotic action mechanism has fueled research toward its application in more effective and safer cancer treatments. However, the low water solubility, recrystallization, and side effects hinder the clinical success of classic paclitaxel chemotherapy. The aim of this study was to evaluate the in vivo efficacy and biodistribution of paclitaxel encapsulated in injectable amphiphilic cyclodextrin nanoparticles of different surface charges. It was found that paclitaxel-loaded amphiphilic cyclodextrin nanoparticles showed an antitumoral effect earlier than the drug solution. Moreover, the blank nanoparticles reduced the tumor growth with a similar trend to the paclitaxel solution. At 24 h, the nanoparticles had not accumulated in the heart and lungs according to the biodistribution assessed by in vivo imaging. Therefore, our results indicated that the amphiphilic cyclodextrin nanoparticles are potentially devoid of cardiac toxicity, which limits the clinical use and commercialization of certain polymeric nanoparticles. In conclusion, the amphiphilic cyclodextrin nanoparticles with different surface charge increased the efficiency of paclitaxel in vitro and in vivo. Cyclodextrin nanoparticles could be a good candidate vehicle for intravenous paclitaxel delivery.

Pharmacokinetic-Pharmacodynamic Modeling of Tumor Targeted Drug Delivery Using Nano-Engineered Mesenchymal Stem Cells.

Nano-engineered mesenchymal stem cells (nano-MSCs) are promising targeted drug delivery platforms for treating solid tumors. MSCs engineered with paclitaxel (PTX) loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) are efficacious in treating lung and ovarian tumors in mouse models. The quantitative description of pharmacokinetics (PK) and pharmacodynamics (PD) of nano-MSCs is crucial for optimizing their therapeutic efficacy and clinical translatability. However, successful translation of nano-MSCs is challenging due to their complex composition and physiological mechanisms regulating their pharmacokinetic-pharmacodynamic relationship (PK–PD). Therefore, in this study, a mechanism-based preclinical PK–PD model was developed to characterize the PK–PD relationship of nano-MSCs in orthotopic A549 human lung tumors in SCID Beige mice. The developed model leveraged literature information on diffusivity and permeability of PTX and PLGA NPs, PTX release from PLGA NPs, exocytosis of NPs from MSCs as well as PK and PD profiles of nano-MSCs from previous in vitro and in vivo studies. The developed PK–PD model closely captured the reported tumor growth in animals receiving no treatment, PTX solution, PTX-PLGA NPs and nano-MSCs. Model simulations suggest that increasing the dosage of nano-MSCs and/or reducing the rate of PTX-PLGA NPs exocytosis from MSCs could result in improved anti-tumor efficacy in preclinical settings.

Enhanced Water Solubility and Oral Bioavailability of Paclitaxel Crystal Powders through an Innovative Antisolvent Precipitation Process: Antisolvent Crystallization Using Ionic Liquids as Solvent.

Paclitaxel (PTX) is a poor water-soluble antineoplastic drug with significant antitumor activity. However, its low bioavailability is a major obstacle for its biomedical applications. Thus, this experiment is designed to prepare PTX crystal powders through an antisolvent precipitation process using 1-hexyl-3-methylimidazolium bromide (HMImBr) as solvent and water as an antisolvent. The factors influencing saturation solubility of PTX crystal powders in water in water were optimized using a single-factor design. The optimum conditions for the antisolvent precipitation process were as follows: 50 mg/mL concentration of the PTX solution, 25 °C temperature, and 1:7 solvent-to-antisolvent ratio. The PTX crystal powders were characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, high-performance liquid chromatography–mass spectrometry, X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Raman spectroscopy, solid-state nuclear magnetic resonance, and dissolution and oral bioavailability studies. Results showed that the chemical structure of PTX crystal powders were unchanged; however, precipitation of the crystalline structure changed. The dissolution test showed that the dissolution rate and solubility of PTX crystal powders were nearly 3.21-folds higher compared to raw PTX in water, and 1.27 times higher in artificial gastric juice. Meanwhile, the bioavailability of PTX crystal increased 10.88 times than raw PTX. These results suggested that PTX crystal powders might have potential value to become a new oral PTX formulation with high bioavailability.

Paclitaxel inhibits the migration of CD133+ U251 malignant glioma cells by reducing the expression of glycolytic enzymes.

Energy metabolic reprogramming (EMR) allows for the rearrangement of a series of metabolic genes and proteins when tumor cells adapt to their microenvironment. EMR is characterized by changes in the metabolic pattern and metabolic intermediates to meet the needs of tumor cells for their malignant proliferation and infiltrative growth. The present study investigated the role of low-dose paclitaxel (PTX) in changing the expression levels of key genes and proteins during glycolysis in CD133+ U251 glioma cells and explored the relevant regulatory mechanisms of action at the molecular level. CD133 immunomagnetic beads were applied to malignant CD133+ U251 glioma cells, which were then divided into a negative control and an experimental group treated with 1, 2, 4 or 8 µM PTX for 72 h. Cell Counting Kit-8 (CCK-8) was used to measure U251 cell proliferation. RNA and protein were extracted from the malignant glioma cells in all groups to observe changes in the expression levels of key glycolytic enzymes, such as glucose transporter 1 (GLUT1), pyruvate kinase M (PKM) and lactate dehydrogenase A (LDHA), using reverse transcription-quantitative PCR and western blot assays. Transwell migration assays were performed to quantify the effects of PTX solution on U251 cells. CD133+ U251 glioma cells were isolated successfully. CD1133+ cells had a higher rate of proliferation compared with CD1133- cells. In CD1133+ cells treated with PTX, a dose-dependent reduction in the expression levels of the key glycolytic enzymes GLUT1, PKM and LDHA was observed at both the mRNA and protein levels. PTX solution also inhibited cell migration. Differences between the control and experimental groups were statistically significant (P<0.05). Since glycolysis plays an indispensable role in the proliferation and migration of stem cell-like glioma cells, PTX may inhibit tumor cell growth by downregulating the gene and protein expression levels of glycolytic enzymes in CD133+ glioma cells.

Facile synthesis of redox-responsive paclitaxel drug release platform using metal-organic frameworks (ZIF-8) for gastric cancer treatment

This paper investigated the dual-role of cystamine as a surface modification linker and stimuli-responsive material, and simplify redox-responsive drug delivery system synthesis. ZIF-8 is used as the drug delivery vehicle (due to its exceptional biocompatibility), cystamine is used as the linker and redox-sensitive material, and paclitaxel (PTX) is selected as the anti-tumor drug. Redox-responsive paclitaxel drug delivery platform based on metal-organic frameworks (MOFs) was synthesized by using ZIF-8 as the drug delivery vehicle, and cystamine as the linker and redox-sensitive material. The morphology of ZIF-8 was determined by the Transmitting Electron Microscope (TEM), and the crystal structure was determined by x-ray diffraction (XRD). The surface modification of ZIF-8 was studied by the Fourier-transform infrared (FT-IR) spectroscopy. The Brunauer–Emmett–Teller (BET) study indicated that surface modification has little impact on the specific surface area and pore size distribution of ZIF-8. The drug release of ZIF-8/cystamine/paclitaxel was studied under different pH and glutathione concentrations. The cytotoxicity was investigated with human gastric cancer cells. Higher glutathione (GSH) concentration and lower pH were favorable to the release of paclitaxel from ZIF-8/cystamine/paclitaxel, and the drug release platform provided a higher tumor-killing effect than free paclitaxel solution.

OPTIMAL 3] A phase III trial to evaluate the efficacy and safety of DHP107 (Liporaxel, oral paclitaxel) compared to Taxol (IV paclitaxel) as first line therapy in patients with recurrent or metastatic HER2 negative breast cancer (BC) (NCT03315364).

TPS1106 Background: Paclitaxel is a microtubule-stabilizing drug used for various cancers including breast cancer (BC) and gastric cancer (GC). DHP107 is an oral paclitaxel solution formulated with non-toxic excipients using DH-LASED technology, which doesn’t require pre-treatment. DHP107 demonstrated comparable efficacy and safety to IV paclitaxel for patients with advanced GC (Ann Oncol 2018), and was market approved as the first oral paclitaxel in 2016 for GC in Korea. In previous OPTIMAL phase II study, the primary endpoint objective response rate (ORR) was 54.5% in HER2 negative metastatic BC (MBC) patients and 44.4% in triple negative BC (TNBC) patients. Disease control rate (DCR) was 90.9% by the investigators’ assessment. Toxicity was manageable (2019 ESMO). OPTIMAL phase III is being conducted in Korea, China and Eastern Europe based on this result and another phase II study (OPERA) is being performed in USA. Methods: OPTIMAL 3 study is a multinational, multi-center, randomized and open-label trial enrolling HER2 negative (HR+/HER2- or TNBC) recurrent or metastatic BC patients. Patients are randomized to either study (DHP107) or control group (IV paclitaxel) in a 1:1 ratio and stratified by disease free interval (DFI≤48 weeks vs &gt;48 weeks), visceral metastasis status (visceral vs non-visceral) and country. Patients are administrated with DHP107 (200mg/m2 p.o. bid) or IV paclitaxel (80mg/m2 infused) on D1, 8, 15, q4wks. Tumor assessments are performed on every 8 weeks (±7 days) from C1D1 until disease progression (RECIST V1.1). Key inclusion &amp; exclusion criteria are hormone receptor (ER/PR) positive or negative, HER2 negative, ECOG performance status ≤1 and no prior chemotherapy in recurrent or metastatic disease. The primary endpoint is progression free survival (PFS). Secondary endpoints include ORR, overall survival (OS), time to treatment failure (TTF), DCR, quality of life (QoL) and safety. Total target number of patients is 476 with an estimated 10% drop-out rate. The test is based on non-inferiority hypothesis (HR=1.33) with 80% power. The primary endpoint will be analyzed using a one-sided test at a 2.5% significance level, and other endpoints will be analyzed using a two-sided test at a 5% significance level, with 95% confidence interval. The first subject was enrolled in Jan 2019 and recruitment is ongoing and is expected to be completed in Dec 2020. Final results of this study will be announced by the end of 2022. Clinical trial information: NCT03315364 .

Development and characterization of paclitaxel and embelin loaded solid lipid nanoparticles for breast cancer

In an effort to develop an alternative formulation of combination of paclitaxel (PTX) and embelin (EMB) suitable for parenteral administration, PTX-EMB loaded sterically stabilized solid lipid nanoparticles (SLNs) were prepared, characterized and examined for in vitro cytotoxicity. The SLNs, comprising glycerol mono stearate (GMS) as a solid lipid core, Brij 35 used as surfactant and PEGylated phospholipid used as stabilizer, were prepared using a hot homogenization method. Optimized PTX-EMB loaded formulation, the particle sizes of the prepared SLNs were around 300 nm, suggesting that they would be suitable as a parenteral formulation. Transmission electron microscopy showed that the SLNs were homogeneous and spherical in shape. Entrapment efficiency of paclitaxel and embelin was 92.83 ± 2.2%, 83.25 ± 2.4% respectively. An in vitro drug release study were performed in PBS (pH 7.4) for 80 hrs and observed that paclitaxel and embelin released from the PEGylated SLNs was 93.91 ± 4.1 % and 75.63 ± 4.37 % respectively. Furthermore, treatment of the MCF-7 breast cancer cell line with PTX-EMB loaded SLNs yielded cytotoxicities comparable to PTX solution, PTX-EMB mixture solution and PTX loaded PEGylated SLNs. These results collectively suggest that our optimized SLN formulation may have a potential as alternative delivery system for parenteral administration of paclitaxel and embelin.&#x0D; Keywords: Embelin, Apoptosis, Cancer, Cytotoxicity, Breast Cancer, Solid lipid nanoparticles.