Mannosylated solid lipid nanoparticles for lung-targeted delivery of Paclitaxel

Objective: The present study discusses paclitaxel (PTX)-loaded mannosylated-DSPE (Distearoyl-phosphatidyl-ethanolamine) solid lipid nanoparticles (M-SLNs) using mannose as a lectin receptor ligand conjugate for lung cancer targeting and to increase the anticancer activity of PTX against A549 lung’s epithelial cancer cells.

Materials and methods: The PTX-SLNs were prepared by solvent injection method and mannose was conjugated to the free amine group of stearylamine. The M-SLNs obtained were characterized for their particle size, polydispersity index, zeta potential and morphology by transmission electron microscope.

Results: The M-SLNs were spherical in shape with 254?±?2.3?nm average size, positive zeta potential (3.27?mV), 79.4?±?1.6 drug entrapment efficiency and showed the lower extent of drug release 40% over 48?h in vitro. Cytotoxicity study on A549 cell lines and biodistrubtion study of drug revealed that M-SLNs deliver a higher concentration of PTX as compared to PTX-SLNs in an alveolar cell site.

Discussion and conclusion: These results suggested that mannosylated M-SLNs are safe and potential vector for lung cancer targeting.     

Investigation of aqueous stability of taxol in different release media

In the present study, the aqueous stability of taxol in different aqueous media and immiscible aqueous/organic systems at 37?°C was investigated. The aqueous media included phosphate buffered saline (PBS) and PBS containing 10% methanol, 10% ethanol, 10% hydroxypropyl β-cyclodextrin (HP-βCD), 1% sodium citrate and 1% Tween 80. The immiscible systems consisted of PBS/octanol, PBS/dichloromethane, PBS/chloroform and PBS/ethyl acetate. The concentrations of taxol and related derivatives in each of the media were determined through the high-performance liquid chromatography assay. Results showed that hydrolysis and epimerization were two major types of degradation for taxol in the aqueous media starting from the initial hours of contact (6 hours). Addition of Tween 80 to PBS moderately increased the aqueous stability of taxol. As well, using PBS containing 10% HP-βCD inhibited the taxol hydrolysis, while epimerization still in process. In the case of immiscible systems, except for PBS/ethyl acetate system, no evidences of taxol hydrolysis were observed. Meanwhile, epimerization of taxol in PBS/dichloromethane and PBS/chloroform systems underwent due to the ability of C–Cl bonds to form hydrogen bonding with the hydroxyl group of C7 of taxol.     

A pH-Sensitive Polymeric Micellar System Based on Chitosan Derivative for Efficient Delivery of Paclitaxel

In this study, an amphiphilic conjugate based on mPEG and cholesterol-modified chitosan with hydrazone bonds in the molecules (mPEG-CS-Hz-CH) was successfully synthesized. Using the polymer as the carrier, the paclitaxel (PTX)-loaded mPEG-CS-Hz-CH micelles were prepared by an ultrasonic probe method. The mean particle size and zeta potential of the optimized PTX-loaded micelles were 146 ± 4 nm and +21.7 ± 0.7 mV, respectively. An in vitro drug release study indicated that the PTX-loaded mPEG-CS-Hz-CH micelles were stable under normal physiological conditions (pH 7.4), whereas rapid drug release was observed in the simulated tumor intracellular microenvironment (pH 5.0). An in vitro cytotoxicity study demonstrated the non-toxicity of the polymer itself, and the PTX-loaded micelles exhibited superior cytotoxicity and significant selectivity on tumor cells. An in vivo antitumor efficacy study further confirmed that the PTX-loaded micelles could improve the therapeutic efficacy of PTX and reduce the side effects. All these results suggested that the mPEG-CS-Hz-CH micelles might be promising pH-sensitive nanocarriers for PTX delivery.     

利用石英晶体微量天平测定紫杉醇在二氧化碳中的溶解度

A quartz crystal microbalance (QCM) is used to determine the phase equilibrium of paclitaxel-carbon dioxide system in the pressure range of 0-11 MPa and at temperatures of 35 °C,40 °C and 45 °C.The experimental results indicated that gaseous CO2 could be absorbed poorly into paclitaxel.The swelling of paclitaxel film in CO2 was observed before paclitaxel dissolved into supercritical carbon dioxide (ScCO2) with the increase of pressure.It was found that ScCO2 was not a good solvent for paclitaxel.The mole fraction of paclitaxel in ScCO2 was in the range of (4.5×10-9)-(7.8×10-9) under all our experimental conditions.Therefore,a much higher pressure than the CO2 supercritical point and/or a cosolvent must be used in any processes wherever paclitaxel dissolution in ScCO2 is required.     

两亲性无规聚合物P（MMA-co-MAA）胶束包覆紫杉醇及体外释放

运用双亲性无规聚合物P(MMA-co-MAA)透析法制备了紫杉醇载药胶束。用芘荧光探针法测定双亲性聚合物的CMC值;对载药、空白的聚合物胶束的粒径、Zeta电位进行了比较;考察紫杉醇加入量对包覆率和载药量的影响;并在磷酸缓冲溶液(pH 7.4)中进行紫杉醇载药胶束模拟药物缓释研究。研究结果表明:两亲性无规聚合物P(MMA-coo-MAA)单体摩尔比7∶3的聚合物的CMC为0.050 mg/mL;载药胶束的粒径比空白胶束增大近两倍,Zeta电位变得更负;当紫杉醇加入量为21%时,包封率和载药量可分别达到85.2%、18.0%;载药胶束在pH 7.4磷酸缓冲液中140 h内可稳定释放,具有良好的缓释效果。     

Charge-Conversional Binary Drug Delivery Polymeric Micelles for Combined Chemotherapy of Cervical Cancer

Candesartan-g-polyethyleneimine-cis-1,2-cyclohexanedicarboxylic anhydride (CD-g-PEI-HHPA, CPH) polymer-drug conjugates based on charge-conversional delivery, enhanced buffering capacity, amidase-triggered drug release, and combined cancer chemotherapy strategies were successfully synthesized for simultaneous and effective codelivery of CD and paclitaxel (PTX) to treat cervical cancer. The CPH polymer-drug conjugates could self-assemble into core-shell structure micelle of around 100 nm in diameter with negative surface charge and were employed to load PTX to formulate binary drug delivery system. The CPH polymeric micelles could mediate quick endosomal escape and amidase-responsive drug-release manners. In vitro cytotoxicity and in vivo investigations confirmed CPH binary drug delivery system exerted strong antitumor efficacy.     

以壳聚糖为基质的智能电荷翻转体系用于紫杉醇的高效输送

通过在羧甲基壳聚糖纳米球(CNP)表面修饰三(2-氨基乙基)胺(TAEA)及2,3-二甲基马来酸酐(DMMA),得到针对肿瘤微酸环境响应的智能电荷翻转体系(CNP:TAEA:DMMA-纳米球),并用于难溶性抗肿瘤药物紫杉醇(PTX)的高效输送. 结果表明,所制纳米球在正常体液(pH 7.4)条件下能保留其负电性(-11 mV),从而减少被巨噬细胞J774A.1摄取;而在肿瘤部位的微酸环境(pH 6.8)下,其表面负电性(-34.8 mV)可迅速转化为正电性(+5 mV),促进被肿瘤细胞LLC摄取,提高肿瘤细胞内的药物浓度. 与市售注射剂相比,纳米球展现出良好的生物相容性,对肿瘤细胞杀伤效果也明显提高,其半抑制浓度从11.3降低至4.09 mg/mL,实现了PTX的高效输送.     

Recent Advances in the Study of the Bioactive Conformation of Taxol

Demystifying Taxol : The structurally complex natural product paclitaxel is among the most important antitumor drugs presently in the clinic. While the mechanism of action is known, the biologically active conformation has been much debated. Herein we summarize the considerable research efforts that have gone into elucidating the bioactive conformation of paclitaxel.

     

PLGA包裹的紫杉醇缓释微球的理化性质及抑瘤活性研究

用化学材料聚乳酸和乙醇酸的共聚物(poly(lactic—co-glycolicacid),PLGA)制备了紫杉醇缓释微球。用扫描电镜观察了微球的形态和大小,用HPLC法测定了紫杉醇在介质中的释放情况,用MIT法测定了IC50,通过荷瘤裸鼠实验评价了体内抑瘤活性。结果表明,PLGA-紫杉醇微球呈光滑球形,平均粒径7～37μm,微球包封率在90％以上。PLGA-紫杉醇微球具有缓释作用,其抑瘤活性与紫杉醇从微球内的释放密切相关,微球可以维持较长时间的有效药物浓度,达到了更好的抑瘤效果。