Formulation and characterization of 5-Fluorouracil enteric coated nanoparticles for sustained and localized release in treating colorectal cancer

5-Fluorouracil is used in the treatment of colorectal cancer along with oxaliplatin as first line treatment, but it is having lack of site specificity and poor therapeutic effect. Also toxic effects to healthy cells and unavailability of major proportion of drug at the colon region remain as limitations. Toxic effects prevention and drug localization at colon area was achieved by preparing enteric-coated chitosan polymeric nanoparticles as it can be delivered directly to large bowel. Enteric coating helps in preventing the drug degradation at gastric pH. So the main objective was to prepare chitosan polymeric nanoparticles by solvent evaporation emulsification method by using different ratios of polymer (1:1, 1:2, 1:3, 1:4). Optimized polymer ratio was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), entrapment efficiency and particle size and further subjected to enteric coating. In vitro drug release studies were done using dialysis bag technique using simulated fluids at various pH (1.2, 4.5, 7.5, 7.0) to mimic the GIT tract. 5-FU nanoparticles with drug: polymer ratio of 1:2 and 1:3 has shown better particle size (149 ± 1.28 nm and 138 ± 1.01 nm respectively), entrapment efficiency (48.12 ± 0.08% and 69.18 ± 1.89 respectively). 5-FU E1 has shown better drug release after 4 h and has shown 82% drug release till 24 h in a sustained manner comparable to the non-enteric coated tablets, which released more than 50% of the drug before entering the colon region. So we can conclude that nanoparticles prepared by this method using the same polymer with the optimized ratio can represent as potential drug delivery approach for effective delivery of the active pharmaceutical ingredient to the colorectal tumors.     

Nano-liposomal zein hydrolysate for improved apoptotic activity and therapeutic index in lung cancer treatment

Lung cancer is one of the most common cancers in the world with a high mortality rate. Zein is a protein compound whose protein isolate is not useful and whose protein hydrolysis produces biological activity. By encapsulating this bioactive compound inside the nanoparticles (NPs), it causes itself to reach the tumor site and destroy it rapidly. In this study, the effects of zein hydrolysate (ZH) and nano-liposomal ZH (N-ZH) were investigated on the human A549 cell line. Western blotting and cell cycle analyses showed that ZH and N-ZH caused cytotoxicity. They induced apoptosis via cell cycle arrest at the G0 phase, as well as significant increases in pro-apoptotic genes, such as Bax, caspase-3, -8, -9, and p53, accompanied with significant decreases in the anti-apoptotic marker Bcl-2. Based on the results, the cytotoxic and anticancer effects of N-ZH were higher than those of free ZH. In conclusion, liposomes improved the performance of ZH and dramatically reduced the IC₅₀ value of ZH. These findings provided the experimental evidence that N-ZH with favorable anticancer activity can be used as a therapeutic agent and strategy for lung cancer treatment in future clinical trials.     

西妥昔单抗联合化疗治疗转移性结直肠癌的观察

目的 观察西妥昔单抗联合化疗方案治疗转移性结直肠癌的近期疗效及不良反应.方法 11例经病理组织学确诊的转移性结直肠癌患者,给予西妥昔单抗联合FOLFOX方案治疗,西妥昔单抗首次给予负荷剂量400 mg/m2,每周给予维持剂量为250 mg/m2.结果 全组11例患者中,完全缓解1例,部分缓解5例,稳定2例,进展3例,有效率54.5％ (6/11),疾病控制率为72.7％ (8/11),中位肿瘤进展时间为8.4个月.主要不良反应为痤疮样皮疹(9例)和腹泻(6例).5例合并肝转移患者中经治疗后1例转化为可切除病灶.患者耐受良好,无治疗相关死亡.结论 西妥昔单抗联合FOLFOX方案治疗转移性结直肠癌疗效较好,不良反应多可耐受.     

三药联合方案治疗晚期结直肠癌的效果

目的：比较5‐氟尿嘧啶／亚叶酸联合伊立替康和奥沙利铂（FOLFIRINOX方案）和卡培他滨联合伊立替康和奥沙利铂（CAPIRINOX方案）在晚期结直肠癌的治疗效果。方法64例晚期结直肠癌患者随机均分为FOLFIRINOX方案治疗组（A组）和CAPIRINOX方案治疗组（B组）。治疗6周后,评估两组临床疗效和不良反应。结果 A组总有效率、中位无进展生存期和中位总生存期与B组比较无统计学差异（60.0％ vs ．61.3％、9.1个月 vs ．10.0个月和22.7个月 vs ．23.1个月）（ P＞0．05）。两组主要不良反应包括中性粒细胞下降、恶心、呕吐、脱发和周围神经毒性。结论FOLFIRINOX和CAPIRINOX方案均是治疗晚期结直肠癌的有效方案。     

Antitumor activity of electrospun polylactide nanofibers loaded with 5-fluorouracil and oxaliplatin against colorectal cancer

The purpose of this study was to evaluate both in vitro and in vivo anticancer activities against colorectal cancer (CRC) of electrospun polylactide (PLA) nanofibers loaded with 5-fluorouracil (5-Flu) and oxaliplatin. For in vitro evaluation, human CRC HCT8 cells were directly exposed to the drug-loaded fiber mats, followed with MTT and flow cytometry (FCM) assay. For in vivo evaluation, the drug-loaded fiber mats were locally implanted into mouse colorectal CT26 tumor-bearing mice, followed with histological analysis and detection of survival rate. The results showed that the drug-loaded fiber mats was similar to that of the combination of free 5-Flu and oxaliplatin in vitro cytotoxicity but was much superior to intravenous injection of free drug in vivo anticancer activities, presenting with suppressed tumor growth rate and prolonged survival time of mice. In conclusion, anticancer activities of 5-Flu and oxaliplatin against CRC can be significantly improved by using PLA electrospun nanofibers as local drug delivery system.     

MC5免疫组织化学在大肠癌中的定位诊断研究

目的 研究免疫组织化学法检测MC5在大肠癌定位诊断中的意义.方法 选取2014年1月至2015年2月在我校附属医院病理科存档的确诊为大肠癌的蜡块标本102例及内镜中心活检病理为正常粘膜的40例,通过免疫组化法检测102例大肠癌和40例正常人群粘膜的MC5表达水平,研究其在大肠癌早期定位诊断中的价值.结果 40例正常人群的粘膜MC5表达均为阴性,102例大肠癌患者的MC5阳性表达率为89.21％(91/102),且定位于胞浆和胞膜,在癌旁正常组织中MC5阳性表达率为37.25％(38/102),两者相较差异有统计学意义(P＜0.05).在35例高分化癌中,表达结果为-的7例,+的20例,++的4例,+++的4例;在28例中分化癌中,表达结果为-的4例,+的4例,++的17例,+++的3例;在39例低分化癌中,表达结果为-的0例,+的6例,++的2例,+++的31例;MC5表达水平与大肠癌的分化程度呈负相关,MC5表达水平随着分化程度的上升而下降.结论 MC5在大肠癌中呈阳性表达,具有一定的特异性,且分化程度越低表达水平越高,可作为大肠癌早期定位诊断的指标之一.     

Recent achievements in colorectal cancer diagnostic and therapy by the use of nanoparticles

Colorectal cancer is a major public health issue, being the third most common cancer in men and the second in women. It is one of the leading causes of cancer deaths. Nanomedicine is an emerging field of interest, many of its aspects being linked to cancer research. Chemotherapy has a well-established role in colorectal cancer management, unfortunately being limited by inability to have a selective distribution, by multidrug resistance and adverse effects. Researches carried out in recent years about nanotechnologies aimed, among others, to resolve the issues mentioned above. Targeted and localized delivery of the chemotherapeutic drugs, using nanoparticles, with selective destruction of cancerous cells would minimize the toxicity on healthy tissues. Also, the use of nanomaterials as contrast agent could improve sensitivity and specificity of diagnosis. The purpose of this review is to highlight the recent achievements of cancer research by use of nanomaterials, in the idea of finding the ideal composite, capable to simultaneous diagnostic and treat cancer.     

Pharmacokinetics and gamma scintigraphy evaluation of two enteric coated formulations of didanosine in healthy volunteers

AIMS: The aims of the study were to evaluate the bioavailability of didanosine from the encapsulated enteric coated beads (1 x 200 mg; enteric beads) and enteric coated mini-tablets (4 x 50 mg; enteric tablet) formulations relative to the chewable/dispersible buffered tablets (2 x 100 mg; buffered tablet), and to study their rate of gastrointestinal transit. METHODS: This was a single-dose, randomized, three-way crossover study in 18 healthy male volunteers. A 200 mg dose of didanosine was given in each period and each formulation contained a gamma radiation-emitting isotope. Pharmacokinetic parameters determined were Cmax, tmax, AUC(0, infinity ) and t1/2. Bioequivalence was assessed using the confidence interval (CI) of 0.80, 1.25 for Cmax and AUC(0, infinity ). Scintigraphic images were recorded and gastrointestinal transit profiles were generated. RESULTS: The point estimate and 90% CI of the ratio of Cmax for the enteric beads and enteric tablet relative to the buffered tablet was 0.71 (0.59, 0.85) and 0.55 (0.46, 0.66), respectively. The tmax was significantly different for the enteric beads (median, 1.33 h) and the enteric tablet (median, 2.83 h) than for the buffered tablet (median, 0.67 h). The AUC(0, infinity ) satisfied the bioequivalence criteria, and the point estimate and 90% CI of the ratio were 1.02 (0.91, 1.15) and 0.92 (0.82, 1.04) for the enteric beads and enteric tablet, respectively. The AUC(0, infinity ) values appeared to be less variable with the enteric beads (% CV = 19%) than with the enteric tablet (% CV = 33%). The t1/2 values were not significantly different between formulations, and the mean values ranged from 1.82 to 1.92 h. Inspection of the individual scintigraphy profiles and concentration-time curves suggested that didanosine was absorbed throughout the small intestine. Gastrointestinal transit parameters were higher for both enteric formulations than for the buffered tablet, indicating slower transit of the enteric formulations. Between the enteric formulations, gastric emptying was slower for the enteric beads than for the enteric tablet; however, plasma didanosine concentrations were observed sooner for the enteric beads, suggesting that the enteric coat for the beads dissolved more rapidly. CONCLUSIONS: The enteric beads and enteric tablet formulations of didanosine were equivalent to the buffered tablet in their extent of absorption. Although the gastric emptying of the enteric tablet was faster, based on the rapid uncoating and the lower variability in AUC, the enteric beads were chosen for further clinical development.     

miR-222在结直肠癌组织中的表达及意义

目的探讨miRNA-222(miR-222)在结直肠癌组织中的表达及意义。方法采用实时定量PCR检测44例结直肠癌组织及癌旁正常组织中miR-222的表达水平,分析其与临床病理指标之间关系。结果 miR-222在44例癌组织标本中的表达量为0.0085(0.0041,0.0428),低于癌旁正常组织中的0.0188(0.0120,0.0326)(P<0.01)。miR-222在黏液性腺癌中的表达量为0.1461(0.0478,0.4251),低于非黏液性腺癌的0.4373(0.2012,1.1882)(P<0.05)。miR-222表达与患者的性别、年龄和结直肠癌的分化程度、临床分期、浸润深度、淋巴结和远处转移均无明显相关性(P>0.05)。结论 miR-222参与结直肠癌发生和发展的调控。     

Recent and ongoing clinical trials for treating colorectal cancer

Colorectal cancer is one of the most common cancers worldwide. Through well-designed clinical trials, advances have been made in the treatment of localised and advanced colorectal cancer. It has been established that 6 months of 5-fluorouracil-based chemotherapy will improve overall survival in patients with stage III colon cancer. The role of adjuvant chemotherapy in stage II colon cancer remains an unresolved issue. Recent studies have demonstrated an improved survival with the addition of irinotecan to 5-fluorouracil and leucovorin for the treatment of advanced colorectal cancer. Immunotherapy, molecular targeted therapy and liver-directed therapy, in addition to new chemotherapy combinations, are all being evaluated for the treatment of localised and advanced colorectal cancer. Ongoing and proposed studies are incorporating the identification of genetic and molecular abnormalities, which may provide prognostic information as well as direct treatment decisions.     

癌性结肠梗阻术式选择的临床研究

目的 探讨结直肠癌引起肠梗阻的手术治疗方法.方法 回顾性分手术治疗癌性肠梗阻50例患者资料,并对围手术期的治疗和手术后疗效进行评估.结果 一期切除吻合21例,Hartmann术11例,全结肠、膀胱部分切除回肠造口术1例,捷径术和单纯造口术17例,术后切口感染3例,无吻合口瘘及死亡患者.结论 结直肠癌引起的肠梗阻在谨慎选择手术方式的基础上可考虑一期切除吻合.     

Panitumumab safety for treating colorectal cancer

Introduction: Panitumumab is a human IgG2 mAb against the EGFR, inhibiting tumor cell proliferation, survival and angiogenesis. It has demonstrated clinical efficacy in metastatic colorectal cancer (CRC) in combination with chemotherapy in first- and second-line settings and as monotherapy in third-line setting. Recently, mutations in the RAS genes have been shown to be predictive of lack of efficacy, panitumumab should be restricted to patients with RAS wild-type (wt) tumors.

Areas covered: This review focuses on main efficacy results of panitumumab in metastatic CRC in first-, second- and third-line settings in combination with chemotherapy or as monotherapy. Additionally, we have covered safety aspects of this agent in these indications, especially in K-RAS and all RAS wt patients. These safety aspects refer to the most common toxicities (i.e., acne-like skin rash, diarrhea and hypomagnesaemia).

Expert opinion: Panitumumab adds to the armamentarium of effective agents in the treatment of metastatic CRC. Due to its human origin, panitumumab is a well-tolerated agent with low rates of infusional reactions. Skin toxicity is frequent and should be pre-emptively treated. Other common toxicities related to panitumumab treatment, such as diarrhea and hypomagnesaemia, should be closely monitored to ensure early treatment or substitution.     

青年结直肠癌分析

目的：探讨青年结直肠癌的临床特征。方法：收集48例35岁以下的结直肠癌病例临床资料并进行系统性分析。结果：青年人结直肠癌主要临床表现为粘液血便或便血、腹痛、大便习惯改变,肿瘤主要在直肠及乙状结肠,组织学类型以分化不良为主,Duke＇s分期以C、D期为主,根治率43.75%,5年生存率为28.21%。结论：青年结直肠癌临床症状不典型,恶性程度高,手术根治率低,预后差。早期诊断,早期治疗是提高生存率的关键。     

Abelson相关基因在大肠癌中的表达及其临床意义

目的探讨Abelson相关基因(Arg)在人大肠癌组织中的表达及其意义。方法免疫组织化学染色法检测80例大肠癌组织、30例癌旁大肠组织和30例大肠腺瘤中Arg的表达,并分析Arg表达水平与临床病理特征的相关性。结果 Arg在大肠癌组织中阳性表达率为70%,癌旁结肠组织和大肠腺瘤组织均无Arg表达。Arg表达与大肠癌的分化程度、浸润深度、淋巴结转移、TNM分期及癌胚抗原(CEA)水平有关(P<0.05),Arg高表达者生存期低(P<0.05)。结论 Arg可能在大肠癌发病过程中起重要作用,可作为大肠癌预后判断的有价值指标之一。     

Epigenetics and chemoresistance in colorectal cancer: An opportunity for treatment tailoring and novel therapeutic strategies

Colorectal cancer is the second leading cause of cancer-related deaths in the world. Despite many therapeutic opportunities, prognosis remains dismal for patients with metastatic disease, and a significant portion of early-stage patients develop recurrence after chemotherapy. Epigenetic gene regulation is a major mechanism of cancer initiation and progression, through the inactivation of several tumor suppressor genes. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance. In the present review, we summarize epigenetic mechanisms triggering resistance to three commonly used agents in colorectal cancer: 5-fluorouracil, irinotecan and oxaliplatin. Those epigenetic biomarkers may help stratify colorectal cancer patients and develop a tailored therapeutic approach. In addition, epigenetic modifications are reversible through specific drugs: histone-deacetylase and DNA-methyl-transferase inhibitors. Preclinical studies suggest that these drugs may reverse chemoresistance in colorectal tumors. In conclusion, an epigenetic approach to colorectal cancer chemoresistance may pave the way to personalized treatment and to innovative therapeutic strategies.     

Anti-cancer effects of fenbendazole on 5-fluorouracil-resistant colorectal cancer cells

Benzimidazole anthelmintic agents have been recently repurposed to overcome cancers resistant to conventional therapies. To evaluate the anti-cancer effects of benzimidazole on resistant cells, various cell death pathways were investigated in 5-fluorouracil-resistant colorectal cancer cells. The viability of wild-type and 5-fluorouracil-resistant SNU-C5 colorectal cancer cells was assayed, followed by Western blotting. Flow cytometry assays for cell death and cell cycle was also performed to analyze the anti-cancer effects of benzimidazole. When compared with albendazole, fenbendazole showed higher susceptibility to 5-fluorouracil-resistant SNU-C5 cells and was used in subsequent experiments. Flow cytometry revealed that fenbendazole significantly induces apoptosis as well as cell cycle arrest at G2/M phase on both cells. When compared with wild-type SNU-C5 cells, 5-fluorouracil-resistant SNU-C5 cells showed reduced autophagy, increased ferroptosis and ferroptosis-augmented apoptosis, and less activation of caspase-8 and p53. These results suggest that fenbendazole may be a potential alternative treatment in 5-fluorouracil-resistant cancer cells, and the anticancer activity of fenbendazole does not require p53 in 5-fluorouracil-resistant SNU-C5 cells.     

Improved anti-tumor activity of oxaliplatin by encapsulating in anti-DR5 targeted gold nanoparticles

Oxaliplatin is one of the chemotherapeutic agents in the first line therapy for treatment of colorectal cancer. But, limitations of chemotherapy affects the clinical applicability of oxaliplatin depriving its activity at targeted site attributed to the lack of site specificity. This limitation paves the way for undesirable toxic effects to healthy cells resulting in sub-standard drug amount at the tumors obliging for increased dose. The present study emphasizes on formulating gold nanoparticles encapsulating oxaliplatin and later conjugating with anti-DR5 antibody for improved anti-cancer activity in a synergistic and site-specific manner. Oxaliplatin immuno-nanoparticles (Co-Ox-AuNPs) had shown sustained release and confirmed by fluorescence and flow cytometry studies. MTT assay exhibited 3-fold decrease in cell viability of nanoparticles comparable to oxaliplatin. Triple fluorescence method employed in HCT 116 and MCF-7 cells justified its site specificity. Annexin-propidium iodide (PI) and Acridine orange-ethidium bromide assays further supported the apoptotic activity. Moreover, caspase-dependent molecular mechanism behind oxaliplatin induced anti-cancer activity was explored by western blot analysis. Reduction in tumor size and volume in xenograft tumor models justified its in vitro activity. Oxaliplatin side effects were analyzed in mice and were confirmed for their clinical efficacy highlighting our formulation as an alternative to chemotherapy.     

预防术后大肠吻合口瘘的大肠腔内引流临床观察

目的探讨大肠腔内引流对大肠癌术后吻合口瘘的预防效果。方法回顾分析2000年1月至2010年12月间的大肠癌根治性切除腹腔内肠吻合159例(其中机械吻合76例)的资料。159例病例随机分成两组。甲组(治疗组)行大肠腔内引流96例,乙组(对照组)。未行大肠腔内引流63例。结果 159例吻合口瘘共发生8例(5.03%),其中甲组2例(2.08%),乙组6例(9.52%),经统计学处理有显著差异(P<0.05)。结论 159例病例随机分成两组。甲组(治疗组)行大肠腔内引流96例,乙组(对照组)大肠癌术中放置大肠腔内引流管能降低吻合口瘘的发生率。     

Cyclodextrin based nanoparticles for smart drug delivery in colorectal cancer

The advancement of colorectal cancer (CRC) prevention, detection, and treatment is essential to ensure that survivors live longer and higher-quality lives. The field of cancer detection and therapy has undergone a revolution with the development of nanotechnology for targeted drug delivery. The significant problems with the delivery of cancer drugs are their solubility, stability, and nonspecific distribution. There is a challenge that the acidic and enzymatic environment in the digestive tract will modify or destroy the medication or the active pharmaceutical ingredient. To overcome the problems, nanoparticles have been widely employed during the past several years to increase the specificity, selectivity, and controlled release of drug delivery systems. The site-specific and targeted delivery leads to reduce toxicity and side effects. With respect to the capability and utilization of cyclodextrin-based nanoparticles in different aspects of the tumour microenvironment and gut microbiota, a survey of current research papers was conducted via looking through databases including GoogleScholar, PubMed, Web of Science, and Scopus. This review aims to summarize cutting-edge nanoparticulate-based technologies and therapies for CRC.     

结直肠癌患者术前血小板计数水平与肿瘤临床病理分期的关系

目的 探讨结直肠癌患者术前血小板计数水平与肿瘤临床病理分期的关系。方法 回顾性分析2015年1月至2016年12月安徽省肿瘤医院胃肠外科经组织病理学确诊的420例结直肠癌患者的临床资料，统计不同临床分期结直肠癌患者血小板增多症的发生率。结果 结直肠癌血小板增多症发生率与肿瘤分化程度、淋巴转移、性别、年龄、肿瘤部位均无密切关系（P>0.05）。初诊时发现血小板增多症70例（16.67%），术后TNM I期70例，Ⅱ期99例，Ⅲ期217例，Ⅳ期34例，血小板增多症发生率依次为7.14%、14.14%、18.89%和29.41%，差异有统计学意义（P<0.05）。结论 结直肠癌患者临床病理分期与血小板增多有密切关系。