P-selectin is a nanotherapeutic delivery target in the tumor microenvironment.
P-selectin is a nanotherapeutic delivery target in the tumor microenvironment.
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DOI：
10.1126/scitranslmed.aaf7374
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发表时间：
2016-06-29
影响因子：
17.1
通讯作者：
Heller DA
中科院分区：
文献类型：
--
作者：
Shamay Y;Elkabets M;Li H;Shah J;Brook S;Wang F;Adler K;Baut E;Scaltriti M;Jena PV;Gardner EE;Poirier JT;Rudin CM;Baselga J;Haimovitz-Friedman A;Heller DA
由于血管屏障减弱了肿瘤部位的外渗，纳米级药物输送系统很难接近播散性肿瘤。我们研究了 P-选择素，一种在激活的脉管系统上表达的分子，通过将肿瘤细胞阻滞在内皮来促进转移，其通过将纳米药物阻滞在肿瘤内皮来靶向转移的潜力。我们发现 P-选择素在许多人类肿瘤的癌细胞上表达。为了开发靶向药物递送平台，我们使用了与 P-选择素具有纳摩尔亲和力的岩藻糖基化多糖。纳米颗粒以肿瘤微环境为目标，将化疗药物和靶向 MEK（丝裂原激活蛋白激酶激酶）抑制剂定位在原发性和转移性模型的肿瘤部位，从而产生卓越的抗肿瘤功效。在缺乏 P-选择素的肿瘤中，我们发现电离辐射通过诱导 P-选择素表达来引导纳米颗粒到达疾病部位。辐射同时产生了一种类似远隔的现象，其中 P-选择素出现在未辐射的肿瘤脉管系统中，这表明将不同的药物类别靶向几乎任何肿瘤的潜在策略。
Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor.
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影响因子：
10.9
作者：
Jena PV;Shamay Y;Shah J;Roxbury D;Paknejad N;Heller DA
通讯作者：
Heller DA
影响因子：
12.4
作者：
Bonnard T;Yang G;Petiet A;Ollivier V;Haddad O;Arnaud D;Louedec L;Bachelet-Violette L;Derkaoui SM;Letourneur D;Chauvierre C;Le Visage C
通讯作者：
Le Visage C
MEK抑制剂selumetinib（AZD6244，Arry-142886）的II期试验对BRAFV600E/K-突变的黑色素瘤患者。
DOI：
10.1158/1078-0432.ccr-12-3476
发表时间：
2013-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Catalanotti F;Solit DB;Pulitzer MP;Berger MF;Scott SN;Iyriboz T;Lacouture ME;Panageas KS;Wolchok JD;Carvajal RD;Schwartz GK;Rosen N;Chapman PB
通讯作者：
Chapman PB
影响因子：
78.5
作者：
Bernier, J;Hall, EJ;Giaccia, A
通讯作者：
Giaccia, A
影响因子：
2.9
作者：
Carvalho, Ana C. S.;Sousa, Rhamon B.;de Souza, Marcellus H. L. P.
通讯作者：
de Souza, Marcellus H. L. P.