纳米粒子为基础的选择性靶向肝癌

StephenW

A Nanoparticle-based Approach to Selectively Target Hepatocellular Carcinomas                                                                                    405                                                                                                                                                                                Cancer                                                                                ,                                                                                                                                                          Liver/Biliary                                                                                                                                                                                                                         2 days ago                                Kristine Novak                                                                                                                                                              0                                                                                                                                  
                        
                                    Researchers have created nanoparticles that selectively kill hepatoma cells and reduce growth of liver tumors in rats, they report in the February issue of Gastroenterology. They show that the particles induce tumor-specific necrosis by selectively disrupting redox balance within cancer cells.
Dietary intake of the natural omega-3 fatty acid docosahexaenoic acid (DHA) has been reported to protect patients with viral hepatitis from developing hepatocellular carcinoma (HCC).
However, little is known about the effects of DHA on established solid tumors. Xiaodong Wen et al describe a low-density lipoprotein-based nanoparticle that transports unesterified DHA (LDL−DHA) and has selective cytotoxicity toward HCC cells.
They investigated the ability of LDL−DHA to reduce growth of hepatomas grown from intrahepatic injections of rat hepatoma cells. Rats with a mean tumor diameter of approximately 1 cm were given a single hepatic artery injection of LDL nanoparticles loaded with DHA (LDL−DHA) or triolein, or underwent a sham surgery (controls).
First, Wen et al showed that the LDL−DHA (60 μM) killed cultured malignant hepatoma cells but did not affect primary hepatocytes.
Rats given the single injection of LDL−DHA had smaller, pale tumors that were devoid of vascular supply and more than 80% of the tumor tissue was necrotic. Four to 6 days after injection of LDL−DHA, the tumors were 3-fold smaller than those of control rats. The liver tissue that surrounded the tumors showed no histologic or biochemical evidence of injury.
Wen et al also showed that the LDL−DHA deregulated redox reactions in tumor tissues by increasing levels of reactive oxygen species and lipid peroxidation, depleting and oxidizing glutathione and nicotinamide adenine dinucleotide phosphate (NADPH), and significantly down-regulating the antioxidant enzyme glutathione peroxidase-4.
The authors were surprised to find that the redox balance in the surrounding liver was not disrupted. Serum markers of hepatocellular injury, alanine aminotransferase, and aspartate aminotransferase were significantly lower in the rats given LDL−DHA than in controls.
This finding is important because most chemoembolic treatments delivered via the transarterial route to HCC also cause injury to the surrounding liver and in rare cases, lobar atrophy, or even fatal liver failure.
Wen et al conclude that reformulation of DHA into an LDL nanoparticle expands the utility of this omega-3 polyunsaturated fatty acid, enabling its use as an anticancer agent. Transarterial administration of LDL nanoparticles delivers DHA to tumors at sufficiently high concentrations to induce significant tumoricidal effects, with no evidence of injury or hepatoxicity in the surrounding liver.
The researchers are planning longer-term survival studies to evaluate effects of repeated LDL−DHA administration.
In an editorial that accompanies the article, Riccardo Lencioni and Filip Braet explain that it was important that the authors used a hepatic transarterial approach, which minimizes the drugs systemic exposure yet ensures adequate concentrations of LDL NPs in the tumors.

Lencioni and Braet say that more information is needed on the potentially synergistic effect of systemic, molecular targeted agents such as sorafenib and LDL–DHA nanoparticles. Building on the current transarterial administration route, alternative methods to deliver nanoparticles to the tumor should be considered, such as the tortuous arterial and venous hepatic microcirculation.
Lencioni and Braet propose covalently attaching a fluorescent tag to LDLs to assist surgeons in administering nanoparticles to tumors or resected areas, via intraoperative fluorescent navigation imaging technology (see figure).

StephenW

纳米粒子为基础的选择性靶向肝癌
肿瘤，肝/胆3天前克里斯汀·诺瓦克0

研究人员已经创造了纳米颗粒选择性地杀死肝癌细胞，降低大鼠肝肿瘤的生长，它们在胃肠病学二月号报告。它们表明，颗粒诱导肿瘤特异性坏死通过选择性破坏肿瘤细胞内的氧化还原平衡。

从食物中摄取的天然ω-3脂肪酸二十二碳六烯酸（DHA）已经被报道为保护病毒性肝炎患者来自发展中国家的肝细胞癌（HCC）。

然而，知之甚少DHA对建立实体瘤的影响。小东闻等人描述了一种低密度脂蛋白的基于纳米颗粒即输送的未酯化的DHA（LDL-DHA）和具有选择性杀伤朝向HCC细胞。

他们研究了LDL-的DHA，以减少从大鼠肝癌细胞的肝内注射生长肝细胞癌的生长的能力。大鼠大约为1厘米的平均肿瘤直径分别获得了单一的肝动脉注射低密度脂蛋白纳米颗粒的装载DHA（LDL-DHA）或三油酸甘油酯，或接受了假手术（对照组）。

首先，温家宝等人表明，LDL-DHA（60微米）杀死培养的恶性肝肿瘤细胞，但不影响原代肝细胞。

考虑到单次注射LDL-DHA对大鼠有小的，苍白的肿瘤是缺乏血管供应和超过80％的肿瘤组织坏死脱落。注射LDL-DHA后第4〜6天，肿瘤呈3倍比对照组大鼠的小。肝组织包围肿瘤均未见病理或伤害的生化证据。

闻等人还表明，LDL-DHA的失调的在肿瘤组织中的氧化还原反应，通过增加的活性氧和过氧化脂质的水平，消耗和氧化的谷胱甘肽和烟酰胺腺嘌呤二核苷酸磷酸（NADPH），和显著下调抗氧化酶谷胱甘肽过氧化物酶-4。

笔者惊讶地发现，在周围的肝脏氧化还原平衡不会中断。肝细胞损伤，谷丙转氨酶和谷草转氨酶的血清标志物在给定的LDL-DHA比对照组大鼠显著降低。

这一发现很重要，因为通过transarterial路线HCC提供最chemoembolic的治疗也造成伤害到周围的肝脏和在罕见的情况下，叶萎缩，甚至是致命的肝功能衰竭。

闻等人得出结论的DHA该改写成LDL纳米颗粒膨胀此ω-3多不饱和脂肪酸的用途，使得其作为抗癌剂使用。低密度脂蛋白纳米颗粒Transarterial管理提供了DHA对肿瘤在足够高的浓度，诱导显著肿瘤杀伤作用，没有证据受伤或肝毒性周围肝。

研究人员正计划长期生存的研究，以评估重复LDL-DHA管理的效果。

在随文章发表社论，里卡多伦乔尼和菲利普Braet解释说，这是重要的是，作者用肝transarterial办法，最大限度地减少了药物的全身暴露又保证低密度脂蛋白纳米粒子在肿瘤足够的浓度。

重绘模板

伦乔尼和Braet说需要更多的信息对全身，分子靶向剂如索拉非尼和LDL- DHA纳米颗粒的潜在协同作用。构建对当前transarterial给药途径，替代方法来提供纳米颗粒的肿瘤，应考虑，如曲折动脉和静脉肝脏微循环。

伦乔尼和Braet提出共价结合的荧光标记的LDL协助外科医生在管理纳米粒子肿瘤或切除区域，通过术中导航荧光成像技术（见图）。

MP4

DHA，海鱼

StephenW

Study: LDL, omega-3 nano-strategy eliminates liver cancer cells in rats

Wednesday, February 10, 2016 | By John Carroll


UT Southwestern's Ian Corbin

There's been a considerable amount of controversy over the past decade whether omega-3 fatty acids can actually promote better health and guard against cancer. But a researcher at UT Southwestern says he has developed a nanoparticle treatment out of LDL and omega-3 that was able to eliminate liver cancer cells in rats while leaving healthy cells unharmed.

Cancer, of course, has been cured in rodents time and again in studies that couldn't be successfully reproduced in humans. But Ian Corbin, an assistant professor in the Advanced Imaging Research Center (AIRC) and of Internal Medicine at UT Southwestern, says that injecting LDL-DHA nanoparticles into an artery that feeds the liver proved toxic for at least some of the cancerous liver cells in the rat model for the disease. And he adds that there's no certainty that the therapeutic strategy could eliminate all the cancer cells.

In studying the impact of the therapy, the investigators on the team observed that tumors were smaller and weaker in the drug arm, and far more robust among the placebo arm.

There's also good reason to believe that the liver cells would be susceptible to this approach.

"We knew that cancer cells like to take up LDL in order to acquire cholesterol and other lipids to help build their cell membranes as they proliferate. So what we have here is a classic example of a Trojan horse. The cancer cell thinks it's getting cholesterol to provide the nutritional building blocks needed to grow and proliferate. Instead, it gets a payload of fish oil in the form of LDL-DHA nanoparticles that are selectively toxic to cancer cells without harming normal liver cells," he said.

- here's the release

研究：LDL，ω-3纳米的策略消除了肝癌细胞的大鼠

周三，2016年2月10日|由约翰·卡罗尔


UT西南的伊恩·科尔宾

还有的是在过去十年中的Omega-3脂肪酸是否能真正促进健康和防止癌症的相当数量的争议。但在UT西南研究员说，他已经开发出一种纳米粒子治疗了LDL和ω-3脂肪酸，这是能够消除肝癌细胞的大鼠，同时使健康细胞安然无恙。

癌，当然，已经固化在啮齿动物的时间，并再次在不能在人类中成功地再现研究。但伊恩·科尔宾，在高级成像研究中心（AIRC）的助理教授，德克萨斯大学西南医学杂志说，注射LDL-DHA纳米粒子成饲料肝动脉证明有毒，至少对某些肿瘤的肝脏细胞中大鼠模型的疾病。他补充说，有没有确定性的治疗策略可以消除所有的癌细胞。

在研究治疗的影响，在队研究者观察到，肿瘤是安慰剂组中更小，并在药物臂弱，更强大。

还有充分的理由相信，肝细胞可能会受到这种方法。

“我们知道，癌细胞喜欢占用LDL以获取胆固醇等脂类，以帮助建立其细胞膜，因为它们繁殖。因此，我们在这里的是一个木马的一个经典例子，癌细胞认为它越来越胆固醇提供生长和增殖所需要的营养积木。相反，它得到的鱼油中的LDL-DHA的纳米颗粒对癌细胞具有选择性毒性，而不伤害正常肝细胞的形式的有效载荷，“他说。