金纳米颗粒在恶性肿瘤放疗中的基础与临床应用研究进展

对45篇有关金纳米颗粒在恶性肿瘤放疗中应用文献(近5年20篇,近10年20篇)进行阅读,并通过对金纳米颗粒特点简介、理论研究、细胞实验、动物实验,以及靶向放疗临床前景进行综述。目前金纳米颗粒放射增敏研究尚未解决3个关键问题:金纳米颗粒在肿瘤细胞内微观分布及其影响因素;金纳米颗粒微观剂量提升作用;金纳米颗粒放射增敏的分子生物学机制。因此,该技术投入临床应用还有很多工作要做。     

曲妥珠金纳米探针对乳腺癌细胞抑制影响体外实验

目的：构建新型曲妥珠纳米生物探针,探讨其对乳腺癌细胞抑制影响的体外实验。方法：以柠檬酸盐还原法制备金纳米颗粒（goldnanoparticles,GNPs）,通过静电作用吸附曲妥珠单抗（Herceptin）,进而合成曲妥珠金纳米探针（GNP@Herceptin）;免疫组化检测MCF-7与SK-BR-3细胞HER-2蛋白表达;GNPs增殖抑制检测设12．5、25．0、50．0、100．0、200．0和400．0μg／mL6个浓度,并设置空白细胞组（0mg／mL）,试剂盒检测GNPs细胞毒性;综合细胞增殖抑制检测设GNPs、Herceptin和GNP@Herceptin组,每组设6．25、12．5、25．0、50．0、100．0和200．0ng／mL6个浓度,并设置空白细胞组（0ng／mL）,试剂盒检测MCF-7与SK-BR-3细胞增殖抑制效果;设0．25、0．5和1．0μg／mL3个浓度的Herceptin、GNP@Herceptin,并设置空白细胞组（0μg／mL）,试剂盒检测SK-BR-3细胞凋亡与周期阻滞;利用方差分析与独立样本t检验处理相应实验数据。结果：金纳米颗粒近似圆形,粒径大小（14．11±1．134）nm,与曲妥珠单抗吸附后,溶液澄清透亮,GNPs与Herceptin结合率为2．25：1;GNPs浓度在400μg／mL时,MCF-7细胞存活率减少至43．9％（t=39．709,P=0．001）,在100μg／mL时,SK-BR-3细胞存活率为65．1％（t=6．796,P=0．002）,均有明显细胞毒性效果,但金纳米颗粒浓度下降至50ug／mL时,SK-BR-3与MCF-7细胞生存率分别为82．8％（t=1．979,P：0．119）、99．3％（t=0．177,P=0．868）,且未显示出细胞增殖抑制效果,低浓度GNPs有良好的生物相容性。Herceptin处理SK-BR-3细胞后,最佳用药剂量为每10000个细胞7．143ng,GNP@Herceptin处理细胞后最佳用药量从50ng／mL降低至25ng／mL,差异有统计学意义,t=14．774,P〈0．001;GNP@Herceptin最高浓度处理细胞时,细胞凋亡率从9．37％增大至16．87％,差异有统计学意义,t=6．537,P=0．001;Gl期阻滞从74．70％增大到83．12％,差异有统计意义,t=5．286,P=0．006;G2／M期细胞数从14．14％减少至6．22％,差异有统计学意义,t=6．732,P=0．003。结论：构建的曲妥珠金纳米探针GNP@Herceptin性状稳定,可大比例降低Herceptin用药剂量,对HER-2过表达乳腺癌治疗具有实用研发前景。     

Breast cancer and meningioma

A unique association between meningioma and breast cancer has recently been observed. A review of the literature reveals 33 such cases. Certain similarities exist between these two tumors. They each occur more frequently in women in the fifth and sixth decade, and pregnancy accelerates the symptoms of both entities. Furthermore, an increase in estrogen and progesterone receptor protein has been noted in each. A patient with established breast cancer who presents with central nervous system symptoms cannot be assumed to have cerebral metastases. A thorough workup to rule out meningioma is necessary. Furthermore, patients with proven meningioma must be observed closely for the subsequent development of breast cancer.     

AS1411-conjugated gold nanospheres and their potential for breast cancer therapy

AS1411 is a quadruplex-forming DNA oligonucleotide that functions as an aptamer to target nucleolin, a protein present on the surface of cancer cells. Clinical trials of AS1411 have indicated it is well tolerated with evidence of therapeutic activity, but improved pharmacology and potency may be required for optimal efficacy. In this report, we describe how conjugating AS1411 to 5 nm gold nanospheres influences its activities in vitro and in vivo. We find that the AS1411-linked gold nanospheres (AS1411-GNS) are stable in aqueous and serum-containing solutions. Compared to unconjugated AS1411 or GNS linked to control oligonucleotides, AS1411-GNS have superior cellular uptake and markedly increased antiproliferative/cytotoxic effects. Similar to AS1411, AS1411-GNS show selectivity for cancer cells compared to non-malignant cells. In a mouse model of breast cancer, systemic administration of AS1411-GNS could completely inhibit tumor growth with no signs of toxicity. These results suggest AS1411-GNS are promising candidates for clinical translation.     

载乳腺癌裂解蛋白纳米粒子的制备及其体外免疫效应的初步评估

[目的]使用聚乳酸聚乙醇酸共聚物（PLGA）制备纳米颗粒,用来包载MCF7乳腺癌细胞的裂解蛋白,并初步评估其在乳腺癌免疫治疗中的作用。[方法]用二次乳化法制备载MCF7裂解蛋白的纳米粒子,对其包封效率、粒径、形态和Zeta电位进行测定,优化制备参数以提高包封效率;用该纳米粒子刺激人外周血单个核细胞,检测纳米粒子的体外抗肿瘤免疫效应。[结果]制备的载MCF7裂解蛋白纳米颗粒呈球形,尺寸较均匀,平均粒径75nm,表面带负电荷,对MCF7裂解蛋白的包裹率可达85%,并能显著提高人淋巴细胞对乳腺癌细胞的体外杀伤能力,约是对照组的3倍（P〈0.05）。[结论]该制备方法所得载MCF7裂解蛋白纳米粒理化性质优良,包裹率高,在体外实验中可提高MCF7裂解蛋白的免疫原性,在提升抗肿瘤免疫效应方面具有应用潜能。     

In vitro cancer cell imaging and therapy using transferrin-conjugated gold nanoparticles

Gold nanoparticles were conjugated with transferrin molecules for targeting, imaging and therapy of breast cancer cells (Hs578T, ATCC). Results show that, the transferrin-transferrin receptor-mediated cellular uptake of gold nanoparticles is six times of that in the absence of this interaction. As a consequence, the laser power effective for photothermal therapy of the cancer cells was reduced to values of two orders of magnitude lower. To demonstrate the efficiency of the conjugated gold nanoparticles in selectively targeting cancer cells, the cellular uptake of the gold nanoparticles by noncancerous cells (3T3, ATCC) was also investigated. The cellular uptake by the normal cells is only one fourth of that by the cancerous cells indicating that the transferrin-transferrin receptor interaction plays an important role in controlling the cellular uptake of the gold nanoparticles.     

40例男性乳腺癌随访资料分析

背景与目的 :探讨男性乳腺癌的临床特点 ,治疗方法和影响预后的因素。 材料与方法 :回顾性总结40例男性乳腺癌的临床特点和治疗方法 ,分析其影响预后的因素。 结果 :全部病例经手术后病理检查确诊。全组患者治疗后的5、10年生存率分别为65 %、52.5 %。根治术与改良根治术患者的5、10年生存率分别为72.2 %、71.4 %。腋窝部淋巴结转移率为62.5 %。 结论 :男性乳腺癌比女性病程长 ,更具有激素依赖性。容易发生腋窝淋巴结转移 ,预后较差。治疗上首选改良根治术并根据不同情况辅以放疗、化疗和内分泌治疗。     

Peptide mediated active targeting and intelligent particle size reduction-mediated enhanced penetrating of fabricated nanoparticles for triple-negative breast cancer treatment

Triple-negative breast cancer (TNBC) is one of the most invasively malignant human cancers and its incidence increases year by year. Effective therapeutics against them needs to be developed urgently. In this study, a kind of angiopep-2 modified and intelligently particle size-reducible NPs, Angio-DOX-DGL-GNP, was designed for accomplishing both high accumulation and deep penetration within tumor tissues. On one hand, for improving the cancerous targeting efficiency of NPs, angiopep-2 was anchored on the surface of NPs to facilitate their accumulation via binding with low density lipoprotein-receptor related protein (LRP) overexpressed on TNBC. On the other hand, for achieving high tumor retention and increasing tumor penetration, an intelligently particle size-reducible NPs were constructed through fabricating gelatin NPs (GNP) with doxorubicin (DOX) loaded dendrigraft poly-lysine (DGL). In vitro cellular uptake and ex-vivo imaging proved the tumor targeting effect of Angio-DOX-DGL-GNP. Additionally, the degradation of large-sized Angio-DOX-DGL-GNP by matrix metalloproteinase-2 (MMP-2) led to the size reduction from 185.7 nm to 55.6 nm. More importantly, the penetration ability of Angio-DOX-DGL-GNP after incubation with MMP-2 was dominantly enhanced in tumor spheroids. Due to a combinational effect of active targeting and deep tumor penetration, the tumor growth inhibition rate of Angio-DOX-DGL-GNP was 74.1% in a 4T1 breast cancer bearing mouse model, which was significantly higher than other groups. Taken together, we successfully demonstrated a promising and effective nanoplatform for TNBC treatment.     

纳米金对SPC-A1肺癌细胞体外放射增敏作用的研究

目的 研究纳米金联合兆伏级射线对肺腺癌SPC-A1细胞的体外放射增敏作用,并从细胞周期、细胞凋亡角度探讨纳米金的放射增敏机制。方法 选用肺腺癌SPC-A1细胞进行体外培养,采用CCK-8法检测不同浓度纳米金（0、1、0.5、0.25、0.125、0.0625 mmol／L）处理SPC-A1细胞24、48、72 h后的细胞毒性,确定纳米金溶液的实验浓度;经纳米金溶液培养的SPC-A1细胞株分别给予6 MV X线和4 MeV电子线照射0、1、2、4、6、8 Gy后,体外细胞培养克隆法研究纳米金的放射增敏作用,计算存活分数。使用单击多靶模型公式拟合,计算出Dq、D0等放射生物学参数和放射增敏比（SER）;流式细胞仪检测纳米金处理SPC-A1细胞24 h后各组的细胞凋亡和细胞周期的变化。结果 不同浓度纳米金处理不同时间后,对SPC-A1细胞的增殖无明显抑制,确定以纳米金溶液初始浓度（0.25 mmol／L）作为实验浓度。直径25 nm、0.25 mmol／L的纳米金粒子联合6 MV X线和4 MeV 电子线照射SPC-A1细胞的SER分别是1.111和1.214。流式细胞仪检测显示,纳米金不增加细胞的凋亡,但能明显增加射线对细胞的凋亡作用。细胞周期显示纳米金能加速细胞的G0／G1期,使细胞周期阻滞在G2／M期。结论 纳米金联合6 MV X线或4 MeV 电子线对SPC-A1细胞有放射增敏作用,其机制可能与增加射线对细胞的凋亡和细胞周期同步化有关。     

Breast cancer and importance of zygosity determination in triplet sisters

Summary This study is the first to examine the genetic risk in a breast cancer-prone family wherein two of three triplet sisters and their mother manifested breast cancer. The unaffected triplet, the proband, was found to be monozygotic with her deceased sister through DNA testing of tumor blocks and dizygotic to her living affected sister. Genetic counseling implications are discussed.     

Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor

Breast cancer cells frequently metastasize to the skeleton, where they induce OCL formation and activity, resulting in extensive bone destruction. However, the mechanisms by which breast cancer cells mediate increased osteolysis remain unclear. To elucidate this point, we investigated how 3 human breast cancer cell lines, MDA-MB-231, MDA-MB-435 and MCF-7, induce OCL formation using a murine osteoblast-spleen cell coculture system and compared their effects with a human colorectal cancer cell line, HCT-15; a human lung cancer cell line, HT-1080; and a normal human breast cell line, HME. The breast cancer cell lines supported OCL formation only when osteoblasts were present in spleen cell cocultures, whilst the non-breast cancer cell lines and the normal breast cell line, HME, had no effect. Fractionation of BCCM by ultrafiltration established that osteoclastogenic activity was associated with factors having m.w. >3 kDa. Breast cancer cell lines produced primarily PTHrP, with lesser amounts of IL-6, IL-11 and TNF-alpha. The effect of BCCM on OCL formation in osteoblast-spleen cell cocultures was partially prevented by a neutralising antibody to human PTHrP and completely prevented by a neutralising antibody to either murine IL-11 or the murine IL-11 receptor; neutralising antibodies to human IL-6, IL-11 or TNF-alpha were without effect. BCCM or human PTHrP induced an increase in murine osteoblast IL-11 mRNA and protein production, effects that were prevented in the presence of a neutralising antibody to human PTHrP. The osteoclastogenic activity of IL-11 was mediated by enhancing osteoblast production of PGE(2) effects, which were abrogated by an inhibitor of cyclooxygenase. PGE(2) apparently enhanced OCL formation by downregulating GM-CSF production by spleen cells since recombinant murine GM-CSF inhibited OCL formation and a neutralising antibody to murine GM-CSF blocked these inhibitory effects. We conclude that breast cancer cells induce OCL formation by stimulating osteoblastic production of IL-11. The subsequent release of PGE(2) followed by inhibition of GM-CSF production by cells within the bone microenvironment plays an important part in mediating the effects of breast cancer cells on OCL formation and their resorptive activity.     

金纳米颗粒在肿瘤放射增敏中的研究进展

金纳米颗粒(AuNPs)以其独特的理化性质及良好的生物相容性在生物医药方面广泛应用,其中金纳米颗粒肿瘤放射增敏作用是目前研究热点。大量体、内外研究证实AuNPs具有放射增敏效果,但AuNPs放射增敏相关机制仍有待进一步研究,目前普遍认为增敏主要由AuNPs促进肿瘤细胞由放疗不敏感期(G₀+G₁期)转为放疗敏感期(G₂+M期)所致。影响AuNPs放射增敏效果的因素有很多,其中包括AuNPs粒径大小及其表面修饰和微观分布、放射线能量及剂量大小和肿瘤细胞类别等。此外值得注意的是,AuNPs用于肿瘤放射增敏的同时也要关注它的安全性。目前已开展了AuNPs有关临床试验,尚需继续进行AuNPs放射增敏的研究才能实现真正的临床转化。     

Breast cancer survival and prognosis by screening history

Background:

Cancers not detected by breast screening are commonly assumed to have poorer prognosis.

Methods:

We examined the survival experience of all women aged 50–74 years diagnosed with a first breast cancer between 1998 and 2006 in British Columbia, Canada and determined their screening experience. Disease-specific survival rates were calculated and, for cases diagnosed in 2002, prognostic factors (size, nodal involvement, grade ER status and stage) were examined by time since screening.

Results:

Breast cancers diagnosed at screening had the best survival (P<0.001). Cancers detected within 12 months of a negative screen had similar survival rates (P=0.98) to those diagnosed within 12–23 and 24–47 months, with other non-screen-detected cancers having poorer survival (P<0.001). The prognostic profile of cancers diagnosed in 2002 followed a similar pattern.

Interpretation:

There was no evidence that cancers diagnosed within 12 months had poorer prognosis than those diagnosed up to 48 months following screening.     

Breast cancer screening uptake in women at increased risk of developing hereditary breast cancer

This multicenter study assessed breast cancer screening uptake in 461 unaffected women at increased risk of developing breast cancer on the basis of family history who approached familial cancer clinics for advice about surveillance options. At the time of attending the clinic, 89% and 90% of participants were vigilant with respect to age- and risk-specific recommendations for mammography and clinical breast examination, respectively, and 51% reported practicing breast self-examination monthly or more frequently. The degree to which health outcomes are perceived to be under one's personal control (²=–2.09, p=0.0037) and breast cancer anxiety (²=8.11,p=0.044) were both associated with monthly or more frequent breast self-examination, while there were no associations with sociodemographic characteristics. A significantly lower percentage (56%) of women aged <30 were vigilant with respect to mammography recommendations, compared to 77%, 96% and 98% of women aged 30–39, 40–49 and >50, respectively (²=37.2,p<0.0001). These relatively low rates of mammographic screening in young women may reflect concerns about increased cancer risk associated with early and repeated radiation exposure or lack of sensitivity in young women with radiographically dense breasts. If mammographic screening is ultimately shown to lower mortality in women at high risk, there will be a strong case to promote screening in young women. The need for regular mammographic screening would then need to be highlighted and reinforced amongst young women and their referring physicians. Awareness amongst general practitioners, who are largely responsible for referral to screening services, would also need to be increased.     

Breast cancer therapy affects the expression of antineonatal Nav1.5 antibodies in the serum of patients with breast cancer

Neonatal Nav1.5 (nNav1.5) is the alternative splice variant of Nav1.5 and it has been widely associated with the progression of breast cancer. The immunological context of nNav1.5 with respect to breast cancer metastases remains unexplored. The presence of antibodies against nNav1.5 may highlight the immunogenicity of nNav1.5. Hence, the aim of the present study was to detect the presence of antineonatal Nav1.5 antibodies (antinNav1.5-Ab) in the serum of patients with breast cancer and to elucidate the effects of breast cancer therapy on its expression. A total of 32 healthy female volunteers and 64 patients with breast cancer were randomly recruited into the present study as the control and breast cancer group, respectively. Patients with breast cancer were divided equally based on their pre- and ongoing-treatment status. Serum samples were tested with in-house indirect enzyme-linked immunosorbent assay (ELISA) to detect antinNav1.5-Ab, CD25 (T regulatory cell marker) using an ELISA kit and Luminex assay to detect the expression of metastasis-associated cytokines, such as vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-10, IL-8, chemokine (C-C motif) ligand 2 and tumor necrosis factor-alpha (TNF-α) The mean difference in the expression of antinNav1.5-Ab among the three groups (control, pretreatment and ongoing-treatment) was significant (P=0.0005) and the pretreatment breast cancer group exhibited the highest expression. The concentration of CD25 was highest in the pretreatment breast cancer group compared with the control and ongoing-treatment groups. There was a significant positive correlation between antinNav1.5-Ab and IL-6 in the pretreatment group (r=0.7260; P=0.0210) and a significant negative correlation between antinNav1.5-Ab and VEGF in the ongoing-treatment group (r=−0.842; P-value=0.0040). The high expression of antinNav1.5-Ab in the pretreatment group was in accordance with the uninterrupted presence of metastasis and highlighted the immunogenicity of nNav1.5 whereas the low expression of antinNav1.5-Ab in the ongoing-treatment group reflected the efficacy of breast cancer therapy in eliminating metastases. The augmented manifestation of T regulatory cells in the pretreatment group highlighted the functional role of nNav1.5 in promoting metastasis. The parallel expression of antinNav1.5-Ab with the imbalanced expression of cytokines promoting metastasis (IL-8, IL-6 and TNF-α) and cytokines that prevent metastasis (IL-10) indicated the role of nNav1.5 in breast cancer growth. The expression of antinNav1.5-Ab in accordance to the metastatic microenvironment indicates the immunogenicity of the protein and highlights the influence of breast cancer therapy on its expression level.     

联氨基姜黄素脂质体纳米颗粒对乳腺癌细胞增殖、凋亡、侵袭和迁移的影响

目的：研究联氨基姜黄素脂质体纳米颗粒（HC －NPs）对乳腺癌细胞的抑制作用及其机制。方法：制备 HC －NPs,培养人乳腺癌 MDA －MB －231细胞。以对数生长期的细胞为研究对象。分成对照组和实验组,对照组及实验组分别予以脂质体纳米颗粒空载（NPs）、HC －NPs 处理。测定细胞生长抑制率、移行愈合率,并测定相关蛋白 CyclinD1、Bcl －2、Bax、Survivin、MMP －9、p －STAT3的表达情况。结果：HC －NPs 处理人乳腺癌 MDA －MB －231后,与 NPs 对照组相比,可明显抑制细胞的增殖,差异有统计学意义（P ＜0．05）。FCM法检测实验组凋亡率高于对照组,差异有统计学意义（P ＜0．05）。细胞周期测定有显著差异,P 均＜0．05。HC－NPs 作用于人乳腺癌 MDA －MB －231细胞24h 后,细胞周期停滞在 G2期。Transwell 法检测到 HC －NPs 处理后,测定侵袭迁移,与对照组比较,HC －NPs 组侵袭迁移能力明显低于对照组（P 均＜0．05）。Western blot-ting 法测定相关蛋白 p －STAT3、CyclinD1、Bcl －2、Survivin、MMP －9的表达情况,HC －NPs 组明显降低且低于对照组,而 Bax 明显增高且高于对照组,总 STAT3水平无明显差异。结论：HC －NPs 对乳腺癌细胞的抑制作用机制与下调 JAK／STAT 信号通路有关。     

Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade

Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies. Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures.     

Breast cancer and pregnancy.

BACKGROUND: The management of women who have breast cancers diagnosed whilst they are pregnant is challenging. The aim is to give optimal treatment to the mother to maximise the chances of survival, whilst minimising the risks of harm to the fetus. However, few breast surgeons or oncologists develop expertise in this area owing to the rarity of the association. DESIGN: In this review we evaluate and summarise the current literature regarding the diagnosis, management and prognosis of pregnancy-associated breast cancer. Data were identified by searches of Medline, PubMed and references from relevant articles for the period from 1966 to 2004. Papers were selected based on their size and adequacy of design. RESULTS: There is a lack of controlled data concerning the management of pregnancy-associated breast cancer. The data available suggest that diagnosis and surgery may be carried out as for the non-pregnant patient, with some limitations on staging investigations. Radiotherapy is contraindicated during pregnancy although, in terms of immediate complications, chemotherapy can be used after the first trimester. CONCLUSIONS: Data from prospective databases that are currently recruiting will provide further important information concerning the management of this condition, and in particular the long-term sequelae for mother and fetus.