Meta-analysis of Nanoparticulate Paclitaxel Delivery System Pharmacokinetics and Model Prediction of Associated Neutropenia

Purpose

Nanoparticulate paclitaxel carriers have entered clinical evaluation as alternatives to the Cremophor-based standard Taxol^? (Cre-pac). Their pharmacokinetics (PK) is complex, and factors influencing their pharmacodynamics (PD) are poorly understood. We aimed to develop a unified quantitative model for 4 paclitaxel carriers that captures systems-level PK, predicts micro-scale PK processes, and permits correlations between carrier properties and observed PD.

Methods

Data consisting of 54 PK profiles and 574 observations were extracted from 20 clinical studies investigating Cre-pac, albumin-(A-pac), liposome-(L-pac), and tocopherol-(T-pac) nanocarriers. A population-PK approach was used for data analysis. All datasets were simultaneously fitted to produce a unified model. Model-based simulations explored relationships between predicted PK and myelosuppression for each formulation.

Results

The final model employed nonlinear drug-binding mechanisms to describe Cre-pac and a delayed-release model for A-pac, L-pac, and T-pac. Estimated drug-release rate constants (h^?1): Cre-pac (5.19), L-pac (1.26), A-pac (0.72), T-pac (0.74). Simulations of equivalent dosing schemes ranked neutropenia severity (highest to lowest): T-pac~Cre-pac>L-pac~A-pac and predicted remarkably well the clinically-observed relationships between neutropenia and free drug exposure relative to a threshold concentration.

Conclusions

Paclitaxel disposition was well-described for all formulations. The derived model predicts toxicodynamics of diverse paclitaxel carriers.     

Enhanced solubility and stability of PEGylated liposomal paclitaxel: in vitro and in vivo evaluation

An improved PEGylated liposomal formulation of paclitaxel has been developed with the purpose of improving the solubility of paclitaxel as well as the physicochemical stability of liposome in comparison to the current Taxol formulation. The use of 3% (v/v) Tween 80 in the hydration media was able to increase the solubility of drug. The addition of sucrose as a lyoprotectant in the freeze-drying process increased the stability of the liposome particles. There was no significant difference in the entrapment efficiency of paclitaxel between the conventional non-PEGylated liposomes and our PEGylated liposomes. Cytotoxicity in human breast cancer cell lines (MDA-MB-231 and SK-BR-3) of our paclitaxel formulation was less potent compared to Taxol after 24h incubation, but was equipotent after 72 h due to the slower release of drug from the liposome. Our PEGylated liposomes increased the biological half-life of paclitaxel from 5.05 (+/-1.52)h to 17.8 (+/-2.35)h compared to the conventional liposomes in rats. Biodistribution studies in breast cancer xenografted nude mouse model showed that our liposomes significantly decreased the uptake in reticuloendothelial system (RES)-containing organs (liver, spleen and lung) while increasing the uptake in tumor tissues after injection compared to Taxol or the conventional liposomal formulation. Moreover, the PEGylated liposome showed greater tumor growth inhibition effect in in vivo studies. Therefore, our PEGylated liposomal formulation of paclitaxel could serve as a better alternative for the passive targeting of human breast tumors.     

Pharmacokinetics, tissue distribution and anti-tumour efficacy of paclitaxel delivered by polyvinylpyrrolidone solid dispersion

Objectives Paclitaxel is a potent anti‐cancer drug that has exhibited clinical activity against several tumours. Unfortunately, serious side effects are associated with Taxol, the commercial formulation of paclitaxel, which contains Cremophor EL (CrEL). Currently, the main focus of developing paclitaxel formulations is on improving efficacy and reducing toxicity. A novel, Cremophor‐free, paclitaxel solid dispersion (PSD) was prepared in our laboratory previously. The primary aim of this study was to evaluate the pharmacokinetics, tissue distribution, acute toxicity and anti‐tumour efficacy of the PSD compared with Taxol. Methods SD rats were used to examine the pharmacokinetics and tissue distribution of PSD. The acute toxicity of PSD was evaluated in ICR mouse. The anti‐tumor activity of PSD was assessed in an in vivo anti‐tumor nude mice model inoculated with human SKOV‐3 cancer cells. Key findings The two formulations presented different pharmacokinetic behaviour. The plasma AUC of paclitaxel in the PSD was 5.84‐fold lower than that of Taxol, and the mean residence time, total body clearance and apparent volume of distribution of paclitaxel in the PSD were increased by 1.73, 4.67 and 8.57 fold, respectively. However, the two formulations showed similar tissue distribution properties. CrEL, the vehicle in Taxol, decreased the clearance of paclitaxel from plasma. The LD50 (median lethal dose) was 34.8 mg/kg for Taxol, whereas no death was observed at 160 mg/kg for the PSD. The anti‐tumour activity of PSD was similar to that of Taxol at a dose of 15 mg/kg. Most importantly, the improved tolerance of PSD enabled a higher administrable dose of paclitaxel, which resulted in improved efficacy compared with Taxol administered at its maximum tolerated dose. Conclusions These results suggest that the PSD, a CrEL‐free formulation, is a promising approach to increase the safety and efficacy of paclitaxel.     

A folate receptor-targeted liposomal formulation for paclitaxel

A novel liposomal formulation of paclitaxel targeting the folate receptor (FR) was synthesized and characterized. This formulation was designed to overcome vehicle toxicity associated with the traditional Cremophor EL-based formulation and to provide the added advantages of prolonged systemic circulation time and selective targeting of the FR, which is frequently overexpressed on epithelial cancer cells. The formulation had the composition of dipalmitoyl phosphatidylcholine/dimyristoyl phosphatidylglycerol/monomethoxy-polyethylene glycol (PEG)2000-distearoyl phosphatidylethanolamine/folate-PEG3350-distearoyl phosphatidylethanolamine (DPPC/DMPG/mPEG-DSPE/folate-PEG-DSPE) at molar ratios of (85.5:9.5:4.5:0.5) and a drug-to-lipid molar ratio of 1:33. The liposomes were prepared by polycarbonate membrane extrusion. The mean particle size of the liposomes was 97.1 nm and remained stable for at least 72 h at 4 degrees C. FR-targeted liposomes of the same lipid composition entrapping calcein were shown to be efficiently taken up by KB oral carcinoma cells, which are highly FR+. FR-targeted liposomes containing paclitaxel showed 3.8-fold greater cytotoxicity compared to non-targeted control liposomes in KB cells. Plasma clearance profiles of paclitaxel in the liposomal formulations were then compared to paclitaxel in Cremophor EL formulation. The liposomal formulations showed much longer terminal half-lives (12.33 and 14.23 h for FR-targeted and non-targeted liposomes, respectively) than paclitaxel in Cremophor EL (1.78 h). In conclusion, the paclitaxel formulation described in this study has substantial stability and favorable pharmacokinetic properties. The FR-targeted paclitaxel formulation is potentially useful for treatment of FR+ tumors and warrants further investigation.     

In vivo pharmacokinetic and tissue distribution studies in mice of alternative formulations for local and systemic delivery of Paclitaxel: gel, film, prodrug, liposomes and micelles

The aim of this study was to increase the understanding on the pharmacokinetic and tissue distribution of paclitaxel as influenced by formulation approach. For this purpose, various formulations investigated in Swiss mice included liposomes, poloxamer 407 gel and chitosan film for subcutaneous route; and water-soluble methacrylate prodrug, liposomes and poloxamer micelles for systemic administration. During this study, the currently marketed formulation of Cremophor EL of paclitaxel was used as the reference. A highest plasma concentration following intravenous administration of paclitaxel was observed for rigid and 'Stealth((R))' liposomes containing the prodrug while, least was for covalently incorporated paclitaxel micelles. Further, poloxamer micelles demonstrated both the highest mean residence time of 7.34 h and volume of distribution (VSS=4.82 and VZ=5.87 L/kg) for paclitaxel. This was followed by prodrug loaded 'Stealth' liposomes, which showed a mean residence time of 4.96 h but were least distributed into apparent physiological volume (VSS=2.12 and VZ=3.16 L/kg). These results clearly signify the role of formulation/excipient in drug disposition and possible interactions. Importantly, due to decrease in the clearance rate of drug, the area under curve values of paclitaxel increased by 1.64- and 2.5-fold for micellar and prodrug loaded 'Stealth' liposomal formulations, respectively over reference formulation. While thermoreversible gels served to decrease plasma concentration of paclitaxel (8-fold) after subcutaneous administration, systemic levels were totally absent after implantation of films. In tissue distribution studies, maximum percent of paclitaxel was observed in liver for reference formulation, conventional liposomes and micelles whereas highest levels of prodrug and 'Stealth((R))' liposomes were in kidney and spleen, respectively. The novel formulations significantly altered tissue accumulation profiles of paclitaxel relative to the reference formulation, for example, reduction in uptake by heart from liposomes and micelles, as well as the major recognition mechanism for elimination. It is proposed that a combination therapy with liposomes and micelles of paclitaxel for systemic delivery along with implantation of chitosan film for local delivery, may serve not only to improve patient compliance by obliterating the need to administer Cremophor EL, but also increase patient survival.     

Evaluation of biosafety and intracellular uptake of Cremophor EL free paclitaxel elastic liposomal formulation

The present study examines the acute, sub-acute toxicity, and cytotoxicity of paclitaxel elastic liposomal formulation in comparison to a marketed Cremophor EL (polyoxyethylated castor oil):ethanol (1:1, v/v) based formulation. In the previous study, Cremophor EL free paclitaxel elastic liposomal formulation was developed and characterized. Cytotoxicity of formulation was evaluated by MTT assay using A549 cell lines. Percentage intracellular uptake of paclitaxel elastic liposomal and marketed formulation was determined using a fluorescence activating cell sorting assay (FACS) and fluorescence microscopy techniques. Single and repeated dose toxicity measurement showed no mortality, hematological, biochemical, or histopathological changes up to a dose of 120?mg/kg for paclitaxel elastic liposomal formulation, in comparison the marketed formulation showed toxicity at a dose of 40?mg/kg. Maximum tolerated dose (MTD) for paclitaxel elastic liposomal and marketed formulation was found to be 160?mg/kg and 40?mg/kg, respectively. Results of FACS analysis showed a 94.6?±?2.5% intracellular uptake of fluorescence marker acridine orange (AO) loaded in elastic liposomes; in comparison the AO solution showed only a 19.8?±?1.1% uptake. Paclitaxel elastic liposomal formulation seems to be a better alternative for safe and effective delivery of paclitaxel. This study proves the safety and higher intracellular uptake of paclitaxel elastic liposomal formulation.     

Biodistribution of liposome-entrapped human gamma-globulin

The present study was aimed at the preparation and performance evaluation of Intacglobin-loaded liposomes for selective drug presentation to the lungs. Egg phosphatidylcholine- and cholesterol-based liposomes (1:1 and 1:0.25 mol/mol) were prepared by a dehydration-rehydration procedure. A tissue distribution study after single intranasal administration of 0.5 microCi 125I-Intacglobin-loaded liposomes was conducted in Balb/c mice. The efficiencies of drug entrapment (30%) and the average diameters did not differ significantly between the two liposome formulations. However, liposomes composed of an increased cholesterol amount showed a lower in vitro drug release rate. The airway penetration efficiency of the liposomal formulation was determined by the cumulative percentage of the dose reaching the lungs (AUC) and its sojourn time therein, and were 1.7- and 2.2-times higher compared with the plain 125I- Intacglobin solution-based formulation, respectively. A significantly greater (p<0.001) drug localization index after 24 h was found at the lungs in comparison with the other tissues (p<0.01), although similar values were detected between groups following administration of either liposomes or control solutions, despite the formulations attributes. In conclusion, it is suggested that longer Intacglobin exposure at the pulmonary region is observed after administration of the liposomal formulation. The results open future perspectives in assessing local passive immunization for the treatment of respiratory infectious diseases.     

Liposomal topotecan formulation with a low polyethylene glycol grafting density: pharmacokinetics and antitumour activity

Objectives PEGylated liposomes could evade recognition by the reticulo‐endothelial system and prolong the circulation time of vesicles, resulting in enhanced targeting efficiency and antitumour effect. Typically, vesicles are modified with distearoylphosphatidylethanolamine (DSPE)‐polyethylene glycol (PEG) at a high PEG grafting density. However, long circulation time and slow drug release rate might induce severe hand‐foot syndrome in clinical practice. In this study, a liposomal topotecan formulation with a low PEG grafting density was prepared and its pharmacokinetics, acute toxicity and antitumour effect were investigated. Methods Topotecan was loaded into liposomes using an ammonium sulfate gradient. The resulting formulation was injected to healthy Wistar rats at different dose levels to investigate whether its clearance followed linear kinetics. Biodistribution was performed in Lewis lung cancer‐bearing mice. The acute toxicity was evaluated in healthy mice and beagle dogs. To compare the antitumour effects of different formulations and dose schedule, RM‐1 prostate, Lewis lung, H446 and L1210 cancer models were used. Key findings Topotecan could be encapsulated into low DSPE‐PEG liposomes with ～100% loading efficiency. The clearance of the liposomal formulation followed linear kinetics at a dose level ranging from 0.5 to 4 mg/kg despite the fact that the vesicles were coated at a low PEG density. Compared with free topotecan the liposomal formulation preferentially accumulated into tumour zones instead of normal tissues. Both formulations could rapidly accumulate into liver and tumour, but the liposomal formulation was cleared from tissues at a slow rate relative to the conventional formulation. In rats and beagle dogs, liposomal formulations could not induce skin toxicity. In all the tumour models, smaller split doses were more therapeutically active than larger doses when the overall dose intensity was equivalent. Conclusions This has been the first report that plasma kinetics of a liposomal formulation with a low PEG density followed linear kinetics. Moreover, due to its short circulation half‐life, the formulation did not induce skin toxicity. Our data revealed that the dose schedule of liposomal drugs should be adjusted in accordance with the biophysical and biological properties of the formulations to achieve the optimal therapeutic efficacy.     

Intravenous Hydrophobic Drug Delivery: A Porous Particle Formulation of Paclitaxel (AI-850)

No HeadingPurpose. To develop a rapidly dissolving porous particle formulation of paclitaxel without Cremophor EL that is appropriate for quick intravenous administration.Methods. A rapidly dissolving porous particle formulation of paclitaxel (AI-850) was created using spray drying. AI-850 was compared to Taxol following intravenous administration in a rat pharmacokinetic study, a rat tissue distribution study, and a human xenograft mammary tumor (MDA-MB-435) model in nude mice.Results. The volume of distribution and clearance for paclitaxel following intravenous bolus administration of AI-850 were 7-fold and 4-fold greater, respectively, than following intravenous bolus administration of Taxol. There were no significant differences between AI-850 and Taxol in tissue concentrations and tissue area under the curve (AUC) for the tissues examined. Nude mice implanted with mammary tumors showed improved tolerance of AI-850, enabling higher administrable does of paclitaxel, which resulted in improved efficacy as compared to Taxol administered at its maximum tolerated dose (MTD).Conclusions. The pharmacokinetic data indicate that paclitaxel in AI-850 has more rapid partitioning from the bloodstream into the tissue compartments than paclitaxel in Taxol. AI-850, administered as an intravenous injection, has been shown to have improved tolerance in rats and mice and improved efficacy in a tumor model in mice when compared to Taxol.     

Enhancement of Tissue Delivery and Receptor Occupancy of Methylprednisolone in Rats by a Liposomal Formulation

A liposomal formulation of methylprednisolone (L-MPL) was developed to improve localization of this immunosuppressant in lymphatic tissues. Liposomes containing MPL were formulated from a mixture of phosphatydylcholine and phosphatydylglycerol (molar ratio, 9:1) and sized by extrusion through a 0.1-µm membrane. Male Sprague–Dawley rats received a bolus dose of 2 mg/kg of L-MPL or free MPL in solution (control). Samples of blood, spleen, liver, thymus, and bone marrow were collected at intervals over a 66-hr period. Concentrations of MPL in plasma and organs and free cytosolic glucocorticoid receptors (GCR) in spleen and liver were determined. The plasma MPL profiles for free and L-MPL were bi- and triexponential. Although the alpha phase kinetics of both dosage forms were similar, L-MPL showed a substantially slower elimination phase than did free drug. Incorporation of MPL into liposomes caused the following increases: terminal half-life, from 0.48 (MPL) to 30.13 hr (L-MPL); MRT, from 0.42 to 11.95 hr, V _ss, from 2.10 to 21.87 L/kg; and AUC, from 339 to 1093 ng · hr/mL. Uptake of liposomes enhanced significantly the delivery of drug to lymphatic tissues and liver; AUC tissue:plasma ratios for spleen increased 77-fold; for liver, 9-fold; and for thymus, 27-fold. The duration of GCR occupancy was extended 10-fold in spleen and 13-fold in liver by the liposomal formulation. Lymphatic tissue selectivity and extended receptor binding of liposome-delivered MPL offer promise for enhanced immunosuppression.     

Localized delivery of paclitaxel using elastic liposomes: Formulation development and evaluation

In the present study an elastic liposomes-based paclitaxel formulation was developed with the objective to remove Cremophor EL. Cremophor EL is currently used for solubilizing paclitaxel in the marketed formulation and is known to produce toxic effects. Elastic liposomal paclitaxel formulation was extensively characterized in vitro, ex-vivo, and in vivo. The results obtained were compared against the marketed paclitaxel formulation. The maximum amount of paclitaxel loaded in the elastic liposomal formulation was found to be 6.0?mg/ml, which is similar to the commercial strength of marketed paclitaxel formulation. In vitro skin permeation and deposition studies showed 10.8-fold enhanced steady state transdermal flux and 15.0-fold enhanced drug deposition in comparison to drug solution. These results further confirmed with the vesicle–skin interaction study using FTIR technique. Results of the hemolytic toxicity assay indicate that elastic liposomal formulation induced only 11.2?±?0.2% hemolysis in comparison to the commercial formulation which showed 38?±?3.0%. Further, results of the Draize test showed no skin irritation of paclitaxel elastic liposomal formulation. Findings of the study demonstrate that elastic liposomes as a carrier is an attractive approach for localized delivery of paclitaxel.     

Reduced hepatic toxicity, enhanced cellular uptake and altered pharmacokinetics of stavudine loaded galactosylated liposomes.

The aim of the present investigation was to reduce the hepatic toxicity, enhance the cellular uptake and alter the pharmacokinetics of stavudine using galactosylated liposomes. beta-D-1-Thiogalactopyranoside residues were covalently coupled with dimyristoyl phosphatidylethanolamine, which was then used to form liposomes. The galactosylated liposomal system was assessed for in vitro ligand-specific activity. The drug release from liposomes was studied by dialysis method. Ex vivo cellular uptake study was performed using liver parenchymal cells harvested from male albino rats. Changes in hematological parameters, hepatic enzymes, hepatomegaly, plasma and tissue distribution of the formulations (free stavudine solution, uncoated liposomal and galactosylated liposomes) were determined using albino rats. Percent cumulative drug release in 24h was low (34.8+/-2.6%). Enhanced hepatic cellular d4T uptake (27.96+/-2.41pg d4T/million cells) was seen in case of galactosylated liposomal d4T. Galactosylated liposomes maintained a significant level of d4T in tissues rich in galactose specific receptors and had a prolonged residence (11.44+/-1.25h) in the body resulting in enhanced half-life of d4T (23.07+/-1.25h). This formulation did not show either hematological or hepatic toxicity. Galactosylation of liposomes alter the biodistribution of encapsulated drug thereby delivering the drug to cells bearing galactose specific receptors.     

Localized delivery of paclitaxel using elastic liposomes: formulation development and evaluation

In the present study an elastic liposomes-based paclitaxel formulation was developed with the objective to remove Cremophor EL. Cremophor EL is currently used for solubilizing paclitaxel in the marketed formulation and is known to produce toxic effects. Elastic liposomal paclitaxel formulation was extensively characterized in vitro, ex-vivo, and in vivo. The results obtained were compared against the marketed paclitaxel formulation. The maximum amount of paclitaxel loaded in the elastic liposomal formulation was found to be 6.0 mg/ml, which is similar to the commercial strength of marketed paclitaxel formulation. In vitro skin permeation and deposition studies showed 10.8-fold enhanced steady state transdermal flux and 15.0-fold enhanced drug deposition in comparison to drug solution. These results further confirmed with the vesicle-skin interaction study using FTIR technique. Results of the hemolytic toxicity assay indicate that elastic liposomal formulation induced only 11.2 ± 0.2% hemolysis in comparison to the commercial formulation which showed 38 ± 3.0%. Further, results of the Draize test showed no skin irritation of paclitaxel elastic liposomal formulation. Findings of the study demonstrate that elastic liposomes as a carrier is an attractive approach for localized delivery of paclitaxel.     

Safety and pharmacokinetic studies of liposomal antioxidant formulations containing N-acetylcysteine, α-tocopherol or γ-tocopherol in beagle dogs

Abstract

The safety and pharmacokinetic profile of liposomal formulations containing combinations of the antioxidants α-tocopherol, γ-tocopherol or N-acetylcysteine in beagle dogs was examined. Each group consisted of beagle dogs of both genders with a control group receiving empty dipalmitoylphosphatidylcholine (DPPC) liposomes (330?mg/kg DPPC, EL), and test groups receiving liposomes prepared from DPPC lipids with (i) N-acetylcysteine (NAC) (60?mg/kg NAC [L-NAC]); (ii) NAC and α-tocopherol (αT) (60?mg/kg NAC and 25?mg/kg α-tocopherol [L-αT-NAC]) and (iii) NAC and γ-tocopherol (60?mg/kg NAC and 25?mg/kg γ-tocopherol (γT) [L-γT-NAC]). The dogs in the control group (EL) and three test groups exhibited no signs of toxicity during the dosing period or day 15 post treatment. Weight gain, feed consumption and clinical pathology findings (hematology, coagulation, clinical chemistry, urinalysis) were unremarkable in all dogs and in all groups. Results from the pharmacokinetic study revealed that the inclusion of tocopherols in the liposomal formulation significantly increased the area under the curve (AUC) and β-half life for NAC; the tocopherols had greater impact on the clearance of NAC, where reductions of central compartment clearance (CL) ranged from 56% to 60% and reductions of tissue clearance (CL₂) ranged from 73% to 77%. In conclusion, there was no treatment-related toxicity in dogs at the maximum feasible dose level by a single bolus intravenous administration while the addition of tocopherols to the liposomal formulation prolonged the circulation of NAC in plasma largely due to a decreased clearance of NAC.     

Preparation and the in-vivo evaluation of paclitaxel liposomes for lung targeting delivery in dogs

Objectives The aim of this study was to develop paclitaxel liposomes for a lung targeting delivery system. Methods The liposomes composed of Tween‐80/HSPC/cholesterol (0.03 : 3.84 : 3.84, mol/mol), containing paclitaxel and lipids (1 : 40, mol/mol), were prepared by a combination of solid dispersion and effervescent techniques, and then subjected to ultrasonication. The pharmacokinetics and biodistribution of liposomal and injectable formulation of paclitaxel in dogs were studied after intravenous administration. Key findings The mean diameter, polydispersity index, zeta‐potential and entrapment efficiency of the liposomes were 501.60 ± 15.43 nm, 0.28 ± 0.02, ?20.93 ± 0.06 mV and 95.17 ± 0.32%, respectively. The liposomal formulation kept stable for at least 3 months at 6 ± 2°C and didn't cause haemolysis. The liposome carrier decreased the area under the curve and terminal half‐life of paclitaxel compared with paclitaxel injection ranging from 0.352 ± 0.031 mg/l*h and 0.0671 ± 0.144 h to 0.748 ± 0.062 mg/l*h and 1.978 ± 0.518 h, respectively. The paclitaxel liposomes produced a drug concentration in the lung that was markedly higher than that in other organs or tissues and was about 15‐fold of that of paclitaxel injection at 2 h. Conclusions To sum up, these results demonstrated that the paclitaxel liposomes are an effective lung targeted carrier in the treatment of lung cancer.     

两种紫杉醇注射剂在荷瘤小鼠体内药动学与组织分布的比较研究

目的比较以聚氧乙烯蓖麻油为增溶剂的紫杉醇注射液（Taxol）与以白蛋白为载体的紫杉醇纳米注射剂（ABI）在荷瘤小鼠体内药动学及组织分布的差异。方法 BALB/c小鼠经前肢腋下皮下接种鼠源乳腺癌EMT6细胞,待瘤体长到约1 g,按既定分组经尾静脉分别给予Taxol和ABI,给药剂量以紫杉醇计均为20 mg.kg-1。HPLC-UV测定血浆、瘤组织及心、肝、脾、肺、肾等主要组织器官中紫杉醇含量,并计算相应药动学参数。结果 ABI组动物瘤组织中的紫杉醇AUC高于Taxol组23.3%,而血浆中紫杉醇的AUC则显著低于Taxol组,并具有更大的Vd和CL（P〈0.05）。两种不同制剂给药,紫杉醇在心、肝、脾、肾中的分布趋势基本一致,但ABI组动物肺中的紫杉醇分布显著低于Taxol组（P〈0.05）。结论和传统紫杉醇注射液相比,白蛋白紫杉醇纳米粒制剂的瘤组织分布靶向性和药动学特性显著改善,应用前景广阔。     

Safety, efficacy and pharmacokinetics of tuftsin-loaded nystatin liposomes in murine model

Present study was performed to evaluate the efficacy, toxicity and pharmacokinetics of antifungal drug nystatin incorporated in immunomodulator tuftsin-bearing liposomes. In vitro toxicity of free nystatin and nystatin incorporated in tuftsin-free or tuftsin-loaded liposomes was assessed by incubation of nystatin formulations with human erythrocytes. The toxicity profile of free nystatin and liposomal formulations of nystatin with or without tuftsin was also analyzed by monitoring the level of blood urea nitrogen (BUN) and serum creatinine in the treated BALB/c mice. The results of the present work showed that tuftsin-loaded nystatin liposomes like conventional nystatin liposomes exerted less toxicity to human erythrocytes as compared with free nystatin. Moreover, mice treated with tuftsin-loaded nystatin liposomes showed insignificant elevation in the biochemical values of serum creatinine and blood urea. The stability of nystatin liposomes upon incorporation of tuftsin was evaluated by monitoring the leakage of the entrapped drug in human serum. Tuftsin-loaded liposomes held nystatin for longer duration in the presence of serum than identical nystatin liposomes without tuftsin. Pharmacokinetics of the both tuftsin-free or tuftsin-loaded liposomal formulations nystatin was analyzed by determining the level of nystatin in the systemic circulation of mice at different time points. Mice injected with tuftsin-loaded nystatin liposomes showed higher level of the drug in the systemic circulation compared with those treated with conventional nystatin liposomes. The efficacy of tuftsin-loaded nystatin liposomes against A. fumigatus was evaluated by assessing the fungal burden in the lungs of treated mice. Treatment with tuftsin-loaded nystatin liposomes was most effective in eliminating fungal burden from lung tissues of infected mice compared to those treated with free nystatin or nystatin liposomes without tuftsin. The immunopotentiating activity, increased stability and less toxicity of tuftsin-incorporated nystatin liposomes, supports the idea for its prophylactic and therapeutic use in the clinical setting.     

Intravenous administration of paclitaxel in Sprague‐Dawley rats: what is a safe dose?

Few studies describe the administration of Taxol to rats; however, rats are typically used to study the toxicity of new drugs or novel formulations. A dose finding study was conducted to determine a safe dose of Taxol following intravenous administration in rats. Male Sprague-Dawley rats received a bolus of paclitaxel 5-20 mg/kg i.v. Blood was drawn before administration and at the following times after administration: 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 h. Plasma concentrations were determined using high performance liquid chromatography. Two rats received paclitaxel 20 mg/kg and died immediately. Nine rats received paclitaxel 10 mg/kg; seven of these rats died within 12 h and two rats were killed due to moribund conditions. Ten rats received paclitaxel 5 mg/kg with no morbidity. The following pharmacokinetics for paclitaxel in the plasma were estimated: C0, 8977 ng/ml; AUC(0 --> infinity), 7477 ng*h/ml; CL(s), 668 ml/h*kg; V(ss), 1559 ml/kg; V(z) 2557 ml/kg and t(1/2), 2.6 h. It is concluded that further pharmacokinetic studies that are rationally designed to include appropriate measures of preclinical toxicity associated with paclitaxel are needed to identify formally the safest dose in rats following intravenous administration; however, these data indicate that male Sprague-Dawley rats can safely receive Taxol in a 5 mg/kg i.v. bolus.     

紫杉醇新型制剂及临床研究进展

紫杉醇是一种临床应用广泛的广谱抗肿瘤药物,其独特的阻碍微管蛋白解聚的作用机制使其对多种实体瘤具有良好的疗效。但由于紫杉醇的水溶性极低,早期上市的传统制剂采用了高浓度的聚氧乙烯蓖麻油(Cremophor EL)作为增溶剂,后者易引发一系列过敏反应,用药前需进行脱敏处理,严重限制了紫杉醇的临床使用,同时给患者带来极大的痛苦。不含Cremophor EL的紫杉醇新制剂的开发多年来持续受到国内外的广泛关注,其中成功上市的有紫杉醇脂质体(力扑素~)、注射用白蛋白结合型紫杉醇(Abraxane~)和紫杉醇聚合物胶束Genexol~-PM,进入Ⅰ~Ⅲ期临床研究的有脂质体LEP-ETU、阳离子脂质体EndoTAG~-1、胶束化纳米粒NK105和新型口服制剂DHP107。本文对上述新型制剂的特点及临床研究进展进行回顾和综述。     

Formulating Paclitaxel in Nanoparticles Alters Its Disposition

Purpose Paclitaxel is active and widely used to treat multiple types of solid tumors. The commercially available paclitaxel formulation uses Cremophor/ethanol (C/E) as the solubilizers. Other formulations including nanoparticles have been introduced. This study evaluated the effects of nanoparticle formulation of paclitaxel on its tissue distribution.Methods We compared the plasma and tissue pharmacokinetics of paclitaxel-loaded gelatin nanoparticles and the C/E formulation. Mice were given paclitaxel-equivalent doses of 10 mg/kg by intravenous injection.Results The nanoparticle and C/E formulations showed significant differences in paclitaxel disposition; the nanoparticles yielded 40% smaller area under the blood concentration-time curve and faster blood clearance of total paclitaxel concentrations (sum of free, protein-bound, and nanoparticle-entrapped drug). The two formulations also showed different tissue specificity. The rank order of tissue-to-blood concentration ratios was liver > small intestine > kidney >> large intestine > spleen = stomach > lung > heart for the nanoparticles, and liver > small intestine > large intestine > stomach > lung kidney > spleen > heart for the C/E formulation. The nanoparticles also showed longer retention and higher accumulation in organs and tissues (average of 3.2 ± 2.3-fold), especially in the liver, small intestine, and kidney. The most striking difference was an 8-fold greater drug accumulation and sustained retention in the kidney.Conclusions These data indicate that formulation of paclitaxel affects its clearance and distribution into tissues, with preferential accumulation of nanoparticles in the liver, spleen, small intestine, and kidney.