In Situ Encapsulation of Nile Red or Doxorubicin during RAFT‐Mediated Emulsion Polymerization via Polymerization‐Induced Self‐Assembly for Biomedical Applications

Hydrophobic agents, a fluorescent dye (Nile red, NR) or an anticancer drug (doxorubicin, DOX), are encapsulated into poly((N‐[3‐(dimethylamino) propyl] methacrylamide)‐b‐poly (methyl methacrylate) (PDMAPMA‐b‐PMMA) nanoparticles (NPs) via one‐pot reversible addition‐fragmentation chain‐transfer (RAFT)‐mediated emulsion polymerization in water. The macroRAFT, PDMAPMA, is chain‐extended with the methyl methacrylate (MMA), with the hydrophobic agents soluble in MMA, resulting in loaded NPs, with either NR or DOX via polymerization‐induced self‐assembly (PISA). The NR‐loaded NPs are visualized by structured illumination microscopy (SIM), thus indicating the successful loading of the fluorescent dye into the PMMA core. The DOX‐loaded NPs exhibit a sustained release profile over 5 d, showing a small burst effect during the first 2 h, as compared with the free DOX. The DOX‐loaded NPs show higher cell toxicity than the free DOX in RAW 264.7 cell line. The results demonstrate the potential of using emulsion polymerization for synthesis of tailored and reproducible NPs encapsulating hydrophobic agents.     

骨肉瘤细胞脱逸化疗诱导的细胞衰老可重新增殖成瘤细胞

目的探讨骨肉瘤细胞(OS)能否脱逸化疗至细胞衰老和再增殖;评价逃逸衰老的细胞成瘤能力,从新的角度解释骨肉瘤复发的机制。方法多柔比星(DOX)诱导骨肉瘤细胞U2OS和MG63制备衰老的细胞模型,SA-Gal染色法检测细胞衰老;Western blot检测衰老相关分子。更换成不含DOX的培养基培养75 d,细胞计数检测细胞增殖和计算脱逸率。而后分为3组:对照组、衰老细胞组和脱逸衰老细胞组,琼脂糖克隆实验检测集落形成和裸鼠成瘤实验检测成瘤能力。结果超过90%的U2OS和MG63呈SA-Gal染色阳性;衰老相关的细胞分子p-p53、p-Rb和p-γH2AX明显升高(P<0.05)。75 d后,观察到有细胞重新增殖(脱逸率百万分之一),具有集落形成和裸鼠成瘤能力。结论衰老的骨肉瘤细胞能够脱逸细胞衰老状态重新增殖并具有成瘤能力。     

免疫磁性海藻酸钠载药纳米微球的制备与评价

靶向治疗系统是目前研究的热点,用微乳化-离子交联方法制备包覆阿霉素的碳包铁/海藻酸钠复合纳米微球,以水溶性碳二亚胺为交联剂,将载药微球与单抗Hab18连接,制备出了免疫磁性药物纳米微球.对该免疫磁性微球的理化性能进行了表征,同时检测了免疫磁性微球中抗体的活性和免疫磁性微球与靶细胞的体外结合情况,结果表明,免疫磁性药物纳米微球平均粒径约为171.2nm,外观为球型,铁含量为14.6%,载药量为10.8%,且具有强磁响应性和长时间药物缓释效果.同时在体外该微球能够与靶细胞特异性结合.这种免疫磁性药物纳米微球有望成为一种优良的靶向肿瘤药物载体.     

Hemodynamic effects of chronic 4′ epi-adriamycin administration

Summary Adriamycin (ADM) is an effective antineoplastic drug. However, the amount of ADM that can be administered must be limited because of the risk of developing a severe dose-dependent cardiomyopathy. 4Epi-adriamycin (4 ADM) is a new anthracycline analog with similar antineoplastic properties as ADM, but with perhaps less cardiac toxicity. To determine myocardial performance after a chronic treatment with 4ADM, we studied 17 patients (mean age 36.6 years) suffering from lymphomas by means of 24-hour ambulatory ECG, x-ray, M-mode echocardiogram, and rest-exercise gated radionuclide ventriculography (RNV), performed prior to and 2 months after the end of the treatment. Pretreatment and post-treatment shortening fractions, basal pretreatment and post-treatment ejection fractions, and postexercise pretreatment and post-treatment ejection fractions, were tested for correlation with individual 4ADM doses and pretreatment with ADM. No association was noted among them, showing the lack of correlation between doses and impairment of ventricular performance. 4ADM doses ranged from 400 to 1100, 748±174 mg/m²; allnoninvasive studies including RNV doses and RNV (Pearson's correlation coefficient, p=ns). No deterioration of ventricular performance could be demonstrated. Conversely, the basal pretreatment ejection fraction changed from 56.17±7.6% to 61.52±8.3% in posttreatment (p<0.0001). Surprisingly, the postexercise pretreatment ejection fraction also increased from 55.47±7.7% to 63.35±10% in post-treatment (p<0.03). The shortening fraction changed from 35.47±4.8% to 36.47±4.2% after 4ADM treatment (ns). No impairment of cardiac function could be shown in patients previously treated with ADM or radiotherapy. On the basis of these data, treatment with 4ADM did not impair but improved cardiac function     

Protecting spermatogonia from apoptosis induced by doxorubicin using the luteinizing hormone-releasing hormone analog leuprorelin

PURPOSE: The present study was performed to investigate the protective effect of leuprorelin (LH-RH analog), on spermatogonia apoptosis induced by doxorubicin (DXR) in the Sprague-Dawley rat model. METHODS: Twenty-four adult male rats were divided into the following four groups: (i) control group; (ii) group given doxorubicin (intravenous injection, 8 mg/kg); (iii) group given leuprorelin (subcutaneous injection, 3 mg/kg); and (iv) group given both doxorubicin (intravenous injection, 8 mg/kg) and leuprorelin (subcutaneous injection, 3 mg/kg). Evaluation for quantification of apoptotic spermatogonia was made by the ratio of TUNEL-labeled spermatogonia versus 100 Sertoli cells in each seminiferous tubule. Two hundred seminiferous tubules of each rat were assessed. RESULTS: The ratio of apoptotic spermatogonia versus 100 Sertoli cells at stages II-IV of the groups given DXR (groups 2 and 4) were significantly higher than those of the other groups. However, the value at stages II-IV of the group given both DXR and leuprorelin (group 4) was significantly lower than that of the group given DXR (group 2). CONCLUSION: The significant prophylactic effect (P < 0.05) of LH-RH analog against doxorubicin-induced spermatogonial apoptosis was observed in a stage specific manner by microscopic evaluation with TUNEL.     

Acute effects of doxorubicin (adriamycin) on left ventricular function in dogs

Although chronic doxorubicin (adriamycin) cardiotoxicity often is attributed to repeated episodes of acute myocardial injury, the acute effects of doxorubicin on in vivo left ventricular performance have not been studied in a carefully controlled setting. Accordingly, we recorded high-fidelity left ventricular pressures and segmental dimensions before and after either intravenous or intracoronary doxorubicin in twelve open-chest dogs. Propranolol was administered to prevent reflex sympathetic stimulation, and heart rate was held constant by atrial pacing. Intravenous doxorubicin (1.5 mg/kg) (n = 6) caused significant decreases in all measured indices of myocardial contractility, in association with a large decrease in left ventricular systolic pressure (125 ± 28 and 81 ± 23 mm Hg before and 5 min after doxorubicin, respectively, P < 0.01). Intracoronary doxorubicin (0.075 to 0.3 mg/kg) (n = 6) caused similar decreases in percent segment shortening (from 19 ± 7 to 16 ± 8, P < 0.05), mean normalized shortening rate (from 0.87 ± 0.34 to 0.71 ± 0.37 segment lengths/sec, P < 0.05), and peak positive left ventricular $\text{dP}\text{dt}$ (by 10 ± 11%, P < 0.07), although left ventricular systolic pressure was only modestly decreased (126 ± 20 and 113 ± 17 mm Hg before and after doxorubicin, respectively, P < 0.01). Intracoronary doxorubicin also slowed the rate of left ventricular relaxation, as evidenced by an increase in the time constant for isovolumic pressure fall from 32.0 ± 9.0 to 36.9 ± 7.5 msec, and significantly altered the relationship between left ventricular pressure and dimension at end-diastole.We conclude that a single dose of doxorubicin can acutely alter both systolic and diastolic left ventricular function in dogs. These effects are nearly immediate in onset, and are independent of potential functional alterations due to drug-induced systemic hypotension.     

Comparison of the protective effects of curcumin and caffeic acid phenethyl ester against doxorubicin-induced testicular toxicity

Whether testicular toxicity is mediated by matrix metalloproteinases (MMPs) is an important question that has not been examined. This study investigated the suppressive effect of curcumin and caffeic acid phenethyl ester (CAPE) on oxidative stress, apoptosis, and whether MMPs mediate doxorubicin (DOX)-induced testicular injury. Male rats were randomly divided into eight groups (n = 8 per group). The groups were as follows: sham, dimethyl sulphoxide (100 µL), DOX (3 mg/kg), CAPE (2.68 mg/kg), curcumin (30 mg/kg), DOX+CAPE (3 mg/kg DOX and 2.68 mg/kg CAPE), DOX+curcumin (3 mg/kg DOX and 30 mg/kg curcumin) and DOX+CAPE+curcumin (3 mg/kg DOX, 2.68 mg/kg CAPE and 30 mg/kg curcumin). Injections were administered daily for 21 days. The oxidative stress, MMPs, proinflammatory cytokines and apoptotic markers in the DOX group were higher than the sham group (p < .05); these measures were lower in the groups treated with CAPE and curcumin together with DOX compared with the DOX group (p < .05). The results showed that MMPs mediated DOX-induced testicular injury, but CAPE and especially curcumin suppressed testis injury and cell apoptosis by suppressing DOX-induced increases in MMPs, oxidative stress and proinflammatory cytokines. However, curcumin exhibited more pronounced effects than CAPE in terms of all studied parameters.     

Clinical outcome of adjuvant radiotherapy for squamous cell carcinoma of the breast; a multicenter retrospective cohort study

BackgroundBecause primary squamous cell carcinoma (SCC) of the breast is a rare disease, the standard therapy has not been established. We examined the clinical outcomes of postoperative adjuvant radiotherapy for breast SCC.Material and methodsWe conducted a multicenter retrospective cohort study. Patients diagnosed with primary breast SCC who received adjuvant radiotherapy as part of their primary definitive treatment were included. Overall survival (OS), breast cancer-specific survival (BCSS), and recurrence-free interval (RFi) were evaluated.ResultsBetween January 2002 and December 2017, 25 breast SCC patients received adjuvant radiotherapy as a primary treatment were included. Median follow-up time was 43.5 months. Three (12%), fifteen (60%) and seven (28%) patients had clinical stage I, II and III disease, respectively. Fourteen patients underwent breast-conserving surgery and subsequent adjuvant radiotherapy. Eleven patients underwent mastectomy and post-mastectomy radiotherapy. Ten patients received regional lymph node irradiation. Nine (36%) patients had disease recurrence. The first site of recurrence was locoregional in five, but distant metastasis arose in one. Concurrent local and distant metastasis were seen in two. Six cases of local recurrence occurred within the irradiated site. Seven patients died, and six of the deaths were due to breast cancer. Five-year OS, BCSS, and Rfi were 69%, 70%, and 63%, respectively. In multivariate analysis, age and lymphatic invasion were associated with increased risk of recurrence.ConclusionBreast SCC has a high incidence of locoregional recurrence and poor prognosis. Age and lymphatic invasion are significant risk factors for recurrence.