Enhanced tumor-targeted delivery of anticancer drugs by folic acid-conjugated pH-sensitive polymeric micelles

In order to enhance the targeted delivery of anticancer drugs by polymeric micelles, folic acid (FA), the ligand of folate receptor (FR) over-expressed in the most cancer cells, modified pH-sensitive polymeric micelles were designed and fabricated to encapsulate doxorubicin (DOX) by combination of pH-sensitive amphiphilic polymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) with FA-conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide). The prepared micelles were characterized to have about 36 nm in diameter with narrow distribution, well-defined spherical shape observed under TEM and pH-responsive drug release behavior. Moreover, the tumor targeting ability of the FA-modified pH-sensitive polymeric micelles was demonstrated by the cellular uptake, in vitro cytotoxicity to FR-positive KB cells and in vivo real time near-infrared fluorescence imaging in KB tumor-bearing nude mice. The efficient drug delivery by the micelles was ascribed to the synergistic effects of FR-mediated targeting and pH-triggered drug release. In conclusion, the designed FR-targeted pH-sensitive polymeric micelles might be of great potential in tumor targeted delivery of water-insoluble anticancer drugs.     

Improved intestinal absorption of paclitaxel by mixed micelles self-assembled from vitamin E succinate-based amphiphilic polymers and their transcellular transport mechanism and intracellular trafficking routes

To ensure that antitumor drugs can be effectively transported across intestinal barrier and then quickly released in tumor cells, mixed polymeric micelles (Mix-PMs) were designed and fabricated by combining poly(2-ethyl-2-oxazoline)-vitamin E succinate (PEOz-VES) with TPGS1000 for enhancing intestinal absorption of paclitaxel. PEOz-VES exhibited an extremely low critical micelle concentration and negligible cytotoxicity. The Mix-PMs were characterized to have about 20?nm in diameter, uniform spherical morphology, high drug-loading content and sustained drug release profile with a retained pH-sensitivity. The results of the transport through Caco-2 cell monolayers and intestinal absorption revealed that Mix-PMs displayed higher transcellular transport efficiency compared with PEOz-VES micelles and Taxol^®. The possible mechanism of transcellular transport for Mix-PMs was elucidated to be mainly through clathrin- and caveolae/lipid rafts-mediated transcytosis. Confocal laser scanning micrographs revealed that late endosomes, lysosomes, endoplasmic reticulum, Golgi apparatus, and mitochondria were all involved in intracellular trafficking of Mix-PMs. The proteins involved in transcytosis of Mix-PMs and finally excreted were unraveled for the first time by the analysis of proteins in the basolateral media according to the proteomics method. Consequently, the fabricated mixed polymeric micelles may have great potential in enhancing intestinal absorption and accelerating drug release in tumor cells.     

Preparation and characterization of dual pH-sensitive polymer-doxorubicin conjugate micelles

In the present study, we designed and fabricated pH-sensitive polymeric micelles based on the conjugate of poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) with doxorubicin (PEOz-PLA-imi-DOX) to efficiently inhibit tumor cell growth. Hence, PEOz-PLA-imi-DOX was successfully synthesized by connecting DOX to the hydrophobic end of pH-sensitive PEOz-PLAvia acid cleavable benzoic imine linker and characterized by ¹H NMR spectrum and thin layer chromatography. The critical micelle concentration of PEOz-PLA-imi-DOX was determined to be (14.84±3.85) mg/L. The conjugate micelles (denoted as PP-DOX-PM) formed by PEOz-PLA-imi-DOX using film-hydration method were characterized to have a nano-scaled size of about 21 nm in diameter, and the drug loading content was 1.67%. PP-DOX-PM showed pH-dependent drug release behavior with gradually accelerated release of DOX with decrease of pH value, illustrating the micelles’ distinguishing feature of endo/lysosomal pH from physiological pH by accelerating drug release. As anticipated, PP-DOX-PM maintained the cytotoxicity of DOX against MDA-MB-231 cells. Collectively, PP-DOX-PM might have great potential for effective suppression of tumor growth.     

Preparation and characterization of intestinal transporter-targeted polymeric micelles

The intestinal epithelium is the main barrier to the oral delivery of poorly water-soluble drugs. Based on the specific transporters expressed on the apical membrane of the intestinal epithelium, novel polymer micelles targeting to the organic cation transporter 2 (OCTN2) were constructed by combining carnitine conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (Car-PEOz-PLA) with monomethoxy poly(ethylene glycol)-poly(D,L-lactide) (mPEG-PLA). The structure of the synthesized Car-PEOz-PLA was confirmed by ¹H NMR, TLC and ammonium reineckate precipitation reaction, and the number-average molecular weight determined by GPC was 7260 g/mol with a low PDI of 1.44. Coumarin 6-loaded carnitine modified polymeric micelles prepared by film hydration method were characterized to have a nano-scaled size of about 31 nm in diameter, uniform spherical morphology, high drug loading content of 0.098%±0.03% and encapsulation efficiency of 92.67%±2.80%. Moreover, the carnitine-modified micelles exhibited the similar in vitro release behavior in SGF and SIF, and evidently enhanced intestinal absorption of poorly water-soluble agent. Therefore, the designed OCTN2-targeted micelles might have a promising potential for oral delivery of poorly water-soluble drugs.     

Environmental-sensitive micelles based on poly(2-ethyl-2-oxazoline)-b-poly(L-lactide) diblock copolymer for application in drug delivery

Anticancer drug doxorubicin (DOX) was physically loaded into the micelles prepared from poly(2-ethyl-2-oxazoline)-b-poly(L-lactide) diblock copolymers (PEOz-PLLA). PEOz-PLLA consists of hydrophilic segment PEOz and hydrophobic segment PLLA showed pH-sensitivity in the aqueous solution. The DOX-loaded micelle exhibited a narrow size distribution with a mean diameter around 170 nm. The micellar structure can preserve hydrophobic drug DOX under the physiological condition (pH 7.4) and selectively release DOX by sensing the intracellular pH change in late endosomes and secondary lysosomes (pH 4-5). At 37 degrees C, the cumulated released rate of DOX from micelles was about 65% at pH 5.0 in the initial 24 h. Additionally, polymeric micelles had low cytotoxicity in human normal fibroblast HFW cells for 72 h by using MTT assay. Moreover, DOX-loaded micelles could slowly and efficiency decrease cell viability of non-small-cell lung carcinoma CL3 cells. Taken together, PEOz-b-PLLA diblock polymeric micelles may act as useful drug carriers for cancer therapy.     

紫杉醇mPEG-PLA共聚物胶束的制备及工艺优化

目的：制备紫杉醇mPEG-PLA共聚物胶束（PM-PTX）,优化处方及工艺。方法：采用薄膜水化法制备PM-PTX,通过星点设计一效应面优化法设计和优化处方工艺,并评估药物的体外释放。结果：以投药量和水化体积作为自变量,包封率和载药量作为因变量,行多元线性回归及二次多项式拟合,优选最佳处方工艺并进行验证,得最优工艺条件为投药量2.71 mg,水化体积7.04 mL。按照优化处方制得的PM-PTX包封率为（83.04±1.96）%,载药量为（15.01±0.28）%,与预测值的偏差分别为1.91%和0.99%。PM-PTX溶液为无色透明,透射电镜下显示胶束呈类圆形,胶束粒径为（87.74±2.3）nm,多分散指数为0.259±0.014,Zeta电位为（-1.22±0.133）mV。在3种pH环境下,胶束的药物释放速率无明显差异（P>0.05）,96 h的累积释放率分别为（92.19±3.17）%,（88.37±5.62）%和（86.04±2.16）%（pH=5.8,7.2,7.4）。结论：星点设计-效应面优化法对PM-PTX的制备工艺优化有效,所建立的模型预测性良好。     

Reduction-responsive PEtOz-SS-PCL micelle with tailored size to overcome blood–brain barrier and enhance doxorubicin antiglioma effect

A series of novel reduction-responsive micelles with tailored size were designed and prepared to release doxorubicin (DOX) for treating glioma, which were developed based on amphiphilic block copolymer poly (2-ethyl-2-oxazoline)-b-poly (ε-caprolactone) (PEtOz-SS-PCL) and the micelle size could be regulated by designing the polymer structure. The DOX-loaded PEtOz-SS-PCL micelles had small size and rapid drug release in reductive intracellular environments. Biodistribution and in vivo imaging studies in C6 glioma mice tumor model showed that DOX loaded PEtOz-SS-PCL43 micelles with the smallest size had superior accumulation and fast drug release in tumor sites. In vivo antitumor activity demonstrated that DOX-loaded PEtOz-SS-PCL43 micelles improved antitumor efficacy in contrast to PEtOz-SS-PCL micelles with larger size toward the orthotopic C6-Luci cells-bearing mice. This study shows great potential in tailoring the micelle size and introducing the responsive bonds or compartment for intracellular drug delivery and release in glioma treatment by designing the architecture of the polymer.     

紫杉醇Pluronic P105聚合物胶束的制备、表征与逆转肿瘤多药耐药性的体外研究

药物递送系统是克服肿瘤多药耐药性(MDR)的一种新策略。本文以聚合物胶束系统和难溶性药物紫杉醇(PTX)为研究对象，旨在制备一种新型的PTX给药系统，既能增溶难溶性药物，又具有克服肿瘤MDR的能力。以Pluronic P105为载体，采用固体分散-水化法制备PTX聚合物胶束，并以星点设计-效应面优化法进行处方优化。对其粒径、体外释放等性质进行表征后，以人耐药卵巢癌细胞SKOV-3/PTX为细胞模型，体外评价PTX聚合物胶束的细胞摄取及其逆转肿瘤细胞耐药性的作用。结果显示，聚合物胶束制剂的载药量约为1.1%、药物浓度约为700 μg·mL^-1、平均粒径约为24 nm。胶束制剂与普通制剂(Taxol)在6 h内的累积释放分别为45.4%和95.2%，前者具有较强的缓释作用；胶束制剂与Taxol对SKOV-3/PTX的IC₅₀值分别为1.14和5.11 μg·mL^-1，二者的耐药逆转指数(RRI)分别为9.65和2.15。胶束制剂可促进耐药细胞对P-糖蛋白(P-gp)底物(PTX或Rhodamine-123)的摄取。结果表明，Pluronic P105可有效增溶难溶性药物PTX，并形成具有较强缓释作用的纳米级聚合物胶束制剂，该制剂可显著提高PTX对人卵巢癌耐药细胞的细胞毒性，能逆转其耐药性。     

Pharmacokinetics and biodistribution of polymeric micelles of paclitaxel with pluronic P105/poly(caprolactone) copolymers

A novel polymeric micellar formulation of paclitaxel (PTX) with Pluronic/poly(caprolactone) (P105/ PCL50) has been developed with the purpose of improving in vitro release and in vivo circulating time of PTX in comparison to the current Taxol injection. This study was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of the PTX-loaded, biodegradable, polymeric, P105/PCL50 micelle system. The drug-loaded micelles were prepared by dialysis using the hydrophobic drug, PTX, and the nonionic surfactant Pluronic P105 modified with a low molecular weight PCL. The results of dynamic light scattering (DLS) experiment indicated that the PTX-loaded micelles had a mean size of approximately 150 nm with narrow size distribution (polydispersity index < 0.3). The in vitro release study showed that the release of PTX from the micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic assessment in rats, in which t1/2 beta and AUC of the PTX micelle formulation were 4.0 and 2.2-fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX micelle formulation not only decreased drug uptake by the liver, but also prolonged drug retention in the blood, and increased the distribution of drug in kidney, spleen, ovaries and uterus. These results suggested that the P105/ PCL50 polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i.v. administration of PTX.     

Dual thermoresponsive and pH-responsive self-assembled micellar nanogel for anticancer drug delivery

Abstract

In this article, we prepared a dual thermoresponsive and pH-responsive self-assembled micellar nanogel for anticancer drug delivery by using a degradable pH-responsive ketal derivative, mPEG2000-Isopropylideneglycerol (mPEG-IS, PI) polymer. The purpose of this study is to develop an injectable dual-responsive micellar nanogel system which has a sol-gel phase transition by the stimulation of body temperature with improved stability and biocompatibility as a controlled drug delivery carrier for cancer therapy. The pH-responsive PI was designed with pH-responsive ketal group as hydrophobic moieties and PEG group as hydrophilic moieties. The PI micelles encapsulated paclitaxel (PTX) was fabricated. Then, the PI micelles were formed in a thermo-nanogel. The micellar nanogel could improve the solubility and stability of PTX. The physiochemical properties of PI micelles and micellar nanogel were characterized. The results showed that dual-responsive micellar nanogel could carry out sol-gel transition at 37?°C. The PI polymer can spontaneously self-assemble into micellar structure with size of 100–200?nm. The dual-responsive micellar nanogel could be degraded under lower pH condition. The test in vitro PTX release showed that dual-responsive micellar nanogel could release about 70% for 70?h under pH 5.0 while about 10% release at pH 7.4 and pH 9.0. The dual-responsive micellar nanogel was of lower cytotoxicity and suppressed tumor growth most efficiently. The micellar nanogel will be a new potential dual-responsive drug delivery system for cancer therapy.     

多西他赛pH敏感嵌段共聚物胶束的制备

本文在合成pH敏感两亲性嵌段共聚物聚(2-乙基-2-噁唑啉)-聚乳酸(PEOz-PDLLA)的基础上，采用薄膜分散法制备多西他赛pH敏感嵌段共聚物胶束，利用芘荧光探针技术测定胶束的临界胶束浓度(CMC)；通过高效液相色谱测定胶束的载药量及包封率；分别利用透射电镜、动态光散射法和zeta电位分析仪对胶束的形态、粒径和表面电位进行了表征；采用透析法考察了载药聚合物胶束的体外释放行为。结果表明，胶束的临界胶束浓度值为1.0×10^-3 g·L^-1；载药量可达15.0%，包封率为91.1%；胶束的粒度分布很窄，平均粒径为28.7nm；胶束粒子为圆球形且分散良好，其表面zeta电位值为(1.19±0.12)mV；在pH 7.4释放介质中，多西他赛胶束具有缓释作用；而在pH 5.0条件下，胶束释药明显加快，体现出PEOz-PDLLA胶束释药行为的pH敏感性。综合上述研究可见，PEOz-PDLLA嵌段共聚物胶束作为疏水性抗肿瘤药物的给药系统具有很好的应用前景。     

去氧胆酸修饰的聚合物胶束的构建及其跨膜转运的研究

口服给药是患者顺应性最好的给药方式,而小肠上皮是口服药物吸收的主要屏障.为了克服小肠上皮屏障口服递送难溶性药物,本研究设计合成了小肠胆酸转运体的底物脱氧胆酸偶联的聚(2-乙基-2-噁唑啉)-聚(D,L-乳酸)(DA-PEOz-PLA),并基于小肠胆酸特殊的转运途径构建了由DA-PEOz-PLA和mPEG-PLA组成的聚...     

Nucleobase-crosslinked poly(2-oxazoline) nanoparticles as paclitaxel carriers with enhanced stability and ultra-high drug loading capacity for breast cancer therapy

Poly(2-oxazoline)(POx) has been regarded as a potential candidate for drug delivery carrier to meet the challenges of nanomedicine clinical translation, due to its excellent biocompatibility and self-assembly properties. The drug loading capacity and stability of amphiphilic POxs as drug nanocarriers, however, tend to be insufficient. Herein, we report a strategy to prepare nucleobase-crosslinked POx nanoparticles(NPs) with enhanced stability and ultra-high paclitaxel(PTX) loading capacity for b...     

Pharmacokinetics and biodistribution of paclitaxel-loaded pluronic P105/L101 mixed polymeric micelles

A mixed polymeric micelle formulation of paclitaxel (PTX) has been developed with the purpose of improving the solubility and prolonging the time of blood circulation of PTX in comparison to current Taxol injection. The mixed micelles were prepared by thin-film method using a nonionic surfactant Pluronic P105, L101 and PTX. The mean size of PTX-loaded mixed micelles was 185 nm with narrow size distribution shown by a dynamic light scattering sizer and a transmission electron microscopy. The in vitro release profiles indicated that PTX release from the mixed micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic assessment in rats, in which t(1/2beta) and AUC of the mixed micelle formulation were 5.5 and 4.9-fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX-loaded mixed micelles not only decreased drug uptake by liver, but also prolonged drug retention in blood, and increased distribution of the drug in lung, spleen and kidney. These results suggested that the mixed polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for intravenous administration of PTX.     

Enhanced oral bioavailability of paclitaxel in pluronic/LHR mixed polymeric micelles: preparation, in vitro and in vivo evaluation

In order to enhance paclitaxel oral bioavailability, mixed polymeric micelles that comprised of pluronic copolymers and low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate were developed. PTX-loaded mixed polymeric micelles (MPMs) were prepared by dialysis method with high drug loading 26.92 ± 2.08% and 25.82 ± 1.9% for F127/LHR and P188/LHR MPMs respectively, and were found to be spherical in shape with an average size of around 140 nm and a narrow size distribution. In vitro release study showed that pluronic/LHR MPMs exhibited delayed release characteristics compared to Taxol and faster drug release profile compared to LHR plain polymeric micelles (PPMs). The cytotoxic activity of PTX-loaded pluronic/LHR MPMs was slightly higher than LHR PPMs in MCF-7 cells (p<0.01). In situ effective permeability of PTX through rat small intestine was 5- to 6-fold higher with mixed micelles than that of Taxol. Moreover, pluronic/LHR MPMs achieved significantly higher AUC and C(max) level than both of LHR PPMs and Taxol. This enhancement might be due to the inhibition of both P-glycoprotein efflux system and cytochrome P450 metabolism by pluronic copolymers. The current results encourage further development of paclitaxel mixed polymeric micelles as an oral drug delivery system.     

Redox-sensitive micelles for targeted intracellular delivery and combination chemotherapy of paclitaxel and all-trans-retinoid acid

The application of paclitaxel (PTX) in clinic has been restricted due to its poor solubility. Several traditional nano-medicines have been developed to improve this defect, while they are still lack of tumor targeting ability and rapid drug release. In this work, an amphiphilic polymeric micelle of hyaluronic acid (HA) – all-trans-retinoid acid (ATRA) with a disulfide bond, was developed successfully for the co-delivery of PTX and ATRA. The combination chemotherapy of PTX and ATRA can strengthen the anti-tumor activity. Along with self-assembling to micelles in water, the delivery system displayed satisfying drug loading capacities for both PTX (32.62% ± 1.39%) and ATRA, due to directly using ATRA as the hydrophobic group. Rapid drug release properties of the PTX-loaded redox-sensitive micelles (HA-SS-ATRA) in vitro were confirmed under reducing condition containing GSH. Besides, HA-CD44 mediated endocytosis promoted the uptake of HA-SS-ATRA micelles by B16F10 cells. Due to these properties, cytotoxicity assay verified that PTX-loaded HA-SS-ATRA micelles showed concentration-dependent cytotoxicity and displayed obvious combination therapy of PTX and ATRA. Importantly, HA-SS-ATRA micelles could remarkably prolong plasma circulation time after intravenously administration. Therefore, redox-sensitive HA-SS-ATRA micelles could be utilized and explored as a promising drug delivery system for cancer combination chemotherapy.     

Paclitaxel-loaded polymeric micelles based on poly(ɛ-caprolactone)-poly(ethylene glycol)-poly(ɛ-caprolactone) triblock copolymers: in vitro and in vivo evaluation

The purpose of this study was to develop polymeric nanoscale drug-delivery system (nano-DDS) for paclitaxel (PTX) from poly(?-caprolactone)-poly(ethylene glycol)-poly(?-caprolactone) (PCL-PEG-PCL, PCEC) copolymers, intended to be intravenously administered, able to improve the therapeutic efficacy of the drug and devoid of the adverse effects of Cremophor EL. Both of the PTX-loaded polymeric micelles and polymersomes were successfully prepared from PCEC copolymers. The obtained PTX-loaded micelles exhibited core-shell morphology with satisfactory size (93 nm), and were favorable for intravenous injection. In vitro cytotoxicity demonstrated that the cytotoxic effect of PTX-loaded micelles was lower than that of Taxol (Bristol-Myers Squibb, Princeton, New Jersey). Pharmacokinetic results indicated that the PTX-loaded micelles had longer systemic circulation time and slower plasma elimination rate than those of Taxol. Furthermore, PTX-loaded micelles showed greater tumor growth-inhibition effect in vivo on EMT6 breast tumor, in comparison with Taxol. Therefore, the prepared polymeric micelles might be potential nano-DDS for PTX delivery in cancer chemotherapy.From the Clinical EditorIn this paper, a paclitaxel- loaded polymeric micelle system is demonstrated to provide optimized intravenous delivery method of this anti-cancer agent. While the study is early preclinical, this approach may have the potential to eventually be studied in clinical trials as well.     

Pharmacokinetics and biodistribution of paclitaxel-loaded pluronic P105 polymeric micelles

A novel polymeric micelle formulation of paclitaxel (PTX) has been prepared with the purpose of improving in vitro release as well as prolonging the blood circulation time of PTX in comparison to a current PTX formulation, Taxol injection. This work was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of PTX-loaded Pluronic P105 micellar system. The micelles were prepared by thin-film method using a nonionic surfactant Pluronic P105 and a hydrophobic anticancer drug, PTX. With a dynamic light scattering sizer and a transmission electron microscopy, it was shown that the PTX-loaded micelles had a mean size of approximately 24 nm with narrow size distribution and a spherical shape. The in vitro release profiles indicated that the release of PTX from the micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic study in rats, in which t _1/2β and AUC of the micelle formulation were 4.9 and 5.3-fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX-loaded micelles not only decreased drug uptake by liver, but also prolonged drug retention in blood and increased distribution of drug in lung, spleen and kidney. These results suggested that the P105 polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i.v. administration of PTX.     

载紫杉醇的PEG修饰的大黄酸偶联物胶束的表征、体外释放及药动学研究

目的 对载紫杉醇(paclitaxel,PTX)的聚乙二醇修饰的大黄酸偶联物[PEGylated carboxymethyl chiosan-rhein conjugate (polymeric),PTX/CRmP]胶束进行形态与结构表征,考察其体外(模拟血液环境中)释放情况及药动学特征。方法 通过透射电镜(transmission electron microscopy,TEM)、差示扫描量热法(differential scanning calorimetry,DSC)、X射线衍射(X-ray diffraction,XRD)对胶束的粒径、形态及结构等方面进行评价;在pH 7.4磷酸盐缓冲液(含0.8 mol·L^-1水杨酸钠)中进行PTX/CRmP胶束的体外释放研究,计算PTX的累积释放率,绘制累积释放曲线;以大鼠为模型,尾静脉注射PTX/CRmP胶束后,通过药-时曲线、药动学参数等对其进行药动学研究。结果 TEM显示PTX/CRmP胶束呈类球形,粒径约160 nm,分布均匀;DSC和XRD显示PTX几乎全部被CPmP胶束包载入其内核中。PTX/CRmP胶束在pH 7.4磷酸盐缓冲液(含0.8 mol·L^-1水杨酸钠)中24 h内累积释放率为92.2%,药物释放速率显著慢于Taxol^®。药动学研究表明,与Taxol^®组相比,PTX/CRmP胶束中药物的分布和消除较慢,药-时曲线下面积显著增加,CRmP胶束能延长PTX半衰期及其在血液循环系统中的循环时间。结论 CRmP偶联物物理包载PTX于内核中所得的PTX/CRmP胶束,粒径小,在体外模拟血液pH环境中缓释,PTX生物利用度提高。     

紫杉醇原位凝胶在EAC荷瘤小鼠体内药动学研究

目的:考察紫杉醇原位凝胶制剂PECT/PTX小鼠瘤体内植入后的药动学特点,评价该制剂是否具有控释、缓释作用。方法:对EAC荷瘤小鼠分别进行PECT/PTX瘤体内给药(A组,40 mg·kg^-1),PTX瘤体内给药(B组,40 mg·kg^-1)和PTX腹腔给药(C组,40 mg·kg^-1),给药后于设定的时间点采血,应用HPLC法测定血浆中PTX的含量,DAS 2.1.1药动学分析软件计算主要药动学参数。结果:血浆中A、B、C 3组的C_max分别为(2.23±0.16),(25.25±0.83),(258.38±10.34)mg·L^-1;t_1/2分别为(473.81±195.13),(10.89±0.87),(17.87±6.29)h;AUC_0-t分别为(623.57±23.48),(340.72±2.73),(843.35±25.93)mg·L^-1·h;V_d分别为(17.01±2.24),(1.76±0.13),(1.07±0.25)L·kg^-1;CL分别为(0.024±0.010),(0.105±0.001),(0.040±0.004)L·h^-1·kg^-1。与B组相比,A、C 2组主要药动学参数均具有显著的统计学差异(P<0.01)。结论:PECT/PTX原位凝胶制剂瘤体内给药具有缓慢释放PTX的作用。