ObjectiveTo prepare hydroxycamptothecin(HCPT)loaded glycyrrhetinic acid modified polyethyleneimine-poly(lactic-co-glycolic acid)(GA-PEI-PLGA)nanoparticles. MethodsEmulsion-solvent evaporation method was used to prepare HCPT-loaded GA-PEI-PLGA nanoparticles.Based on the single-factor experiments, drug/GA-PEI-PLGA ratio, oil phase/water phase ratio, sonication timeand power were further investigated.The formulation and process were optimized by orthogonal testingdesign using entrapment efficiency and drug loading efficiency as indexes.HCPT-loaded GA-PEI-PLGA nanoparticles'diameter and zeta potential were determined. ResultsHCPT-loaded GA-PEI-PLGA nanoparticles were successfully prepared by emulsion-solvent evaporation method.Drug/GA-PEI-PLGA ratio, in particular, had the uniform particle on the preparation of HCPT-loaded nanoparticles.The optimal process was as follows:drug/GA-PEI-PLGA ratio of 3 to10, oil phase/water phase ratio of 1 to 9, sonication power of 570 W and sonication time of 15 min.The entrapment efficiency and drug loading efficiency of HCPT-loaded GA-PEI-PLGA nanoparticles were(87.52±3.91)%and(20.10±4.72)%, respectively.The average particle size was(218.1±3.23)nm and the zeta potential was(34.98±3.56) mV. ConclusionEmulsion-solvent evaporation method was feasible for preparing HCPT-loaded GA-PEI-PLGA nanoparticles, with uniform particel size distribution, good stability, high entrapment and drug loading efficiency.
Fig.2
Results of single-factor experiments
A.composition of organic phase;B.the volume ratio of dichloromethane to methanol;C.the volume ratio of organic phase to water;D.the mass ratio of drug to carrier;E.sonication time;F.sonication power;*1precipitate was observed a few days after storage of nanosuspension
LI GF,LIY,TANGY,et al.Hydroxyethyl starch conjugates for improving the stability,pharmacokinetic behavior and antitumor activity of 10-hydroxy camptothecin[J].Int J Pharm,2014,417(1-2):234-244.
10-Hydroxy (10-HCPT)-hydroxyethyl (HES) conjugates were prepared to improve the water solubility, prolong the half-life in plasma and increase the antitumor efficacy of 10-HCPT, and the structures of the conjugates were confirmed by NMR and infrared spectroscopy. The 10-HCPT conjugates showed good sustained release effect in phosphate-buffered saline (PBS), plasma and liver homogenate. Meanwhile, 10-HCPT-HES conjugates achieved much lower IC50 and higher cytotoxicity effects than the free 10-HCPT on -3B and SMMC-7721 cell lines. The pharmacokinetics results of 10-HCPT-HES conjugates demonstrated that the biological half-life of 10-HCPT was increased from 10 min to 2.94 h and 3.76 h, respectively, in comparison with the commercial 10-HCPT injection. The pharmacodynamics results indicated that 10-HCPT-HES conjugate had a better antitumor efficiency against nude with -3B than the commercial 10-HCPT injection, and the inhibition ratio of was 78.3% and 31.5%, respectively, at the dose of 1.0 mg/kg. These findings suggest that 10-HCPT-HES conjugate is a promising drug delivery system providing improved long circulating effect, greater stability and better antitumor effect.
VENDITTO VJ,SIMANEK EE.Cancer therapies utilizing the camptothecins:a review of the in vivo literature[J].Mol Pharm,2010,7(2):307-349.
This review summarizes the in vivo assessment—preliminary, preclinical, and clinical—of chemotherapeutics derived from camptothecin or a derivative. Camptothecin is a naturally occurring, pentacyclic quinoline alkaloid that possesses high cytotoxic activity in a variety of cell lines. Major limitations of the drug, including poor solubility and hydrolysis under physiological conditions, prevent full clinical utilization. Camptothecin remains at equilibrium in an active lactone form and inactive hydrolyzed carboxylate form. The active lactone binds to DNA topoisomerase I cleavage complex, believed to be the single site of activity. Binding inhibits DNA religation, resulting in apoptosis. A series of small molecule camptothecin derivatives have been developed that increase solubility, lactone stability and bioavailability to varying levels of success. A number of macromolecular agents have also been described wherein camptothecin(s) are covalently appended or noncovalently associated with the goal of improv...
ZHOU YY,DU YZ,WANGL,et al.Preparation and pharmacodynamics of stearic acid and poly (lactic-co-glycolic acid) grafted chitosan oligosaccharide micelles for 10-hydroxycamptothecin[J].Int J Pharm,2010,393(1-2):143-151.
Stearic acid (SA) and poly (lactic-co-glycolic acid) (PLGA) grafted chitosan oligosaccharide (SA-CSO-PLGA SCP) tripolymer was synthesized via the reaction between the carboxyl group of SA or PLGA with carboxylic side group, and the amine group of CSO in the presence of 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). The degrees of amino-substitution for SA and PLGA were assayed through 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) test and 13 C NMR spectrum, which were 8.15% and 5.82%, respectively; the critical micelle concentrations of SCP in PBS (pH 7.4) and deionized water (DI water) were about 34.9 and 14.5渭g/ml, respectively. Using 10-hydroxycamptothecin (HCPT) as a model drug, the drug-loaded micelles showed above 86% encapsulation efficiency, which not only enhanced the solubility of HCPT in aqueous medium markedly, but also protected the lactone ring of HCPT. Cellular uptakes of SCP micelles against A549, MCF-7 and HepG-2 tumor cells showed a faster cellular internalization. Comparing to the commercial HCPT injection, HCPT-loaded micelles showed higher cytotoxicities against A549, MCF-7 and HepG-2 cells. The increased folds were 22, 18 and 15, respectively. These results suggested the SCP could be applied as a carrier for hydrophobic drugs.
CHENS,WANGQ,GUOP,et al.Intracellular delivery of 10-hydroxycamptothecin with novel solid lipid nanoparticles (SLN) against multidrug resistance[J].J Control Release,2013,172(1):e27.
More and more data indicate the importance of palatability when selecting drugs for children. Since hypertension is uncommon in children, no child-friendly palatable formulations of these agents are currently available. As a consequence, in everyday practice available tablets are crushed and administered mixed with food or a sweet drink. We started investigating the issue of palatability of drugs among children in 2004 using smile-face scales. In the first trial we compared taste and smell acceptability of pulverized angiotensin receptor antagonists among nephropathic children and found that the score assigned to candesartan was significantly higher than that assigned to irbesartan, losartan, telmisartan and valsartan. In the second trial we compared the taste of pulverized amlodipine and lercanidipine among children and found that the score assigned to lercanidipine was significantly higher. Our third trial was performed using pulverized beta-adrenoceptor blockers, angiotensin-converting enzyme inhibitors, calcium-channel antagonists and diuretics among medical officers and pediatricians. The palatability scores assigned to chlorthalidone, hydrochlorothiazide and lisinopril were significantly higher to those assigned to atenolol, bisoprolol, enalapril and ramipril. In conclusion pulverized amlodipine, atenolol, bisoprolol, enalapril, irbesartan, losartan, ramipril, telmisartan and valsartan are poor tasting. From the child's perspective, lercanidipine, candesartan, chlorthalidone, hydrochlorothiazide and lisinopril are preferable. (C) 2013 Elsevier B. V. All rights reserved.
LIANG GF,ZHU YL,SUNB,et al.PLGA-based gene delivering nanoparticle enhance suppression effect of miRNA in Hep G2 cells[J].Nanoscale Res Lett,2011,6(1):447-456.
Abstract<br/>The biggest challenge in the field of gene therapy is how to effectively deliver target genes to special cells. This study aimed to develop a new type of poly(<span class="a-plus-plus emphasis type-small-caps">D</span>,<span class="a-plus-plus emphasis type-small-caps">L</span>-lactide-co-glycolide) (PLGA)-based nanoparticles for gene delivery, which are capable of overcoming the disadvantages of polyethylenimine (PEI)- or cationic liposome-based gene carrier, such as the cytotoxicity induced by excess positive charge, as well as the aggregation on the cell surface. The PLGA-based nanoparticles presented in this study were synthesized by emulsion evaporation method and characterized by transmission electron microscopy, dynamic light scattering, and energy dispersive spectroscopy. The size of PLGA/PEI nanoparticles in phosphate-buffered saline (PBS) was about 60 nm at the optimal charge ratio. Without observable aggregation, the nanoparticles showed a better monodispersity. The PLGA-based nanoparticles were used as vector carrier for miRNA transfection in HepG2 cells. It exhibited a higher transfection efficiency and lower cytotoxicity in HepG2 cells compared to the PEI/DNA complex. The N/P ratio (ratio of the polymer nitrogen to the DNA phosphate) 6 of the PLGA/PEI/DNA nanocomplex displays the best property among various N/P proportions, yielding similar transfection efficiency when compared to Lipofectamine/DNA lipoplexes. Moreover, nanocomplex shows better serum compatibility than commercial liposome. PLGA nanocomplexes obviously accumulate in tumor cells after transfection, which indicate that the complexes contribute to cellular uptake of pDNA and pronouncedly enhance the treatment effect of miR-26a by inducing cell cycle arrest. Therefore, these results demonstrate that PLGA/PEI nanoparticles are promising non-viral vectors for gene delivery.<br/>
ZHANGC,WANGW,LIUT,et al.Doxorubicin-loaded glycyrrhetinic acid-modified alginate nanoparticles for liver tumor chemotherapy[J].Biomaterials,2012,33(7):2187-2196.
Abstract Doxorubicin (DOX)-loaded glycyrrhetinic acid (GA)-modified alginate (ALG) nanoparticles (DOX/GA-ALG NPs) were prepared for targeting therapy of liver cancer. This study focused on the biodistribution of DOX/GA-ALG NPs in Kunming mice as well as their antitumor activity against liver tumors in situ and side effects. The biodistribution data showed that the concentration of DOX in the liver reached 67.8 ± 4.9 μg/g after intravenous administration of DOX/GA-ALG NPs, which was 2.8-fold and 4.7-fold higher compared to non-GA-modified nanoparticles (DOX/CHO-ALG NPs) and DOX·HCl, respectively. The concentration of DOX in the heart of mice treated with DOX/GA-ALG NPs at any sampling time was relatively lower than that of mice treated with DOX·HCl. The liver tumor growth inhibition rate (IR) in situ was about 52.6% and the mortality was 33% in DOX·HCl group. In contrast, the IR was 76.6% and no mice died in the DOX/GA-ALG NPs group. Histological examination showed tumor necrosis in both experimental groups. Most importantly, the heart cells and the liver cells surrounding the tumor were not affected by administration of DOX/GA-ALG NPs, whereas myocardial necrosis and apparent liver cell swelling were observed after DOX·HCl administration. Copyright 08 2011 Elsevier Ltd. All rights reserved.
PANYAMJ,WILLIANSD,DASHA,et al.Solid-state solubility influences encapsulation and release of hydrophobic drugs from PLGA/PLA nanoparticles[J].J Pharm Sci,2004,93(7):1804-1814.
Biodegradable nanoparticles formulated from poly(D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA) polymers are being extensively investigated for various drug delivery applications. In this study, we hypothesize that the solid-state solubility of hydrophobic drugs in polymers could influence their encapsulation and release from nanoparticles. Dexamethasone and flutamide were used as model hydrophobic drugs. A simple, semiquantitative method based on drug-polymer phase separation was developed to determine the solid-state drug-polymer solubility. Nanoparticles using PLGA/PLA polymers were formulated using an emulsion-solvent evaporation technique, and were characterized for size, drug loading, and in vitro release. X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC) were used to determine the physical state of the encapsulated drug. Results demonstrated that the solid-state drug-polymer solubility depends on the polymer composition, molecular weight, and end-functional groups (ester or carboxyl) in polymer chains. Higher solid-state drug-polymer solubility resulted in higher drug encapsulation in nanoparticles, but followed an inverse correlation with the percent cumulative drug released. The XRD and DSC analyses demonstrated that the drug encapsulated in nanoparticles was present in the form of a molecular dispersion (dissolved state) in the polymer, whereas in microparticles, the drug was present in both molecular dispersion and crystalline forms. In conclusion, the solid-state drug-polymer solubility affects the nanoparticle characteristics, and thus could be used as an important preformulation parameter.
WANGW,LIU GJ,WUJ,et al.Co-precipitation of 10-hydroxycamptothecin and poly (l-lactic acid) by supercritical CO2 anti-solvent process using dichlorome-thane/ethanol co-solvent[J].J Supercrit Fluid,2013,74(2):137-144.
In this study, 10-hydroxycamptothecin (HCPT) and poly ( l -lactic acid) (PLLA) are co-precipitated by the supercritical anti-solvent (SAS) process using a mixture of dichloromethane (DCM)/ethanol (EtOH) as co-solvent, and supercritical carbon dioxide as the anti-solvent. The effect of five operating conditions on particle morphology, mass median diameter (Dp 50 ) and HCPT loading is investigated using the single-factor method. The results indicate that HCPT loading can be greatly increased by using DCM/EtOH co-solvent, and the suitable operating conditions for the experimental system are determined. Under suitable conditions, the HCPT loading is 13.3% and Dp 50 is 794.5nm. The drug loaded microparticles are characterized in detail. The SEM images showed that most of the particles were spherical, and PLLA concentration has a major impact on the particle shape. Results of TEM, DSC and XRD indicate that the micronized HCPT is dispersed into the PLLA matrix. For low HCPT loading, most of HCPT existed in the drug loaded microparticles in an amorphous state, but for high HCPT loading, part of the encapsulated drug existed in crystalline form. FT-IR results show that SAS process does not change the chemical structure of HCPT. The result of in vitro drug release test indicated that the crystallinity of HCPT in microparticles affects the control release performance, and the good encapsulated microparticles with higher HCPT loading and higher crystallinity are better.
Preparation and pharmacodynamics of stearic acid and poly (lactic-co-glycolic acid) grafted chitosan oligosaccharide micelles for 10-hydroxycamptothecin
, 吴得天
