Plasma stable,pH-sensitive non-ionic surfactant vesicles simultaneously enhance antiproliferative effect and selectivity of Sirolimus

Abstract

Objective: The purpose of the present investigation was to prepare a plasma stable, pH-sensitive niosomal formulation to enhance Sirolimus efficacy and selectivity.

Materials and methods: pH-sensitive niosomal formulations bearing PEG-Poly (monomethyl itaconate)-CholC6 (PEG-PMMI-CholC6) copolymers and cholesteryl hemisuccinate (CHEMS) were prepared by a modified ethanol injection method and characterized with regard to pH-responsiveness and stability in human serum. The ability of pH-sensitive niosomes to enhance the Sirolimus cytotoxicity was evaluated in vitro using human erythromyeloblastoid leukemia cell line (K562) and compared with cytotoxicity effect on human umbilical vein endothelial cells (HUVEC).

Results and discussion: This study showed that both formulations can be rendered pH-sensitive property and were found to rapidly release their contents under mildly acidic conditions. However, the CHEMS-based niosomes lost their pH-sensitivity after incubation in plasma, whereas, PEG-PMMI-CholC6 niosomes preserved their ability to respond to pH change. Sirolimus encapsulated in pH-sensitive niosomes exhibited a higher cytotoxicity than the control conventional formulation on K562 cell line. On the other hand, both pH-sensitive niosomes showed lower antiproliferative effect on HUVEC cells.

Conclusion: Plasma stable, pH-sensitive PEG-PMMI-CholC6-based niosomes can improve the in vitro efficiency and also reduce the side effects of Sirolimus.     

Novel therapeutic strategy for breast cancer: mammalian target of rapamycin inhibition

Background: Mammalian target of rapamycin (mTOR) plays a central role in regulating cellular protein synthesis. Dysregulation of mTOR signaling pathway is strongly associated with tumorigenesis, angiogenesis, tumor progression and drug resistance. Inhibition of mTOR might not only promote cell cycle arrest, but also sensitize resistant cancer cells to chemotherapeutic and other targeted agents. Objective: To review and summarize the mechanism of mTOR on regulation of protein synthesis and latest clinical data, and to discuss the novel therapeutic strategy for the use of mTOR inhibitors in the treatment of breast cancer. Methods: A review of published literatures and conference abstracts obtained from MEDLINE, American Society of Clinical Oncology Meeting and San Antonio Breast Cancer Symposia proceedings for results of previous preclinical and latest clinical studies of mTOR inhibition in breast cancer was performed. Conclusions: mTOR inhibitors seemed to be potentially useful for the treatment of breast cancer with acceptable safety profile. The challenge remains the identification of suitable candidates with different phenotypes. More structured studies incorporating molecular, clinical and translational research need to be initiated. Future research on mTOR inhibitors for breast cancer should focus on the evaluation of optimal schedule, patient selection and combination strategies to maximize the use of this new class of targeted agents.     

酒石酸长春瑞滨脂质体注射液的安全性及抗肿瘤作用研究

<正>长春瑞滨通过抑制微管聚合,使细胞分裂停止于有丝分裂中期,从而发挥抗癌作用[1]。临床上长春瑞滨是晚期非小细胞肺癌(NSCLC)的一线治疗药物,也用于转移性乳腺癌、难治性淋巴瘤、卵巢癌及头颈部肿瘤的治疗,主要剂量限制性不良反应为较强的神经毒性、骨髓抑制、白细胞下降、胃肠道反应及外周神经毒性[2-3],这使得患者难以长期坚持用药,从而限制了药物疗效的发挥。     

Paradoxical effect of rapamycin on S6 phosphorylation in rats with or without seizures

OBJECTIVE Accumulating data have demonstrated that seizures induced by kainate or pilocarpine activate the mammalian target of rapamycin(mTOR) pathway and mTOR inhibitor rapamycin can inhibit mTOR activation which subsequently has potential anti-epileptic effects.However,a preliminary study showed a paradoxical exacerbation of increased mTOR pathway activity reflected by S6 phosphorylation when rapamycin was administrated within a short period before kainate injection.In the present study,we examined this paradoxical effect of rapamycin in more detail,both in normal rats and kainate-injected animals.METHODS The expression of mTOR signaling target both of phosphorylated and unphosphorylated forms were detected by Western Blotting analysis.Seizure onset and duration was monitored by Video.Neuronal cell death was detected by Fluoro-Jade B staining.RESULTS In normal rats,we found that rapamycin showed the expected dose-dependent inhibition of S6 phosphorylation 3~24 h after injection,while a paradoxical elevation of S6 phosphorylation was observed 1 h after rapamycin.Similarly,pretreatment with rapamycin over 10 h prior to kainate inhibits the kainate-induced mTOR activation.In contrast,rapamycin administered 1-6 h before kainate causes a paradoxical increase in the kainate-induced mTOR activation.Rats pretreated with rapamycin 1h prior to kainate showed an increase in severity and duration of seizures and more neuronal cell death as compared to vehicle treated groups.In contrast,rapamycin pretreated 10 h prior to KA had no effect on the seizures and decreased neuronal cell death.The paradoxical effect of rapamycin on S6 phosphorylation was correlated with upstream mTOR signaling and reversed by pre-treatment of perifosine,an akt inhibitor.CONCLUSION These data indicate the complexity of S6 regulation and its effect on epilepsy.Paradoxical effects of rapamycin need to be considered in clinical applications,such as potential treatments for epilepsy and other neurological disorders.     

New liposomal doxorubicin nanoformulation for osteosarcoma: Drug release kinetic study based on thermo and pH sensitivity

A novel approach was developed for the preparation of stealth controlled‐release liposomal doxorubicin. Various liposomal formulations were prepared by employing both thin film and pH gradient hydration techniques. The optimum formulation contained phospholipid and cholesterol in 1:0.43 molar ratios in the presence of 3% DSPE ‐mPEG (2000). The liposomal formulation was evaluated by determining mean size of vesicle, encapsulation efficiency, polydispersity index, zeta potentials, carrier's functionalization, and surface morphology. The vesicle size, encapsulation efficiency, polydispersity index, and zeta potentials of purposed formula were 93.61 nm, 82.8%, 0.14, and ?23, respectively. Vesicles were round‐shaped and smooth‐surfaced entities with sharp boundaries. In addition, two colorimetric methods for cytotoxicity assay were compared and the IC ₅₀ (the half maximal inhibitory concentration) of both methods for encapsulated doxorubicin was determined to be 0.1 μg/ml. The results of kinetic drug release were investigated at several different temperatures and pH levels, which showed that purposed formulation was thermo and pH sensitive.     

The possible mechanisms of the antiproliferative effect of fullerenol,polyhydroxylated C60, on vascular smooth muscle cells

1. The possible mechanisms of the antiproliferative effect of polyhydroxylated fullerene (fullerenol), a novel free radical trapper, were studied in rat vascular smooth muscle cells (A7r5 cells) and compared with the effect of ascorbic acid.
2. Fullerenol-1 and ascorbic acid inhibited the proliferative responses in a number of cells, including rat aortic smooth muscle cells (A7r5 cells), human coronary artery smooth muscle cells, and human CEM lymphocytes (CEM cells) in a concentration dependent manner.
3. At the concentration range of 10⁻⁶ to 10⁻² M, fullerenol-1 and ascorbic acid concentration-dependently inhibited the proliferative responses stimulated by serum in A7r5 cells. Fullerenol-1 was more potent than ascorbic acid.
4. The production of O₂⁻ induced by alloxan, a diabetogenic compound, was reduced by fullerenol-1 (10⁻⁴ M) in the presence of A7r5 cells.
5. The cytosolic protein kinase C activity of A7r5 cells stimulated by phorbol ester was reduced by 10⁻³ M fullerenol-1, but not ascorbic acid (10⁻⁴–10⁻² M) and fullerenol-1 at lower concentrations (10⁻⁶–10⁻⁴ M).
6. In contrast, the membraneous protein tyrosine kinase activity of A7r5 cells stimulated by foetal calf serum was significantly reduced by fullerenol-1 (10⁻⁶–10⁻³ M) and ascorbic acid (10⁻⁴–10⁻² M). Again, the inhibitory activity of fullerenol-1 was greater than that of ascorbic acid.
7. Our results demonstrate that fullerenol-1 and ascorbic acid exhibit inhibitory effects on transduction signals in addition to their antioxidative property. It is suggested that the antiproliferative effect of fullerenol-1 on vascular smooth muscle cells may partly be mediated through the inhibition of protein tyrosine kinase.

     

卵巢癌患者术后力朴素与顺铂联合静脉化疗的疗效观察

目的观察卵巢癌患者术后应用力朴素与顺铂联合静脉化疗的疗效及毒副反应。方法 24例患者术后采用力朴素与顺铂联合静脉化疗。3周1个疗程,共4~6个疗程。化疗后通过患者的临床症状及化验指标等判断治疗效果及化疗毒副作用。结果治疗有效率为91.67%(22/24),血肿瘤标志物CA125下降率91.67%(22/24)。白细胞下降发生率为45.83%(11/24),胃肠道反应率为70.83%(17/24)。所有患者均未因化疗毒副作用中断或退出治疗。结论力朴素与顺铂联合静脉化疗对术后卵巢恶性肿瘤治疗效果好,毒副反应轻。     

Paclitaxel in a novel formulation containing less Cremophor EL as first-line therapy for advanced breast cancer: A phase II trial

Summary Paclitaxel (Taxol) is formulated in 50% Cremophor EL (CrEL)/absolute ethanol for clinical use. In order to reduce vehicle-related side effects, Genetaxyl was developed to have paclitaxel formulated in a solution containing lesser amounts of CrEL and ethanol plus 2 other solvents. The purpose of the study was to evaluate the efficacy and safety of Genetaxyl as first-line therapy to treat breast cancer patients. Patients with newly diagnosed stage III (N = 8) or IV (N = 10), or recurrent (N = 11) breast cancer received single-agent Genetaxyl at 175 mg/m² administered in a 3-h infusion every 3 weeks for 3–6 cycles. A total of 148 cycles were delivered to 29 patients. The overall response rate was 41.4% (95% confidence interval, 23.4 to 59.2%), and that of patients with metastatic disease (N = 20) was 30%. Median survival for all patients was 32.4 months and 24.3 months for patients having metastatic disease. The toxicity profile seems favorable, especially regarding myelosuppression and myalgia/arthralgia. No severe hypersensitivity reaction occurred. These phase II trial results demonstrate that a 60% reduction of CrEL by Genetaxyls formulation does not affect the activity of paclitaxel and could allow for better control of several CrEL-related toxicities.Taxol is a trademark of Bristol-Myers Squibb Company     

Multiple response optimisation of processing and formulation parameters of pH sensitive sustained release pellets of capecitabine for targeting colon

Purpose: To optimise the Eudragit/Surelease^®-coated pH-sensitive pellets for controlled and target drug delivery to the colon tissue and to avoid frequent high dosing and associated side effects which restrict its use in the colorectal-cancer therapy.

Methods: The pellets were prepared using extrusion-spheronisation technique. Box–Behnken and 3² full factorial designs were applied to optimise the process parameters [extruder sieve size, spheroniser-speed, and spheroniser-time] and the coating levels [%w/v of Eudragit S100/Eudragit-L100 and Surelease^®], respectively, to achieve the smooth optimised size pellets with sustained drug delivery without prior drug release in upper gastrointestinal tract (GIT).

Results: The design proposed the optimised batch by selecting independent variables at; extruder sieve size (X₁?=?1?mm), spheroniser speed (X₂?=?900 revolutions per minute, rpm), and spheroniser time (X₃?=?15?min) to achieve pellet size of 0.96?mm, aspect ratio of 0.98, and roundness 97.42%. The 16%w/v coating strength of Surelease^® and 13%w/v coating strength of Eudragit showed pH-dependent sustained release up to 22.35?h (t_99%). The organ distribution study showed the absence of the drug in the upper part of GIT tissue and the presence of high level of capecitabine in the caecum and colon tissue. Thus, the presence of Eudragit coat prevent the release of drug in stomach and the inner Surelease^® coat showed sustained drug release in the colon tissue.

Conclusion: The study demonstrates the potential of optimised Eudragit/Surelease^®-coated capecitabine-pellets for effective colon-targeted delivery system to avoid frequent high dosing and associated systemic side effects of drug.     

Evaluation of the antianginal effect of nifedipine: influence of formulation dependent pharmacokinetics

Summary Nifedipine capsules t.d.s. and an extended release formulation of nifedipine, nifedipine-ER tablets, given once daily in corresponding daily doses, have been compared with placebo in a double-blind, three-way crossover study in 24 patients with stable angina pectoris. The objective was to study the influence on the antianginal effect of the different pharmacokinetics of several preparations of nifedipine. All patients received concomitant treatment with -adrenoceptor blockers. Antianginal efficacy was assessed by a dynamic exercise test at the end of the dosage intervals, i.e. 8 and 24 h after nifedipine capsules and nifedipine-ER, respectively, as well as 6 h after dosing. Six h after dosing the time of onset of chest pain and total excercise time were longer and total work was significantly higher during both nifedipine-ER (plasma concentration 260 nmol/l) and placebo treatment than after nifedipine capsules (plasma concentration 78 nmol/l). Time to 1 mm ST depression was longer during nifedipine-ER than during nifedipine capsule treatment. No significant difference was seen between nifedipine-ER and placebo. At the end of the dosage interval (24 and 8 h after nifedipine-ER and nifedipine capsules, respectively), no significant difference was found between nifedipine-ER (plasma concentration 75 nmol/l) and the other two treatments. However, placebo was superior to nifedipine capsules (plasma concentration 58 nmol/l) both in the time to onset of chest pain and total exercise time. The lack of effect at the end of the dosage interval was probably due to the subtherapeutic plasma nifedipine level. Nifedipine capsules, but not the extended release formulation, were found to be significantly inferior to placebo both after 6 h and at the end of the dosage interval. This unexpected finding may have been induced by the rapid and extensive fluctuation in plasma levels, with a rapid decline from the peak value after the capsule formulation, since a similar deterioration was not seen with nifedipine-ER, despite similar plasma concentrations at the end of the dosage interval. This phenomenon merits further research.     

GnRH analogues containing conformationally restricted amino acids in positions 3 and 6: differential impact on pituitary binding affinity and direct antiproliferative effect on breast cancer cells†

Abstract: Analogues of GnRH have been widely used in oncology and gynaecology to induce reversible chemical castration. In addition to the classic hypophysiotropic action of GnRH, it has been shown that many malignant cells, such as breast cancer cells, secrete GnRH and express the GnRH receptor/s. In order to study the effect of modifications in position 3 and 6 of GnRH on both pituitary binding affinity and breast cancer cell proliferation, we synthesized eight new GnRH analogues. All GnRH analogues lacked the carboxy–terminal Gly¹⁰–amide of GnRH and an ethylamide residue was added to Pro⁹. Gly⁶ was substituted by α,α‐dialkyl amino acids (Aib: α‐aminoisobutyric acid, Deg: diethylglycine) and Trp³ by D–Trp, D‐ and L‐1,2,3,4,‐tetrahydro‐isoquinoline‐3‐carboxylic acid (Tic). During competition binding experiments in mouse anterior pituitary αT3‐1 cells, [Aib⁶,desGly¹⁰]GnRH‐NHEt bound to the GnRH receptor with IC₅₀ values comparable to those of parent hormone in contrast to the analogues substituted at position 3 . However, [L‐Tic³,Deg⁶,desGly¹⁰]GnRH‐NHEt had high pituitary binding affinity. With the exception of GnRH and [Aib⁶,desGly¹⁰]GnRH‐NHEt, all GnRH analogues significantly inhibited the proliferation of human breast cancer cells (MCF‐7); higher inhibitory effect was observed for analogues modified at position 3 . Results show differential impact of the modifications on the binding affinity to the GnRH receptor in mouse pituitary cells and on the inhibition of human breast cancer cell proliferation and provide insight into structure‐activity relationship of GnRH in different biological systems.     

CAF与CMF方案用于局部晚期乳腺癌新辅助化疗临床观察

目的比较CAF、CMF两组不同新辅助化疗方案治疗局部晚期乳腺癌的疗效及毒性反应。方法用CAF、CMF化疗方案治疗Ⅱ、Ⅲ期乳腺癌94例,3-4周为1个周期。所有患者完成2个周期新辅助化疗后评价疗效。结果 CAF组的总有效率为68．89％(31／45),其中完全缓解(CR)3例,部分缓解(PR)28倒;CMF组的总有效率为 46．94％(23／49),其中CR 0例,PR 23例,P<0.05。两组毒性反应比较:CAF组有较为严重的白细胞下降、胃肠道反应,两组相比有显著性差异,P<0．05。结论两组新辅助化疗方案对乳腺癌治疗均有效,毒性反应均可耐受。CAF组疗效及毒性反应均高于CMF组。     

中西医结合对三阴乳腺癌患者的生存率影响研究

目的：研究辨证服用中药对三阴乳腺癌病患生存率的影响。方法自2010年2月到2013年11月,于该院中医部选取术后被确诊为三阴乳腺癌患者98例,以数字法随机分成观察组（50例）和对照组（48例）。观察组在术后辨证服用中药联合西药治疗,对照组施以单纯的西药治疗。观察组患者服用中药的时间至少达1年;对照组患者按照美国西医指导标准对三阴乳腺癌患者进行治疗。结果观察组无病生存者占比88．00％（44／50）,总生存率为98．00％（49／50）,均显著高于对照组的66．67％（32／48）,83．33％（40／48）,差异均有统计学意义（均P＜0．05）。结论三阴乳腺癌病患通过辨证口服中药能有效提高患者无病生存率及总生存率,减少复发转移率,延长生存期。     

局部进展期乳腺癌新辅助化疗3种方案的不良反应比较

目的:评价3种辅助化疗方案的不良反应,为局部进展期乳腺癌化疗方案的选择提供参考。方法:收集2000年1月至2005年12月应用3种不同新辅助化疗方案治疗的89例女性乳腺癌患者的临床资料,对各组不良反应和近期疗效进行回顾性分析。化疗方案为CEF(环磷酰胺+表阿霉素+氟尿嘧啶)、NEF(长春瑞滨+表阿霉素+氟尿嘧啶)和TAC(多西紫杉醇+表阿霉素+环磷酰胺),28d为1个周期,化疗2周期后手术,入组患者分别为36、32和21例。结果:①所有患者均完成2个周期化疗。CEF、NEF和TAC组肿瘤原发灶有效率分别为47.2%(7/36)、71.9%(23/32)和85.7%(18/21),CEF组与NEF组比较差异有统计学意义(x2=4.251,P=0.039),CEF组与TAC组比较有效率差异有统计学意义(x2=8.292,P=0.004),NEF与TAC组差异无显著性(x2=1.386,P=0.239)。②TAC组的不良反应为白细胞减少(21/21,100%)、脱发(21/21,100%)、关节肌肉痛(12/21,51.1%)、面色潮红(9/21,42.9%)及过敏反应(4/21,19%)。TAC组白细胞减少明显高于CEF组(77.1%)和NEF组(78.1%)。NEF组32例中有13例出现周围静脉炎(40.6%)。其他不良反应如血红蛋白减少、血小板减少及胃肠道反应,3组相似。结论:NEF治疗方案具有良好近期疗效,不良反应易耐受,适用于治疗局部进展期乳腺癌。     

Identification of urushiols as the major active principle of the Siddha herbal medicine Semecarpus Lehyam: Anti-tumor agents for the treatment of breast cancer

Breast cancer (BCa) is the most commonly occurring cancer in women, comprising almost one third of all malignancies. Previously we reported that the n-hexane fraction (hSL) of the Siddha herbal medicine, Semecarpus Lehyam, relatively sensitized estrogen receptor-negative (ER^?) BCa when compared to estrogen receptor-positive (ER⁺) BCa cells. In this study we used a bioassay-guided fractionation approach leading to a simplified fraction of hSL that effectively sensitized both ER⁺ (MCF-7) and ER^? (MDA-231) BCa cells. Further bioassay-guided isolation led to the purification of three potent anti-cancer components from hSL which significantly induced apoptosis in both the BCa cell lines. Their structures were identified through NMR and mass spectroscopic analysis as (7;Z,10;Z)-3-pentadeca-7,10-dienyl-benzene-1,2-diol (1), (8;Z)-3-pentadec-10-enyl-benzene-1,2-diol (2) and 3-pentadecyl-benzene-1,2-diol (3). Compounds (1) and (2) turned out to be more active than (3). The overall results of this study suggest that these major components of hSL may be solely responsible for the anti-tumor effect of SL.     

脂质体多柔比星治疗恶性肿瘤临床疗效及安全性的系统评价

目的 评价脂质体多柔比星（脂质体阿霉素）治疗恶性肿瘤的临床疗效及安全性。方法 计算机检索中国学术文献总库（CNKI）、万方数字化期刊库、中国生物医学文献数据库（CBM）、维普中文科技期刊数据库（VIP）,PubMed数据库、Embase数据库和Cochrane Library数据库,脂质体多柔比星治疗恶性肿瘤的中英文随机对照试验,检索年限从建库至2017年1月。采用RevMan 5.3软件对各效应指标进行Meta分析。结果 纳入23篇RCT文献,计5 546名恶性肿瘤患者。Meta分析结果显示：治疗前后临床疗效I²=63%、OR=1.14[1.02,1.27],P=0.002;两组化疗后心脏毒性不良事件I²=0%,OR=0.18[0.10,0.33],P<0.000 01;脱发不良事件I²=77%,OR=0.24[0.17,0.35],P<0.000 01;神经毒性不良事件I²=46%,OR=0.65[0.42,0.99],P=0.05。结论 脂质体多柔比星治疗恶性肿瘤的临床疗效优于其他化疗方案,且毒副作用低,尤其在改善心脏毒性、脱发等不良事件方面明显优于其他化疗方案。     

Synergistic effect of the anti-PD-1 antibody with blood stable and reduction sensitive curcumin micelles on colon cancer

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a potent anticancer drug with versatile biological activities, while the clinical translation of curcumin is severely limited due to its hydrophobicity, rapid elimination, and metabolism in the blood circulation. Herein, we aim to unravel the potential of curcumin as a synergistic agent with immunotherapy in the treatment of cancers. In an effort to minimize premature release and improve the systemic bioavailability, a superior blood stable and reduction sensitive curcumin micellar formulation, of which the release can be triggered by cancer cells, is rationally designed. We have synthesized a telodendrimer (mPEG-PLA-(LA)₄) capable of forming reversible disulfide crosslinked micelles (DCMs). The curcumin loaded DCMs (Cur/DCMs) are spherical with a uniform size of 24.6 nm. The in vitro release profile demonstrates that curcumin releases significantly slower from DCMs than that from non-crosslinked micelles (NCMs), while the release can be accelerated with the increasing concentration of reducing agent glutathione (GSH). Intravenous administration of Cur/DCMs stably retains curcumin in the bloodstream and efficiently improves the systemic bioavailability. Furthermore, Cur/DCMs exhibit synergistic anticancer efficacy when combined with the anti-PD-1 antibody in an MC-38 colon cancer xenograft model. Our results potentiate the integration of blood stable curcumin nanoformulation and immunotherapy for cancer treatment.     

来曲唑单药治疗ER阳性激素反应性早期乳腺癌的效果及不良反应观察

目的 研究来曲唑单药治疗雌激素受体(ER)阳性激素反应性早期乳腺癌的效果及不良反应.方法 选择2009年2月至2010年2月本院70例早期ER阳性激素反应性乳腺癌患者作为研究对象,随机分为两组,每组35例.观察组行来曲唑单药治疗,对照组行他莫昔芬序贯来曲唑治疗,观察两组治疗效果及不良反应发生情况.结果 观察组近期总有效率为85.71％,对照组为82.86％,差异无统计学意义(P＞0.05).观察组1、3、5年存活率分别为94.29％、90.91％及83.33％,与对照组比较差异无统计学意义(P＞0.05).观察组治疗3年复发率为20.00％,显著低于对照组的46.43％,差异有统计学意义(P＜0.05).观察组高脂血症和关节疼痛发生率显著高于对照组,潮热、阴道出血及静脉血栓发生率显著低于对照组,差异均有统计学意义(P＜0.05).结论 来曲唑单药治疗ER阳性激素反应性早期乳腺癌效果显著,复发率低,临床应用时应充分评估复发风险和不良反应情况,坚持个体化治疗.     

Antitumor activity of new liposomal prodrug of mitomycin C in multidrug resistant solid tumor: Insights of the mechanism of action

The antitumor activity of a novel thiolytically cleavable lipid-based prodrug of mitomycin C (MMC) delivered by STEALTH® liposomes (SL) was studied in drug resistant human ovarian carcinoma A2780/AD model and compared with free MMC and both free and SL forms of an established anticancer drug—doxorubicin (DOX). It was found that SL-prodrug (SL-pMMC) possessed enhanced antitumor activity when compared with the parent MMC, free DOX, and SL-DOX. An observance of the high antitumor efficiency of SL-pMMC was a result of its preferential accumulation in the tumor by the enhanced permeability and retention (EPR) effect, suppression of multidrug resistance (MDR) associated with P-glycoprotein and MRP drug efflux pumps, activation of caspase-dependent apoptosis signaling pathways and suppression of antiapoptotic cellular defense by increasing the BAX/BCL2 ratio. Consequently, the described SL-pMMC formulations can be considered good candidates for the chemotherapy of multidrug resistant tumors.     

pH与吸收促进剂对胰岛素中空栓剂中胰岛素吸收的影响

目的 研究pH值及吸收促进剂对胰岛素中空栓剂中胰岛素吸收的影响,筛选胰岛素中空栓剂的最佳pH值和吸收促进剂.方法 用普通栓剂模具制备,以半合成脂肪酸脂为基质,甘油为溶剂,制成每枚含胰岛素4 U的中空栓剂,再将其置家兔直肠内,用酶-苯酚法测定家兔的血糖.结果 胰岛素中空栓剂的降糖效果在pH4时,氮酮作吸收促进剂最好,与皮下注射胰岛素1 U相当.结论 胰岛素中空栓剂在适当的pH值下,辅以吸收促进剂,有较好的吸收,可能成为胰岛素非注射给药的有效载体.