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International Journal of Cancer Mar 1997Although the current clinical formulation of paclitaxel (Taxol) is an important new anti-cancer agent, it has significant side effects, some of which are related to its...
Although the current clinical formulation of paclitaxel (Taxol) is an important new anti-cancer agent, it has significant side effects, some of which are related to its formulation in Cremophor/ethanol. Paclitaxel is difficult to formulate for i.v. administration because of its poor aqueous solubility. Here, we report the therapeutic effects of 2 liposome formulations of paclitaxel against human ovarian A121 tumor growing as an s.c. xenograft in athymic nude mice. The liposome formulations used were ETL and TTL, which have I or 3 lipid components, respectively. TTL was used as a reconstituted lyophilate or as a stable aqueous suspension. ETL was used as a reconstituted lyophilate only. Both paclitaxel-liposome formulations were much better tolerated than Taxol after i.v. or i.p. administration. The acute reactions seen after Taxol administration did not occur when paclitaxel-liposome formulations were administered. All ETL and TTL preparations significantly delayed A121 tumor growth similarly to Taxol at equivalent doses and schedules. Based on pharmacokinetic data, it is possible that paclitaxel rapidly dissociates from ETL or TTL after i.v. administration and distributes in a manner similarly to Taxol. ETL and TTL formulations may be useful clinically not only for eliminating toxic effects of the Cremophor/ethanol vehicle but also for allowing alterations in route and schedule of drug administration.
Topics: Animals; Drug Stability; Female; Humans; Liposomes; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Paclitaxel; Time Factors; Tumor Cells, Cultured
PubMed: 9096672
DOI: 10.1002/(sici)1097-0215(19970328)71:1<103::aid-ijc17>3.0.co;2-j -
Journal of Controlled Release :... Jun 2019Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect of paclitaxel. Several liposome-based products have been approved and demonstrated superior...
Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect of paclitaxel. Several liposome-based products have been approved and demonstrated superior efficacy and safety profiles for other drugs. The first objective of this work was to evaluate the effect of liposome formulation of paclitaxel (L-PTX) on neurotoxicity in-vitro and in-vivo in comparison to the standard Taxol® formulation. The second aim was to investigate the effect of formulation on paclitaxel biodistribution following intravenous administration in an animal model. Free paclitaxel was toxic to cell of neuronal origin (IC50 = 18.4 μg/mL) at a lower concentration than to lung cancer cells (IC50 = 59.1 μg/mL), and L-PTX demonstrated a comparable toxicity in both cell lines (IC50 = 31.8 and 33.7 μg/mL). Administration of L-PTX at 2 mg/kg per dose for a total of 4 doses on day 0, 2, 4, and 6 to rats did not result in increased sensitivity in response to mechanical or thermal stimulation of hind paws, in comparison to Taxol® administration at the same dose level that resulted in neuropathy. Paclitaxel biodisposition was evaluated for two formulations in plasma, liver, lung, brain, spinal cord, skin and muscle of rats after single intravenous dose at 6 mg/kg. The exposure to paclitaxel in brain, spinal cord, muscle, and skin was lower in the L-PTX group compared to Taxol® group. PEGylated liposomes containing paclitaxel were successfully developed and demonstrated reduced neurotoxicity in-vitro in neuronal cells and prevented development of peripheral neuropathy in-vivo. This proof of concept study showed that formulation in nanoparticles is a promising approach for reducing (or preventing) neurotoxicity caused by cancer drugs.
Topics: Animals; Antineoplastic Agents, Phytogenic; Brain; Cell Line, Tumor; Drug Compounding; Humans; Liposomes; Liver; Lung; Male; Muscles; Nanoparticles; Paclitaxel; Peripheral Nervous System Diseases; Rats, Sprague-Dawley; Skin; Spinal Cord; Tissue Distribution
PubMed: 30981814
DOI: 10.1016/j.jconrel.2019.04.013 -
International Journal of Nanomedicine 2022Ovarian cancer is the most lethal gynecologic malignancy. The combination of paclitaxel (PTX) and carboplatin (CBP) is the first-line remedy for clinical ovarian cancer....
PURPOSE
Ovarian cancer is the most lethal gynecologic malignancy. The combination of paclitaxel (PTX) and carboplatin (CBP) is the first-line remedy for clinical ovarian cancer. However, due to the limitations of adverse reaction and lacking of targeting ability, the chemotherapy of ovarian cancer is still poorly effective. Here, a novel estrone (ES)-conjugated PEGylated liposome co-loaded PTX and CBP (ES-PEG-Lip-PTX/CBP) was designed for overcoming the above disadvantages.
METHODS
ES-PEG-Lip-PTX/CBP was prepared by film hydration method and could recognize estrogen receptor (ER) over-expressing on the surface of SKOV-3 cells. The characterizations, stability and in vitro release of ES-PEG-Lip-PTX/CBP were studied. In vitro cellular uptake and its mechanism were observed by fluorescence microscope. In vivo targeting effect in tumor-bearing mice was determined. Pharmacokinetics and biodistribution were studied in ICR mice. In vitro cytotoxicity and in vivo anti-tumor efficacy were evaluated on SKOV-3 cells and tumor-bearing mice, respectively. Finally, the acute toxicity in ICR mice was explored for assessing the preliminary safety of ES-PEG-Lip-PTX/CBP.
RESULTS
Our results showed that ES-PEG-Lip-PTX/CBP was spherical shape without aggregation. ES-PEG-Lip-PTX/CBP exhibited the optimum targeting effect on uptake in vitro and in vivo. The pharmacokinetics demonstrated ES-PEG-Lip-PTX/CBP had improved the pharmacokinetic behavior. In vitro cytotoxicity showed that ES-PEG-Lip-PTX/CBP maximally inhibited SKOV-3 cell proliferation and its IC values was 1.6 times lower than that of non-ES conjugated liposomes at 72 h. The in vivo anti-tumor efficacy study demonstrated that ES-PEG-Lip-PTX/CBP could lead strong SKOV-3 tumor growth suppression with a tumor volume inhibitory rate of 81.8%. Meanwhile, acute toxicity studies confirmed that ES-PEG-Lip-PTX/CBP significantly reduced the toxicity of the chemo drugs.
CONCLUSION
ES-PEG-Lip-PTX/CBP was successfully prepared with an optimal physicochemical and ER targeting property. The data of pharmacokinetics, anti-tumor efficacy and safety study indicated that ES-PEG-Lip-PTX/CBP could become a promising therapeutic formulation for human ovarian cancer in the future clinic.
Topics: Animals; Antineoplastic Agents; Carboplatin; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Drug Delivery Systems; Estrone; Female; Humans; Liposomes; Mice; Mice, Inbred ICR; Ovarian Neoplasms; Paclitaxel; Polyethylene Glycols; Tissue Distribution
PubMed: 35836838
DOI: 10.2147/IJN.S362263 -
Angiogenesis Jul 2013In the mid 1990s, researchers began to investigate the antiangiogenic activity of paclitaxel as a possible additional mechanism contributing to its antineoplastic... (Review)
Review
In the mid 1990s, researchers began to investigate the antiangiogenic activity of paclitaxel as a possible additional mechanism contributing to its antineoplastic activity in vivo. In the last decade, a number of studies showed that paclitaxel has antiangiogenic activity that could be ascribed to the inhibition of either tubule formation or cell migration, and to an antiproliferative effect towards activated endothelial cells. Furthermore, paclitaxel was shown to downregulate VEGF and Ang-1 expression in tumor cells, and to increase the secretion of TSP-1 in the tumor microenvironment. Moreover, the new pharmaceutical formulations of paclitaxel (such as liposome-encapsulated paclitaxel, ABI-007, and paclitaxel entrapped in emulsifying wax nanoparticles) enhanced the in vivo antiangiogenic activity of the drug. Thus, the preclinical data of paclitaxel may be exploited to implement a novel and rational therapeutic strategy to control tumor progression in patients.
Topics: Angiogenesis Inhibitors; Angiotensin I; Antineoplastic Agents, Phytogenic; Gene Expression Regulation, Neoplastic; Humans; Liposomes; Models, Molecular; Nanoparticles; Neoplasms; Paclitaxel; Thrombospondin 1; Vascular Endothelial Growth Factor A
PubMed: 23389639
DOI: 10.1007/s10456-013-9334-0 -
Anti-cancer Drugs Mar 2014Chemotherapy could be used as an effective treatment for ovarian cancer and subsequent peritoneal metastasis. Administration of chemoagents in a targeted manner may...
Chemotherapy could be used as an effective treatment for ovarian cancer and subsequent peritoneal metastasis. Administration of chemoagents in a targeted manner may bring the advantage of higher efficiency and lower drug resistance. In the present study, folate receptor (FR)-targeted nano-paclitaxel formulations were generated and tested for cytotoxicity in a peritoneal xenograft model of paclitaxel-resistant ovarian cancer and SKOV3/TAX cell lines. Immunocytochemical staining confirmed the expression of FR in both SKOV3 and SKOV3/TAX cells. The enrichment of the folic acid-coupled PEGylated nano-paclitaxel liposome (FA-NP) in FR-positive cells was visualized with fluorescence. The uptake of the FA-NP peaked at 4 h and was more robust than nontargeted PEGylated nano-paclitaxel liposome (NP). FA-NP but not NP markedly inhibited the growth of ovarian cancer cells and induced a two-fold increase in the doubling time. The cytotoxic effects of FA-NP were more potent than NP in both SKOV3 cells [50% of inhibition concentration (IC50), 5.67 vs. 50.2 μg/ml, FA-NP vs. NP] and SKOV3/TAX cells (IC50, 0.38 vs. >200 μg/ml, FA-NP vs. NP). FA-NP caused more G2-M cell cycle arrest and apoptotic changes in ovarian cancer cells than NP or regular paclitaxel. However, these effects were blunted in the presence of free FA, which competitively inhibited the receptor-mediated uptake of FA-NP particles. Intraperitoneal (i.p.) administration of FA-NP but not regular paclitaxel, NP, or vehicle significantly prolonged the survival and reduced tumor nodule number (2.9±0.3) in BALB/c nude mice. FA-NP also markedly enhanced the percentage of apoptotic cells in peritoneal xenografts of paclitaxel-resistant ovarian cancer cells (44.6±8.5 vs. 3.2±1.1% for vehicle, 22.4±5.9% for regular paclitaxel, and 35.2±7.7% for NP; P<0.05). However, intravenous administration of FA-NP at the same dose failed to induce apoptosis (20.1±6.2%; P<0.05) and inhibit tumor nodule number to the same extent as intraperitoneal administration. FA-NP reversed the drug resistance in paclitaxel-resistant SKOV3/TAX ovarian cancer cells both in vitro and in vivo. Localized and targeted administration of the FR-targeted chemoagents might prolong the survival time in patients with drug-resistant ovarian cancer.
Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Cell Line, Tumor; Cystadenocarcinoma, Serous; Drug Resistance, Neoplasm; Female; Folic Acid; Folic Acid Transporters; Humans; Liposomes; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasm Transplantation; Ovarian Neoplasms; Paclitaxel; Peritoneal Neoplasms; Polyethylene Glycols
PubMed: 24275314
DOI: 10.1097/CAD.0000000000000047 -
Langmuir : the ACS Journal of Surfaces... May 2018A long-circulating and pH-sensitive liposome containing paclitaxel (SpHL-PTX) was recently developed by our group. Once in an acidic environment, for example, tumors,...
A long-circulating and pH-sensitive liposome containing paclitaxel (SpHL-PTX) was recently developed by our group. Once in an acidic environment, for example, tumors, these liposomes undergo destabilization, releasing the encapsulated drug. In this way, the aim of this study was to evaluate the molecular and supramolecular interactions between the lipid bilayer and PTX in similar biological environment conditions. High-sensitivity analyses of SpHL-PTX structures were obtained by the small-angle X-ray scattering technique combined with other techniques such as dynamic light scattering, asymmetric flow field-flow fractionation, transmission electron microscopy, and high-performance liquid chromatography. The results showed that PTX incorporation in the liposomal bilayer clearly leads to changes in supramolecular organization of dioleoylphosphatidylethanolamine (DOPE) molecules, inducing the formation of more ordered structures. Changes in supramolecular organization were observed at lower pH, indicating that pH sensitivity was preserved even in the presence of fetal bovine serum proteins. Furthermore, morphological and physicochemical characterization of SpHL-PTX evidenced the formation of nanosized dispersion suitable for intravenous administration. In conclusion, a stable nanosized dispersion of PTX was obtained at pH 7.4 with suitable parameters for intravenous administration. At lower pH conditions, the pH sensitivity of the system was clearly evidenced by changes in the supramolecular organization of DOPE molecules, which is crucial for the delivery of PTX into the cytoplasm of the targeted cells. In this way, the results obtained by different techniques confirm the feasibility of SpHL as a promising tool to PTX delivery in acidic environments, such as tumors.
Topics: Drug Carriers; Hydrogen-Ion Concentration; Liposomes; Paclitaxel
PubMed: 29676924
DOI: 10.1021/acs.langmuir.8b00411 -
International Journal of Pharmaceutics Nov 2022Nanoparticle technology has promising effects on multiple therapeutic purposes, particularly in controlling drug delivery as Drug Delivery System. The unique properties...
Nanoparticle technology has promising effects on multiple therapeutic purposes, particularly in controlling drug delivery as Drug Delivery System. The unique properties of nanoparticles significantly enhance drug delivery, efficiency, and toxicity. For cancer therapy, controlling chemotherapy delivery can increase the drug concentration in the desired locations, improve drug efficacy, and limit drug toxicity. Liposomes are used in this project to encapsulate paclitaxel due to their ability to carry hydrophobic molecules, low toxicity, and prolonged half-life. Among the multiple liposome preparation methods, microfluidic technology was used to produce liposomes. Microfluidics excels in other conventional methods by offering a high-level control of the process's parameters, which help control particle size, size distribution, and physiochemical properties. This project aims to produce paclitaxel-loaded liposomes with a diameter below 200 nm with low polydispersity index, high homogeneity, and good stability. Different lipid types (DMPC, DPPC, DSPC, and DOPC) were used with different ratios to investigate their impact on empty liposome formulation. Alongside changing the different microfluidic parameters including the total flow ratio and flow rate ratio to study their effects on liposomes' physiochemical properties. The obtained formulations were tested to analyse different physiochemical properties (DLS, FTIR) and stability studies. DMPC and DPPC are determined to study their encapsulation efficiency and in vitro drug release of paclitaxel at total flow rate 1 ml min and 1:4 flow rate ratio. The paclitaxel-loaded liposomes are subjected to the same physiochemical characteristics and stability study. Promising encapsulation efficiency was reported from both DPPC and DMPC, and sustained drug release was observed.
Topics: Liposomes; Paclitaxel; Microfluidics; Dimyristoylphosphatidylcholine; Nanoparticles; Particle Size
PubMed: 36272514
DOI: 10.1016/j.ijpharm.2022.122320 -
International Journal of Oncology May 1998Our study was designed to evaluate the pharmacokinetics, tissue distribution, toxicity and therapeutic efficacy of liposome-encapsulated paclitaxel (LET) in comparison... (Comparative Study)
Comparative Study
Our study was designed to evaluate the pharmacokinetics, tissue distribution, toxicity and therapeutic efficacy of liposome-encapsulated paclitaxel (LET) in comparison to conventional paclitaxel. In normal mice, LET was much less toxic than the conventional drug. A dose of 32.5 mg/kg of conventional paclitaxel administered i.v. on three consecutive days produced 100% mortality by day three, while liposomal paclitaxel exhibited no mortality. The control group which received Diluent 12 (Chremophor EL and ethanol; 1:1 v/v), a vehicle used in conventional paclitaxel, 30% mortality was observed at this dosage level. In murine ascitic L1210 leukemia model, liposomal paclitaxel and conventional paclitaxel showed comparable antitumor activity. The pharmacokinetics of conventional paclitaxel and LET was studied in mice at dose levels of 5 mg/kg and 20 mg/kg. After intravenous administration of conventional paclitaxel at a dose of 5 mg/kg, the area under the plasma-concentration-time curve (AUC) was 2-fold lower and, the elimination half-life was 2-times shorter compared to LET. At a dose of 20 mg/kg, the terminal half-lives were comparable, however, conventional paclitaxel displayed non-linear pharmacokinetics with disproportionate increase in AUC. At the two dose levels studied, LET demonstrated linear kinetics. Tissue distribution of paclitaxel after administration of LET showed levels 10-fold higher in spleen and 3.5-fold higher in liver as compared to conventional paclitaxel. The significant decrease in toxicity shown by LET, coupled with an increase in plasma AUC and half-life indicates that LET may be a viable alternative to the therapeutic use of the conventional preparation of paclitaxel.
Topics: Animals; Drug Carriers; Female; Half-Life; Leukemia L1210; Liposomes; Male; Metabolic Clearance Rate; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Paclitaxel; Tissue Distribution
PubMed: 9538125
DOI: 10.3892/ijo.12.5.1035 -
AAPS PharmSciTech Feb 2018Paclitaxel (PTX) and gemcitabine (GEM) are often used in combination due to the synergistic anticancer effects. PTX and GEM combination showed a synergistic effect to...
Paclitaxel (PTX) and gemcitabine (GEM) are often used in combination due to the synergistic anticancer effects. PTX and GEM combination showed a synergistic effect to SKOV-3 cells at a molar ratio of 1 to 1 and in PTX ➔ GEM sequence. Liposomes were explored as a carrier of PTX and GEM combination. We optimized the drug loading in liposomes varying the preparation method and co-encapsulated PTX and GEM in a single liposome preparation maintaining the maximum loading efficiency of each drug. However, drug release kinetics from the co-loaded liposomes (LpPG) was suboptimal because of the detrimental effect of PTX on GEM-release control. Instead, a mixture of LpP and LpG, which were separately optimized according to the desired release kinetics, achieved a greater cytotoxic effect than LpPG, due to the attenuation of GEM release relative to PTX. This study illustrates that co-encapsulation in a single carrier is not always desirable for the delivery of drug combinations, when the activity depends on the dosing sequence. These combinations may benefit from the mixed liposome approach, which offers greater flexibility in controlling the ratio and release kinetics of component drugs.
Topics: Cell Line, Tumor; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Liberation; Humans; Liposomes; Paclitaxel; Gemcitabine
PubMed: 28971370
DOI: 10.1208/s12249-017-0877-z -
Molecules (Basel, Switzerland) Apr 2019Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming...
The Preparation, Determination of a Flexible Complex Liposome Co-Loaded with Cabazitaxel and β-Elemene, and Animal Pharmacodynamics on Paclitaxel-Resistant Lung Adenocarcinoma.
Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung adenocarcinoma. We selected cabazitaxel and β-elemene, which have fewer issues with drug resistance, and successfully prepared cabazitaxel liposome, β-elemene liposome and cabazitaxel-β-elemene complex liposome with good flexibility. The encapsulation efficiencies of cabazitaxel and β-elemene in these liposomes were detected by precipitation microfiltration and microfiltration centrifugation methods, respectively. Their encapsulation efficiencies were all above 95%. The release rates were detected by a dialysis method. The release profiles of cabazitaxel and β-elemene in these liposomes conformed to the Weibull equation. The release of cabazitaxel and β-elemene in the complex liposome were almost synchronous. The pharmacodynamics study showed that cabazitaxel flexible liposome and β-elemene flexible liposome were relatively good at overcoming paclitaxel resistance on paclitaxel-resistant lung adenocarcinoma. As the flexible complex liposome, the dosage of cabazitaxel could be reduced to 25% that of the cabazitaxel injection while retaining a similar therapeutic effect. It showed that β-elemene can replace some of the cabazitaxel, allowing the dosage of cabazitaxel to be reduced, thereby reducing the drug toxicity.
Topics: Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Humans; Liposomes; Mice; Molecular Structure; Paclitaxel; Particle Size; Sesquiterpenes; Taxoids; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 31052317
DOI: 10.3390/molecules24091697