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The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin (DOX)-loaded methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration; DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.
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Objective: To prepare pegylated long-circulating liposomes co-encapsulated by costunolide (Cos) and dehydrocostus lactone (DL), optimize the formulation and process, and evaluate the quality. Methods: The pegylated long-circulating liposomes co-encapsulated by Cos and DL were prepared by film hydration method. Single factor test and Box-Behnken response surface methodology were used to optimize the preparation process with encapsulation efficiency of Cos and DL as the index. The particle size, surface potential, encapsulation efficiency and in vitro release of the liposomes were evaluated. Results: The optimal preparation conditions were as follows: drug-to-lipid ratio was 0.14, ratio of cholesterol to phospholipid was 0.05, mPEG-2000-DSPE addition amount was 6%, hydration time was 30 min, and probe ultrasonic time was 4 min. The obtained liposome was round and uniform in distribution, with an average particle size of (104.8 ± 2.48) nm, a polydispersity index (PDI) of (0.245 ± 0.031), and a Zeta potential of (-9.7 ± 0.23) mV, the encapsulation efficiency of Cos and DL were (91.9 ± 2.6)% and (94.41 ± 1.23)%, respectively. Conclusion: The PEGylated long-circulating liposome prepared by the process and prescription optimization has good appearance and high encapsulation efficiency, which can meet the application requirements.
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The therapeutic application of artemisinin (ART) is restricted in application due to its poor water solubility and stability. In this study, the long-circulating liposomes (L-Lip) were constructed to improve the solubility and stability of ART. The preparation method, physicochemical properties, serum stability, in vitro release profile and cytotoxicity of the ART loaded long-circulating liposomes were investigated. Using the particle size and entrapment efficiency (EE) as the evaluation index, the preparation procedure was optimized by the Box-Behnken response surface design based on the single factor screening method. The ART loaded long-circulating liposomes were prepared by filming rehydration method, and evaluated with particle size and entrapment efficiency. The optimal formulation was as follows:lipid-cholesterol=5.22:1 (mass ratio), drug-lipid=1:23.15 (mass ratio), lipid concentration=14.35 mg·mL-1, and molar percentage of mPEG=2%. The morphology of L-Lip was uniformly spherical shape according to optimal formulation. The mean size and polydispersity index (PDI) were about (113.3 ±4.7) nm and 0.227 ±0.022 respectively, the zeta potential was (-12.9 ±2.6) mV, and the entrapment efficiency (EE) of ART was (95.88 ±4.8)%. The L-Lip had good stability at 4℃ for 15 days and the particle sizes did not exhibit significant variations in 50% rat plasma over 24 h at 37℃. The in vitro release study of formulation showed a sustained release. Moreover, the cytotoxicity exhibited that blank liposomes were of great safety. Compared with the free ART, the liposome formulation achieved lower cytotoxicity at the high concentration. The L-Lip successfully prepared by a simple filming-rehydration method exhibited ideal physicochemical properties and were enhanced safety, which may sever as a promising nanoplatform for clinical application.
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Objective To prepare dihydromyricetin (DMY) long-circulating liposomes and evaluate in vitro release dynamics and in vivo pharmacokinetics in rats. Methods Film-ultrasonic method was used to prepare DMY liposomes by single factor experiment and orthogonal test to optimize the formulation and preparation of DMY liposomes. The particle size and zeta potential of liposomes were determined by laser particle size analyzer. The morphological examination of liposomes was performed by using transmission electron microscopy. The liposome release in vitro was studied using dialysis method. DMY concentration in rat plasma was determined by the established LC-MS/MS method. Results The optimal prescription was 75∶20∶5 for soybean phospholipid-cholesterol-mPEG 2000-DSPE, and 1∶12 for DMY-lipid (wt/wt) with the ultrasonic time of 20 min and loading temperature of 60 ℃ in pH 5.0 PBS buffer. Under the optimized conditions, DMY liposomes was sphere with mean particle size of (117.9 ± 5.5) nm and mean zeta potential of (−2.6 ± 1.7) mV, the encapsulation efficiency and drug-loading content was (54.7 ± 3.3) % and (4.3 ± 0.2) %, respectively. The in vitro accumulative release rate of 48 h was 86% in pH 1.2 and pH 6.8 dissolve medium. Compared with free DMY, the t1/2z and AUC0-∞ of DMY liposome were increased by 2.7-fold and 1.8-fold, respectively. Conclusion Compared with free DMY, DMY liposomes released gently and slowly in vitro, eliminated slowly in vivo, and had higher bioavailability of oral administration.
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Objective To prepare paraoxonase 1 (PON1) liposomes, and investigate pharmacokinetics of common PON1 liposomes (L-PON1) and polyethylene glycol-modified PON1 long circulating liposomes (PEG-PON1-LCL) in rats after intravenous administration. Methods L-PON1 and PEG-PON1-LCL were prepared by film dispersion method. The entrapment efficiency, mean diameter and Zeta potential of the liposomes were measured, and the stability was evaluated. Thirty-six Wistar rats were divided into three groups according to random number table, with 12 rats in each group. The rats were intravenously administrated with PON1, L-PON1 or PEG-PON1-LCL 700 U/kg, respectively. The activity of PON1 in serum was determined by phenyl acetate method, the activity of PON1 at different time points after drug administration was compared with that before drug administration, and the difference value was considered as the activity of exogenous PON1, and PON1 activity-time curve was plotted. The pharmacokinetic parameters were calculated and analyzed by DAS 2.0 pharmacokinetic program and SPSS 17.0. Results The entrapment efficiencies of L-PON1 and PEG-PON1-LCL were above 85%, the mean diameter was about 126 nm, and Zeta potential was -14.35 mV. After 2 weeks of preservation, the above parameters showed no obvious change, indicating that liposomes had good stability and the properties of preparations were basically stable. Compared with purified PON1 administration, after L-PON1 and PEG-PON1-LCL administration, the activity of PON1 was increased, the half-life of PON1 activity in rats was significantly prolonged [the half-life of distribution (T1/2α, hours): 0.142±0.018, 0.147±0.021 vs. 0.126±0.022; the half-life of clearance (T1/2β, hours): 3.877±1.010, 4.520±1.117 vs. 1.226±0.422], the area under PON1 activity-time curve (AUC) was significantly increased [AUC from 0 hour to 24 hours (AUC0-24, U·h-1·L-1): 499.305±64.710, 563.576±70.450 vs. 18.053±2.190; AUC from the immediate injection to the disappearance of PON1 activity (AUC0-∞, U·h-1·L-1): 516.256±60.940, 587.801±76.210 vs. 21.044±3.250], the apparent volume of distribution (Vd) and clearance (CL) were significantly decreased [Vd (L): 0.140±0.065, 0.144±0.064 vs. 0.493±0.032, CL (L/h):0.039±0.008, 0.034±0.006 vs. 0.952±0.082, all P < 0.05]. There was no significant difference in pharmacokinetics between L-PON1 and PEG-PON1-LCL. Conclusions The film dispersion method prepared PON1 liposomes have high entrapment efficiency and small particle size with a good stability. Both liposomes can raise PON1 activity in vivo, change the pharmacokinetics of PON1 in vivo, prolong the resident time of PON1 in the blood circulating system, and compensate for the short half-life of PON1 in vivo.
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Objective To optimize the preparation process of honokiol long-circulating liposomes (HLCL) and study the in vitro and in vivo release. Methods An orthogonal experiment was designed to optimize the composition of HLCL using entrapment efficiency as evaluation indicator. The liposome surface morphology was observed by transmission electron microscope (TEM), and the liposome release in vitro was studied by dialysis method. The concentration of honokiol in rat plasma was determined by the established LC-MS/MS method, and the differences in pharmacokinetic parameters were compared after honokiol and HLCL (20 mg/kg) were orally administered to SD male rats, respectively. Results The optimal composition of HLCL was 8:1:1 for soya phosphatidyl choline-cholesterol-mPEG2000-DSPE, and 1:10 for honokiol-liposome materials with the ultrasonic time of 12 min. Under the optimized conditions, HLCL was sphere with mean particle size of 121.5 nm and mean Zeta potential of -30.8 mV, the encapsulation efficiency and drug-loading content was 84.7% and 10.4%, respectively. In vitro release results showed that the liposomes could be gently and slowly release with the 24 h cumulative release rate at pH 1.2 and pH 6.9 dissolve medium of 80% and 71%, respectively. Based on the pharmacokinetic results, Cmax, tmax, and t1/2 were (23.29 ± 11.76) ng/mL, (0.13 ± 0.05) h and (10.59 ± 5.72) h for HLCL, and (79.34 ± 56.32) ng/mL, (0.30 ± 0.07) h and (4.44 ± 3.14) h for honokiol, respectively. There was no significant difference about the AUC0-∞ following oral administration of honokiol and HLCL at isodose honokiol (20 mg/kg). Conclusion Compared with honokiol, HLCL was released gently and slowly in vitro, absorpted rapidly and eliminated slowly in vivo.
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With the rapid development of modern medicine and pharmacy, the diagnosis and treatment of cancer have made great progress.However, cancer treatment is still a difficult and urgent problem in clinic, because the early detection is difficult for many tumors, the toxic and side effects are serious for drug therapy and treatment effect is poor.Long circulating liposomes delivery system based on nano-medicine are used for the diagnosis and treatment of tumors, which have brought new hope to cancer patients.After administration, long circulating liposomes are known for prolonging the circulation time, increasing the targeting accumulation in tumor, improving the effects of diagnosis and treatment and reducing the toxic and side effects of loading medicine or probe.In this paper, the advantages of long circulating liposome delivery system loaded with diagnostic probe or antitumor agent in targeting diagnosis and treatment of tumor are reviewed.
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Combretastatin A4 (CA4), a vascular inhibitor, can target tubulin and inhibit tubulin polymerization, thus it can inhibit the tumor blood vessels and has antitumor effect. But it is insoluble in water and has low bioavailability. CA4 phosphate (CA4P), the derivative of CA4, can improve the solubility of CA4 and convert into CA4. CA4P is undergoing phase II/III clinical trials abroad. However, CA4P has several undesirable side effects and relative short half-life in vivo. Nanoformulations can increase the dissolution and absorption of the drug and obtain controlled release and targeting, prolong the efficacy and reduce side effects. Working on the physical and chemical characteristics and biological pharmacy defects of CA4 and CA4P nanoformulations may change the dissolution, absorption and distribution of the drug. This paper reviews the current nanoformulations of CA4 and CA4P, including den-drimer, polymeric micelle (PM), nanoparticles (NP), long-circulating liposome (LCL), and discusses the prospects of their nanoformulations.
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Objective: To optimize the preparation process of gambogic acid (GA) liposomes and study the in vitro and in vivo release. Methods: The detection method of GA was established, using the Box-Behnken experiment design to optimize liposomes formula, GA liposomes were obtained with the highest encapsulation efficiency; Using scanning electron micrographs (SEM) to observe liposome surface morphology, using the dialysis method to study the liposome release in vitro, we also measured the stability of liposome in 15 d; Male Wistar rats were injected with GA or GA liposomes (1 mg/mL) via tail vein, UPLC-MS/MS method was used to determine the drug concentration, and differences in pharmacokinetic parameters of the two drugs were compared. Results: After Box-Behnken optimization, the encapsulation efficiency of liposomes was 92.3%, and the optimized liposomes formula is cholesterol of 440 mg, egg phosphatidylcholine of 1823 mg,,and istearoyl phosphoethanolamine-PEG 2000 of 705 mg, liposomes had uniform particle size and smooth surface; In vitro release results showed that the liposomes could be gentle and slowly release and had a long- term effect. The liposomes were stable keeping in 4 ℃ within 15 d; In in vivo study, the half-life of GA liposome was 9.97 h, 4.43 times of GA; AUC0-24 h of GA liposome was 22.55 μg∙h/mL, 4.73 times of GA. Conclusion: Compared with GA, GA liposome has the characteristics of long-circulating, high blood drug concentration, and could release smoothly.
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OBJECTIVE:To prepare Coenzyme Q10 long-circulating liposomes,establish the determination method of content and entrapment efficiency,and prepare it into lyophilized preparation to improve its stability. METHODS:Coenzyme Q10 long-cir-culating liposomes were prepared by film dispersion method. Particle size and Zeta potential of liposomes were determined,and HPLC assay was used to determine the content of coenzyme Q10. Free drugs and liposomes were separated using protamine aggre-gation method,and the encapsulation efficiency was calculated. Lyophilized preparation was prepared by coenzyme Q10 long-circu-lating liposomes,and the changes of content and encapsulation efficiency of drugs were determined 0,30 and 90 days after lyophi-lization. RESULTS:The liposomes were homogeneous in size with mean diameter of(166.0±5.3)nm and Zeta potential of(-22.2± 1.4)mV. Average content(the percentage of content accounted for labeled amount)and entrapment efficiency of 3 batches of sam-ple were 98.2%(RSD=2.8%) and 93.2%(RSD=4.6%),respectively. Compared with 0 d after lyophilization,coenzyme Q10 long-circulating liposomes had no obvious change in the content and encapsulation efficiency 90 d after lyophilization. CONCLU-SIONS:Coenzyme Q10 long-circulating liposomes with high quality and entrapment efficiency and lyophilized preparation being stored stably for 90 d have been prepared successfully.
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Combretastatin A4(CA4),a vascular inhibitor,can target tubulin and inhibit tubulin polymerization,thus it can inhibit the tumor blood vessels and has antitumor effect. But it is insoluble in water and has low bioavailability. CA 4 phosphate (CA4P),the derivative of CA4,can improve the solubility of CA4 and convert into CA4. CA4P is undergoing phaseⅡ/Ⅲclinical tri?als abroad. However,CA4P has several undesirable side effects and relative short half-life in vivo. Nanoformulations can increase the dissolution and absorption of the drug and obtain controlled release and targeting,prolong the efficacy and reduce side effects. Work?ing on the physical and chemical characteristics and biological pharmacy defects of CA4 and CA4P,nanoformulations may change the dissolution,absorption and distribution of the drug. This paper reviews the current nanoformulations of CA4 and CA4P,including den?drimer,polymeric micelle(PM),nanoparticles(NP),long-circulating liposome(LCL),and discusses the prospects of their nanofor?mulations.
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Objective To observe the effect of paclitaxel long-circulating thermo-sensitive liposome ( PLTL) on inhibiting the growth of transplanting Lewis lung cancer cells in C57BL/ 6 mice. Methods The model of mice carried Lewis lung cancer was established. 40 tumor-bearing mice were divided into five groups randomly: blank control group, model control group, PTX group, PTL group and PLTL group, 8 mice for each group. The blank control group and the model control group were injected with 0. 9% sodium chloride solution. In PTX group, PTL group and PLTL group, the dose of per injection was calculated with the reference of PTX for 20 mg·kg-1 , diluted with 0. 9% sodium chloride solution, and the mice were injected via the tail vein with a volume of 0. 2 mL each time. Except for the blank control group, 5 minutes after administration, the tumors of the other groups were subjected to local hyperthermia at (42±0. 5) ℃ for 30 min. During the treatment period, transplantation tumor growth was observed; pathological morphology changes of tumor tissues and cells were detected by HE stain; apoptosis rate of tumor cells was determined by flow cytometry to investigate the inhibition effect of PLTL combined with local thermal therapy on the tumor. Results The inhibition rate of tumor in model control group, PTX group, PTL group and PLTL group was 21. 81% , 48. 87% , 57. 22% and 78. 87% , respectively. The apoptosis rate of tumor cells was (20. 4 ± 4. 2)% , (42. 7 ± 3. 8)% , (54. 6±2. 9)% and (69. 7±5. 0)% , respectively. Observed by pathology, apoptosis rate and necrosis number of tumor cells in PLTL group were significantly increased. Conclusion Compared with PTX and PTL, PLTL has an evident thermo-sensitive feature and can increase the anticancer effect of paclitaxel remarkably when combined with local hyperthermia.
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OBJECTIVE: To prepare vincristine sulfate (VCR) thermosensitive liposomes, and evaluate its particle size and release characteristics in vitro and establish the methods for determination of content, entrapment efficiency and related substances.
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Objective To investigate the tumor inhibition effect of paclitaxel long-circulating thermo sensitive liposomes (PLTL) in mice bearing Lewis lung carcinoma cells. Methods A tumor-bearing mouse model was established, and the mice were randomly divided into five groups: control, heating, paclitaxel (PTX), paclitaxel thermo sensitive liposomes (PTL), and PLTL groups. The living status was observed in the mice. The volume and weight of the tumor were measured. The morphological changes in the tumor cells were observed f by HE staining and apoptosis of the tumor cells was determined by flow cytometry. Results The inhibition rate of tumor in PTX, PTL and PLTL groups was 48.87%, 57.22%and 78.87%, respectively. The apoptotic rate of tumor cell in PTX, PTL and PLTL groups was (42.7 ± 3 .8)%, (54.6 ± 2.9)%and (69.7 ± 5.0)%, respectively. Conclusions PLTL, as compared with PTX and PTL, has an evident thermo sensitive feature and increases the anticancer effect of paclitaxel remarkably in combination with local hyperthermia.
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Objective To improve the stability of epirubicin long circulation liposomes via lyophilizing technology and preliminarily evaluate their quality. Methods The effect of the various cryoprotectant,different pre-freezing and total drying time on the preparation was analyzed. The stability of the lyophilized powder was tested at (25±2) ℃ and (60±10)% relative humidity for 3 months. Results The protective agent trehalose to liposomes was 31. The freeze-drying was conducted with pre-freezing temperature at -70 ℃,precooling for 8 h and total drying for 24 h. There were no significant differences in particle size,encapsulation efficiency and drug content of lyophilized long-circulating liposomes compared with those un-lyophilized. After 3 months under the accelerated condition,it had good redispersibility, entrapment rate (>94%) and drug content (>99%) . Conclusion Lyophilizing the long-circulation epirubicin liposomes can effectively improve the stability of the preparation.
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OBJECTIVE: To prepare amphiphilic long-circulating hydroxycamptothecin nanoparticles and investigate its physicochemical properties and pharmacokinetic characteristics in rats. METHODS: Polyethyleneglycol-polycaprolactone (PEG-PCL) was synthesized. HCPT-PEG-PCL-NPs were prepared by solvent-diffusion method using PEG-PCL block copolymer as the matrix. The obtained NPs were evaluated, and the physical stabilities of both suspl and freeze-dried powder were investigated. High-performance liquid chromatography (HPLC) was used to determine and compare the pharmacokinetic parameters of HCPT injection and HCPT-PEG-PCL-NPs prepared with different copolymers in rats. RESULTS: When using PEG4000-PCL1250, PEG4000-PCL2000, PEG2000-PCL1250, PEG2000-PCL2000 as the carrier materials, the average particle sizes of NPs were 110.0, 116.1, 99.1 and 119.9 nm; the Zeta potentials were -16.9, -22.4, -28.8 and -33.5 mV; the entrapment efficiency were 83.10%, 88.29%, 77.46% and 80.67%; and the drug loading percentages were 2.56%, 2.96%, 2.14% and 2.31%, respectively. The physical stability of the freeze-dried powder was better, and hot environment seemed to be bad for the stability. The t1/2s of HCPT-PEG4000-PCL1250-NPs, HCPT-PEG2000-PCL1250-NPs, HCPT-PEG4000-PCL2000-NPs and HCPT-PEG2000-PCL2000-NPs were 18.07, 9.08, 5.25 and 5.14 times longer than that of HCPT injection which was 0.1418 h. CONCLUSION: The HCPT-PEG-PCL-NPs show sustained-release effect and long-circulation property compared with HCPT injection. Copyright 2012 by the Chinese Pharmaceutical Association.
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OBJECTIVE: To prepare decitabine long-circulating thermosensitive liposome(DCA-LTSL), screen and optimize its formulation, and evaluate its properties. METHODS: DCA-LTSL was prepared by modified reverse phase evaporation method, and the encapsulation efficiency was determined by minicolumn centrifugation-HPLC method. The influences of the concentration of PC, the weight ratio of PC to Chol, the weight ratio of DCA to PC and buffer salts were studied. Orthogonal design was adopted to obtain the optimal prescription using encapsulation efficiency as the main index. RESULTS: The best prescription was as follows; the concentration of PC was 5 g · L-1, the weight ratio of PC to Chol was 4 : 1, the weight ratio of DCA to PC was 40: 1 and the pH value of aqueous phase was 7.0.The encapsulation efficiency of DCA-LTSL was (44.50 ± 1.08)% . The Zeta potential was -8.34 mV. The mean diameter of DCA-LTSL was (140.25 ± 2.40)nm. The burst release effectiveness of DCA-LTSL was 42-43°C. CONCLUSION: The formulation of DCA-LTSL has been optimized with excellent in vitro drug release characteristics at the phase-thransition temperature.
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Objective To prepare the long-circulating liposomes of paraoxonase(PON).Methods The long-circulating liposomes of paraoxonase were prepared by film dispersion method.The encapsulation efficiency was determined by gel column.The effects of the factors on the encapsulation efficiency,such as the weight ratio of paraoxonase to phospholipid,cholesterol(Choi) to phospholipid,PEG-cholesterol (PEG-Chol) and the iron strength of water phase,were investigated respectively.Then the formulation was optimized by orthogonal design.Results The encapsulation efficiency of the paraoxonase liposomes was 87.66±3.46%,and the average diameter of the liposomes was about 126 nm.There was no significant change on encapsulation efficiency on 15 d at 4 ℃,and the activity of paraoxonase was maintained basically stable.Conclusion The preparation of PEG-modified paraoxonase liposomes was easy and practicable,and the property investigation in vitro showed that the paraoxonase liposomes were stable.
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Objective To establish a method for the preparation of long-circulating liposomes (LCL) containing etoposide and to observe its stability in rats plasma.Methods The etoposide-containing liposome was prepared by ethanol injection method. Polyethylene glycol-distearoyl phosphatidylethanolamine (PEG2000-DSPE) was used to modify the membrane of the liposome. Reversed-phase high pressure liquid chromatography (RP-HPLC) was used to detect the concentration of the liposome,and dynamic release method was used to study its stability in mice plasma.Results The mean size of the LCL containing etoposide was (180?26) nm,and the mean concentration of etoposide was (4.78?0.22) mg/mL,with the entrapment efficiency being (88.71?8.2)%. The leakage ratio of the conventional liposome containing etoposide and LCL containing etoposide in mice plasma were (80.14?1.59)% and (46.72?2.61)%,respectively.Conclusion LCL containing etoposide with high entrapment efficiency and low leakage rate can be obtained by using ethanol injection method. Additionally,modification by PEG2000-DSPE could raise the stability of the liposome.
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OBJECTIVE:To study the preparative methods of the long-circulating solid lipid nanoparticles(LSLN)carrying ginkgolides A and B(GAB)and to study the physicochemical characteristics of the GAB-LSLN.METHODS:GAB-LSLN was prepared by ultrasonication or high pressure homogenization.Transmission electron microscopy was employed to study its shape.Particle size,zeta potential,and entrapment efficiency of GAB-LSLN were determined,and its stability after storage under room temperature for 4 weeks was determined as well.RESULTS:The GAB-LSLN prepared by ultrasonication was platelet-shaped and irregular,and that prepared by high pressure homogenization was spherical and regular in shape.The particle diameters of GAB-L SLN prepared by ultrasonication and high pressure homogenization were(219.6?14.3)nm and(173.9?10.4)nm respectively(P0.05).CONCLUSION:High pressure homogenization is superior to ultrasonication in that the prepared GAB-LSLN has small particle size,high stability and high entrapment efficiency.