The efficacy and safety of the targeted drug combined with adriamycin liposome solution for HER-2-positive breast cancer

Objective:To study the efficacy and safety of the targeted drug trastuzumab combined with adriamycin liposome solution for HER-2-positive breast cancer.Methods: A total of 112 patients with breast cancer who received chemotherapy in Department of Cardiothoracic Breast Surgery, Guangdong TongJiang Hospital between May 2014 and April 2016 were selected as the research subjects and divided into two groups by random number table, liposome group received trastuzumab + adriamycin liposome chemotherapy, and the control group received trastuzumab + adriamycin chemotherapy. Before chemotherapy as well as 4 weeks and 8 weeks after chemotherapy, serum levels of tumor markers, cytokines and myocardial injury indexes were detected, the electrocardiography was conducted and the degree of myocardial injury was determined.Results: 4 weeks and 8 weeks after chemotherapy, serum CEA, CA15-3, TPS, CTGF, TGF-β, TSGF, VEGF and MK levels of both groups were significantly lower than those before chemotherapy, serum CK-MB and cTnI levels were significantly higher than those before chemotherapy, limb leads QRS amplitudes and chest leads QRS amplitudes were significantly lower than those before chemotherapy, serum CEA, CA15-3, TPS, CTGF, TGF-β, TSGF, VEGF, MK, CK-MB and cTnI levels of liposome group were significantly lower than those of control group, and the limb leads QRS amplitudes and chest lead QRS amplitudes were significantly higher than those of control group.Conclusion: Targeted drug combined with adriamycin liposome therapy for HER-2-positive breast cancer can improve the curative effect and reduce the cardiotoxicity.

Treatment of hepatoma with liposome-encapsulated adriamycin administered into hepatic artery of rats

AIM： To observe the therapeutic effects of liposomeencapsulated adriamycin （LADM） on hepatoma in comparison with adriamycin solution （FADM） and adriarnycin plus blank liposome （ADM ＋ BL） administered into the hepatic artery of rats. METHODS： LADM was prepared by pH gradient-driven method. Normal saline, FADM （2 mg/kg）, ADM＋BL （2 mg/kg）, and LADM （2 mg/kg） were injected via the hepatic artery in rats bearing liver W256 carcinosarcoma, which were divided into four groups randomly. The therapeutic effects were evaluated in terms of survival time, tumor enlargement ratio, and tumor necrosis degree. The difference was determined with ANOVA and Dunnett test and log rank test. RESULTS： Compared to FADM or ADM ＋ BL, LADM produced a more significant tumor inhibition （tumor volume ratio： 1.243±0.523 vs 1.883±0.708, 1.847±0.661, P 〈 0.01）, and more extensive tumor necrosis. The increased life span was prolonged significantly in rats receiving LADM compared with FADM or ADM＋BL （231.48 vs 74.66, 94.70） （P 〈 0.05）. CONCLUSION： The anticancer efficacies of adriamycin on hepatoma can be strongly improved by liposomal encapsulation through hepatic arterial administration.

Toxicity of Magnetic Albumin Microspheres Bearing Adriamycin

Magnetic albumin microspheres bearing adriamycin (ADM MAM) is a novel chemotherapeutic compound with site specific drug delivery characteristics. The acute and subacute toxic tests of the compound, local irritating test and anaphylactic test were performed on mice and guinea pigs. The results showed there was no macroscopically and microscopically direct cytotoxic injuries of the compound to the animal organs or to the cells. The LD 50 value of the compound was higher than that of the single used adriamycin, indicating that the compound was less toxic than the single adriamycin and quite safe in its therapeutic dosage. Furthermore, there was also no side effects or toxic reactions to be observed on clinical patients with advanced carcinoma or gastric cancer.

Inhibition expression of multidrug resistant in tumor cell by MDR1 antisense RNA gene transfer as a way of increasing toxicity of chemotherapy

A plasmid expressing antisense MDRl cDNAsegment was introduced into KBv200 which inductedmultiple drugs to VCT （vincristine, 175 fold-resistancehigher than that in original KB cells） and ADM（adriamycin, 14. 5 fold） resulting over-expression ofMDRl. We used the primers for antisense RNA asfollowing: upstream 5′OGAATTCTGAAACCTGTAAGCAGCAACC 3′: downstream

Amphotericin B release rate is the link between drug status in the liposomal bilayer and toxicity

Amphotericin B(AmB)is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal infections.Recent studies on the liposomal drug product have shed light on the AmB aggregation status in the bilayer,which heat treatment(curing)modifies.Although toxicity was found related to aggregation status-loose aggregates significantly more toxic than tight aggregates-the precise mechanism linking aggregation and toxicitywas notwell understood.This study directlymeasured drug release rate fromvarious AmB liposomal preparations made with modified curing protocols to evaluate correlations among drug aggregation state,drug release,and in vitro toxicity.UV–Vis spectroscopy of these products detected unique curing-induced changes in the UV spectral features:a∼25nm blue-shift of the main absorption peak(λ_(max))in aqueous buffer and a decrease in the OD_(346)/OD_(322) ratio upon thermal curing,reflecting tighter aggregation.In vitro release testing(IVRT)data showed,by applying and fitting first-order release kinetic models for one or two pools,that curing impacts two significant changes:a 3–5-fold drop in the overall drug release rate and a ten-fold decrease in the ratio between the loosely aggregated and the tightly aggregated,more thermodynamically stable drug pool.The kinetic data thus corroborated the trend independently deduced from the UV–Vis spectral data.The in vitro toxicity assay indicated a decreased toxicity with curing,as shown by the significantly increased concentration,causing half-maximal potassium release(TC50).The data suggest that the release of AmB requires dissociation of the tight complexes within the bilayer and that the reduced toxicity relates to this slower rate of dissociation.This study demonstrates the relationship between AmB aggregation status within the lipid bilayer and drug release(directly measured rate constants),providing a mechanistic link between aggregation status and in vitro toxicity in the liposomal formulations.

Local injection of liposomal adriamycin to inhibit metastatic cell proliferation in axillary nodes in rabbits bearing breast tumors

Objective: To assess the inhibitory effects of local injection of liposomal adriamycin (LADR) on the proliferation of lymph node metastases in rabbits bearing VX2 carcinoma in the mammary gland. Methods:Thirty female New Zealand white rabbits were divided into 3 groups, with 10 in each. VX2 tumor mass suspensions were injected into the breast tissues of rabbits. Treatment initiated once the axillary lymph node reached 5 mm in the maximum diameter. Group 1 received a sham treatment. Group 2 received a subcutaneous injection of LADR adjacent to tumor. Group 3 received an intravenous injection of free ADR (FADR) at the same dose and concentration to group 2. The breast tumors and axillary lymph nodes were resected after the treatment was repeated 3 times. The tumor and node sizes before and after treatment were measured. PCNA mRNA expressions in breast tumors and axillary nodes were determined using RT-PCR. Results: The mean growth ratios of lymph nodes after treatment were 3. 70, 1. 55, and 2. 89,respectively, in groups 1,2, and 3. The slowest node growth was observed in animals of group 2, with significant differences from group 1 (P<0. 001) and group 3 (P = 0. 002). The relative values of PCNA mRNA expression in lymph nodes were 0. 541, 0. 329,and 0. 450, respectively, in groups 1,2, and 3. Group 2 exhibited a significantly reduced PCNA mRNA expression in metastatic lymph node, as compared to group 1 (P<0. 001) and group 3 (P = 0. 004). Intravenous FADR injection effectively lowered the mRNA expressions of PCNA in breast tumors, which were not apparently altered after local LADR injection. Conclusion: Local injection of LADR holds a strong inhibitory effect on the proliferation of metastatic tumor cells in lymph nodes and appears to be an effective method for the treatment of lymphatic metastases of breast cancer.

Local administration of liposomal adriamycin inhibited proliferation of metastatic cells in axillary lymph nodes in rabbit breast cancer model

Objective： To assess the inhibitory effects of liposomal adriamycin （LADR） locally injected into mammary glands of VX2 tumor-bearing rabbits on proliferation of lymph nodal metastatic cells. Methods： Twenty-one VX2 tumor-bearing rabbits were randomly and equally divided into 3 groups. Rabbits were randomized to receive sham treatment （Group I）, subcutaneous LADR around tumor （Group Ⅱ） and intravenous free adriamycin （Group Ⅲ）, respectively. Breast tumor and axillary lymph nodes were harvested after 3 repeated treatment. Nodal sizes of both pre-and post-treatment were measured. Proliferating cell nuclear antigen （PCNA） mRNA in both tumor and lymph nodes were determined by RT-PCR. Results： The mean size of axillary lymph nodes in Group I, Ⅱ and Ⅲ increased by 3.70%, 1.55% and 2.89%, respectively, with significant difference between Group Ⅲ and I （P=-0.004） and between Group Ⅱ and Ⅲ（P=-0.002）. Relative expression values of PCNA mRNA in breast tumors of Group I, Ⅱ and Ⅲ were 0.486, 0.513 and 0.396, respectively. For Group Ⅲ, PCNA mRNA was significantly less expressed than that in Group I （P=-0.023） and Ⅱ（P=0.005）. Relative expression values of PCNA mRNA in axillary lymph nodes of Group I, Ⅱ and Ⅲ were 0.541, 0.329 and 0.450, respectively. Compared with Group I, Group Ⅲ showed a markedly decreased expression of PCNA （P=-0.021）. The least level ofPCNA mRNA was found in Group Ⅱ, with a significant difference from that in Group Ⅲ（P=-0.004）. Conclusion： Local injection of LADR was an effective therapeutic regimen for lymphatic metastases from breast cancer, regardless of its little effect on primary tumor.

The Applications of Mitoxantrone and Its Liposome in Adult Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a rapidly progressing hematopoietic malignancy, can only be cured hopefully by hematopoietic stem cells transplantation (HSCT). Before HSCT, we usually exert effects by attempting certain regimens to induce these tumor cells to death. Administered in AML patients, the classic “3 + 7” intensive induction regimen including anthracyclines and cytarabine is recommended by guidelines worldwide. However, conventional regimens consist of anthracyclines, a category of drug limited by cumulative, dose-related, progressive myocardial damage and congestive heart failure occurs when its total doses break through the cut-off. Based on this background, mitoxantrone (MIT), an anthraquinone, was developed to a new form to reduce cardiotoxicity. Meanwhile, the nanomedicine, mitoxantrone liposome (Lipo-MIT), was characterized by improved bioavailability and limited toxicity. This drug has great therapeutic potential, but different side effects. We conclude the overall history and development of MIT and Lipo-MIT, which show controversial efficacy of MIT compared to doxorubicin and therapeutic potential of Lipo-MIT. This article reviewed the application of MIT and liposome forms in adult AML patients. .

The Effect of Liposome Encapsulated Daunorubicin on Rabbit Eyes after Extracapsular Lens Extraction

Purpose: To investigate the effect of liposome encapsulated daunorubicin (DNR) on rabbit eyes when it was used in prevention of posterior capsule opacification (PCO). Methods: The liposome encapsulated DNR was prepared by modified freeze-thawing method. Each eye was injected with 0. 1 ml liposomes (0. 2 mg/ml and 20 μg/ml DNR) into the capsular bag during the extracapsular lens extraction (ECLE) in 10 rabbit eyes respectively. The phosphate buffer solution (PBS) was injected as control. Besides biomicroscope observation and histology examination of all eyes, the concentration of DNR in aqueous humor was also determined by high performance liquid chromatography (HPLC).Results: The morphology of liposome encapsulated DNR were similar to the blank liposome with round or ellipse shape. The encapsulated effeciency of liposome encapsulated DNR was 45. 1%. The inflammatory response was much more severe both in 0. 2 mg/ml and 20μg/ml DNR group than the control after liposome injection. All eyes in DNR group

Liposome-based delivery of biological drugs

Biological drugs are attracting tremendous attention in disease treatment. However, their application is significantly limited by their inherent properties, such as high hydrophilicity, poor membranepermeability, low stability, and larger size. Liposome-based drug delivery systems are emerging as promising tools to improve their delivery, owing to their ability to reduce toxicity, improve bioavailability,and enhance the therapeutic efficacy of the drug by optimizing delivery to the specific target site. Here,we reviewed the types of liposomes and their applications as carriers for biological drugs to treat various diseases, emphasized the commercial products, and ultimately provided perspectives in this field.

两性霉素B脂质体治疗侵袭性真菌感染病人发生急性肾损伤危险因素分析

目的研究两性霉素B脂质体(L-AMB)治疗侵袭性真菌感染病人发生急性肾损伤(AKI)的危险因素。方法回顾性分析南京医科大学附属淮安第一医院2018年1月至2021年12月61例两性霉素B脂质体治疗侵袭性真菌感染病人的临床资料,根据是否发生两性霉素B脂质体相关AKI分为AKI组23例(37.7%),非AKI组38例(62.3%)。采用单因素分析法比较两组临床资料,logistic回归分析两性霉素B脂质体(L-AMB)治疗侵袭性真菌感染病人发生AKI的危险因素,应用受试者操作特征曲线(ROC曲线)评价L-AMB使用累积剂量及治疗前血清钾水平在诊断AKI方面的能力。结果有23例病人在使用L-AMB治疗过程中发生AKI,AKI发生率为37.7%。L-AMB疗程、累积剂量、日剂量,L-AMB治疗前血钾水平在AKI及非AKI两组病人比较中均差异有统计学意义(均P<0.05);累积剂量是发生L-AMB相关AKI的独立危险因素[OR=1.46,95%CI:(1.08,1.98),P=0.014];在L-AMB治疗前低血钾水平是发生L-AMB相关AKI的另一个独立危险因素[OR=0.05,95%CI:(0.01,0.43),P=0.007]。累积剂量和治疗前血钾水平曲线下面积(AUC)及其95%CI分别为0.88(0.79,0.98)、0.88(0.79,0.96),灵敏度分别为86.9%、81.5%,特异度分别为89.4%、86.9%。结论L-AMB累积剂量及治疗前低血钾水平均是L-AMB相关AKI的独立危险因素,两者在L-AMB相关AKI的诊断中均有一定的预测价值,而且累积剂量的诊断价值大于治疗前低血钾水平。

顺铂脂质体的制备及其体内外评价

目的制备抗肿瘤药物顺铂脂质复合物脂质体(CDDP-MM),以期降低顺铂的毒副作用,并保持其疗效。方法使用逆相蒸发法制备CDDP-MM;以SD大鼠为实验动物考察CDDP-MM的体内药动学行为;以H22荷瘤小鼠为模型,以市售注射用顺铂为参比,考察CDDP-MM的体内抗肿瘤效果及其毒副作用。结果所制备的CDDP-MM平均粒径为109.8 nm,包封率高达90%。大鼠体内药动学结果表明,与注射用顺铂相比,CDDP-MM最大血药浓度(cmax)提高2.93倍(P<0.001),t1/2α延长65.50倍(P<0.01);AUC0-24显著增大41.26倍(P<0.01),CDDP-MM显著改善了注射用顺铂的体内药动学行为。小鼠体内抗肿瘤活性结果表明CDDP-MM的抑瘤率为82.5%,与注射用顺铂组相比小鼠体重显著增加(P<0.0001),肾毒性下降。结论CDDP-MM显著改善顺铂的体内药动学行为且可以有效抑制肿瘤生长、显著降低顺铂的胃肠道毒性和肾毒性。

载阿霉素B7-H3免疫长循环脂质体的制备及其对MCF-7细胞活力的抑制作用

目的以阿霉素(DOX)为模型药物,以B7-H3免疫脂质体为载体,构建载DOX免疫长循环脂质体(BPDL),并评价其在SD大鼠体内的药动学行为以及对人乳腺癌MCF-7细胞的毒性作用。方法采用薄膜分散法制备包载DOX的脂质体BPDL,通过透射电镜观察其微观形态,激光粒度仪测定粒径分布及zeta电位。采用透析法考察其体外释药情况,并以SD大鼠为模型评价体内药动学,比较DOX、DOX-Lips和BPDL在体外对人乳腺癌MCF-7细胞的毒性作用。结果BPDL呈类球状分布,平均粒径为152.27 nm,电位为-25.9 mV,载DOX量为8.16%±0.08%。BPDL在磷酸缓冲溶液中释放96 h时,DOX的累积释放率为60.15%。与原料药比较,BPDL脂质体的MRT、C_(max)、CLz升高,其中的DOX的t_(1/2)比游离药物组延长3.59倍(P<0.05);细胞毒性实验中BPDL中DOX的浓度为160μg·mL^(-1)时,给药72 h条件下,对MCF-7抑制率达到97.48%。结论本研究制备的偶联B7-H3抗体的免疫长循环脂质体可延长药物在血液中的循环时间,对人乳腺癌细胞具有较强的抑制效果,为开发化疗联合免疫治疗方法提供了新的科研思路。

R-CDOP方案治疗弥漫大B细胞淋巴瘤的效果及对免疫功能、预后影响

目的探讨R-CDOP方案治疗弥漫大B细胞淋巴瘤的效果及对免疫功能、预后影响。方法选取2017年10月至2020年6月于浙江省台州市中心医院(台州学院附属医院)诊治且随访至2022年7月的52例弥漫大B细胞淋巴瘤患者作为研究对象,按照随机数字表法分为观察组(予以R-CDOP方案治疗)与对照组(予以R-CHOP方案治疗),各26例。比较两组有效率、免疫功能(CD3^(+)、CD4^(+)、CD8^(+))、毒副作用、2年生存率及生存时间。结果观察组客观有效率、完全缓解率高于对照组,差异有统计学意义(P<0.05)。化疗后,两组CD3^(+)、CD4^(+)低于化疗前,且观察组高于对照组;两组CD8^(+)高于化疗前,且观察组低于对照组,差异有统计学意义(P<0.05)。观察组毒副作用总发生率低于对照组,差异有统计学意义(P<0.05)。观察组2年生存率、生存时间高于对照组,差异有统计学意义(P<0.05)。结论R-CDOP方案治疗弥漫大B细胞淋巴瘤效果显著,有利于减轻对免疫功能的影响,且安全性高。

基于网络药理学与动物实验探究八味沉香散对阿霉素心脏损伤的保护作用及机制

目的基于网络药理学与动物实验探究八味沉香散对阿霉素心脏损伤的保护作用及机制。方法应用网络药理学与动物实验学方法开展研究。借助TCMSP数据库筛选八味沉香散入血成分及靶点;利用OMIM、GeneCards等数据库检索疾病靶点;取交集靶点构建PPI网络。做GO以及KEGG富集分析,并构建“入血成分-关键靶点-作用通路-关键疾病”网络。建立阿霉素心脏损伤大鼠模型。测心电图以及大鼠左心功能;检测血清ALT、AST、LDH、CK-MB含量;检测心肌组织PI3K/AKT信号通路及凋亡相关蛋白表达情况;观察心肌超微结构。结果筛选八味沉香散入血靶点1897个、阿霉素心脏损伤靶点1598个,得到八味沉香散与阿霉素心脏损伤交集靶点198个。筛选AKT1、STAT3、EGFR、SRC、BCL2、TNF、MAPK1、MAPK3、ESR1、CASP3等为关键靶点。通过GO与KEGG分析进一步发现,PI3K/AKT可能为八味沉香散改善阿霉素心脏损伤的重要信号通路。检测结果显示,八味沉香散可改善阿霉素心脏损伤大鼠左心功能,降低血清ALT、AST、LDH、CK-MB含量;上调大鼠心肌组织PI3K、AKT、BCL2蛋白,下调BAX、CASP3蛋白;改善心肌超微结构。结论八味沉香散可有效改善阿霉素心脏损伤大鼠的心脏功能,其可能作用机制为,调节PI3K/AKT信号通路,抑制细胞凋亡。

温度敏感阿霉素脂质体的温度控释特性和稳定性

目的 探讨以 L -α-二软脂酰磷脂酰胆碱 (DPPC)和盐酸阿霉素 (ADM)为原料制备的温度敏感阿霉素脂质体(Ts- L ADM)的温度控释特性和稳定性 .方法 采用改良逆相蒸发法 ,以 DPPC和 ADM为原料制备 Ts- L ADM,动力学光散射法测定其粒径 ,以荧光分光光度法检测样本中阿霉素含量 ,计算包裹率 .纯化后的 Ts- L ADM在不同温度下水浴后经葡聚糖凝胶分离并回收脂质体部分 ,以酸性乙醇法测定阿霉素的释放量 ,计算释放率 .结果 Ts- L ADM粒径分布范围为 0 .1～ 0 .4 3μm,平均粒径 0 .2 8μm;平均包裹率为37.3% ;在不同温度下测定的药物释放率分别为 :4 0℃以下小于 2 0 % ,在 DPPC的相变温度附近突然升高 ,4 1℃和 4 2℃分别为 81.4 %和 81.6 % ,4 4℃时降为 77.2 % .4 2℃下延长加热时间药物释放率无明显增加 (P>0 .0 5 ) .未经纯化的脂质体于常温下避光贮存 5 wk,测定其药物包裹率及渗漏率无明显改变 (P>0 .0 5 ) .

阿霉素脂质体的制备及其活性的初步研究

用超声波脂质体制备法建立一种阿霉素脂质体的制备方法,并观察其体外对人肝癌细胞系n9101及人低分化胃癌MGC803细胞系的杀伤效力.对阿霉素脂质体溶液进行扫描,寻求最佳波长.用sephadexG50柱分离单纯阿霉素和阿霉素脂质体.苔盼蓝拒染法测定杀伤力.阿霉素脂质体在480nm处有最大吸收峰,测定阿霉素脂质体的包封率为99.39%.对n9101和MGC803两种细胞系的杀伤作用与单纯阿霉素相近,作用更持久.此法制备的脂质体包封率高,重现性好,简便易行,所制得的阿霉素脂质体具有高度的杀伤活性.

pH梯度法制备阿霉素脂质体

采用ｐＨ梯度法制备了阿霉素脂质体．用ＳｅｐｈａｄｅｘＧ－２５微型柱分离－紫外分光光度法测定阿霉素脂质体包封率．结果表明，当药物／磷脂重量比为０．０２～０．０５时，包封率均大于９０％；体外泄漏研究显示，２５℃时，２ｈ内泄漏百分率约为２．７％，保证了临床应用．

阿霉素长循环热敏脂质体的研制及其靶向治疗肿瘤作用的研究

目的:研制阿霉素脂质体(AL)、阿霉素长循环脂质体(ALCL)和阿霉素长循环热敏脂质体(ALTSL)。研究不同类型脂质体对H22荷瘤小鼠肿瘤的抑制作用。方法:建立荷瘤小鼠模型,观察各实验组的抑瘤效果,计算抑瘤率和生命延长率;HPLC法研究静脉给药后各实验组阿霉素的药代动力学规律及组织学分布特征;制作病理切片,观察各实验组肿瘤和心脏等组织的病理变化。结果:ALCL和ALTSL对H22荷瘤小鼠肿瘤有显著的抑制作用,抑瘤率分别为57.8%和67.0%(P<0.01);尾静脉注射给药24h后,ALCL和ALTSL组荷瘤小鼠肿瘤组织和血液中的阿霉素含量明显上升,而在心、肺中的含量显著降低;ALTSL使肿瘤细胞大量坏死,而对心肌细胞无明显损伤。结论:ALCL和ALTSL均能提高化疗药阿霉素的抗肿瘤效果,降低阿霉素的心肺毒性,延长荷瘤小鼠的存活时间。