Inorganic Kernel-Reconstituted Lipoprotein Biomimetic Nanovehicles Enable Efficient Targeting "Trojan Horse" Delivery of STAT3-Decoy Oligonucleotide for Overcoming TRAIL Resistance.
Inorganic Kernel-Reconstituted Lipoprotein Biomimetic Nanovehicles Enable Efficient Targeting "Trojan Horse" Delivery of STAT3-Decoy Oligonucleotide for Overcoming TRAIL Resistance.
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无机内核重组脂蛋白仿生纳米载体能够有效靶向“特洛伊木马”递送 STAT3 诱饵寡核苷酸以克服 TRAIL 耐药性
作者：
Shi K;Xue J;Fang Y;Bi H;Gao S;Yang D;Lu A;Li Y;Chen Y;Ke L
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）可选择性地诱导多种肿瘤细胞凋亡，但对大多数正常细胞无明显作用。然而，由于肿瘤细胞，特别是肝细胞癌细胞系中经常发生耐药性，其治疗潜力受到限制。因此，我们研究了STAT 3-诱饵寡核苷酸（ODNs）对TRAIL抗性的逆转作用。方法.考虑到ODNs细胞通透性差和在体内降解快的缺点限制了ODNs的进一步临床应用，我们开发了一种仿生的磷酸钙重组低密度脂蛋白纳米载体（CaP@LDL），它可以作为“特洛伊木马”将STAT 3诱骗ODNs携带到肿瘤细胞中，进而调节TRAIL诱导的细胞凋亡。结果与天然ODNs相比，重组的CaP@LDL包装ODNs具有显著的血清稳定性、细胞转染率、体外协同细胞毒活性和对肝癌细胞的凋亡作用，而对正常细胞无细胞毒活性。提高的TRAIL致敏性归因于阻断STAT 3信号传导和随后下游靶抗凋亡基因的表达。在全身给药后，CaP@LDL显示出类似LDL的药代动力学行为，例如减弱的血液清除率以及增强的肿瘤和肝肾部位的蓄积。在decoyODN/CaP@LDL的协同组合下，TRAIL显著抑制异种移植模型中的肝肿瘤生长，并在体内诱导显著的肿瘤凋亡。结论这些结果表明，CaP@ LDL介导的STAT 3-decoy ODN递送可能是一种有希望的逆转肝癌治疗中的TRAIL抗性的新策略。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in a variety of tumor cells, but not most normal cells. Nevertheless, its therapeutic potential is limited due to the frequent occurrence of resistance in tumor cells, especially hepatocellular carcinoma cell lines. Therefore, we investigated the reversal effect of STAT3-decoy oligonucleotides (ODNs) on TRAIL resistance. Methods. Considering that the drawback of poor cellular permeability and rapid degradation in vivo limited ODNs' further clinical applications, we developed a biomimetic calcium phosphate-reconstituted low density lipoprotein nanovehicle (CaP@LDL) that would serve as a “Trojan horse” to carry STAT3-decoy ODNs into tumor cells and then regulate TRAIL-induced apoptosis. Results. In comparison with native ODNs, the reconstituted CaP@LDL packaged ODNs showed significantly increased serum stability, cellular transfection, in vitro synergistic cytotoxicity and apoptosis in hepatoma cells, while there was no cytotoxicity to normal cells. The improved TRAIL sensitization is attributed to blocking of STAT3 signaling and consequent expression of the downstream target antiapoptotic gene. Following systemic administration, CaP@LDL displayed LDL-mimicking pharmacokinetic behavior such as attenuated blood clearance as well as enhanced accumulation in tumor and hepatorenal sites. With the synergistic combination of decoyODN/CaP@LDL, TRAIL dramatically inhibited hepatic tumor growth in a xenograft model and induced significant tumor apoptosis in vivo. Conclusion. These results suggested that CaP@LDL-mediated STAT3-decoy ODN delivery might be a promising new strategy for reversing TRAIL resistance in hepatocellular carcinoma therapy.
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影响因子：
13.5
作者：
Amarante-Mendes GP;Griffith TS
通讯作者：
Griffith TS
影响因子：
8
作者：
Dimberg LY;Anderson CK;Camidge R;Behbakht K;Thorburn A;Ford HL
通讯作者：
Ford HL
针对JAK/STAT3信号传导的靶向封锁抑制了卵巢癌的生长。
影响因子：
5.7
作者：
Gritsina G;Xiao F;O'Brien SW;Gabbasov R;Maglaty MA;Xu RH;Thapa RJ;Zhou Y;Nicolas E;Litwin S;Balachandran S;Sigal LJ;Huszar D;Connolly DC
通讯作者：
Connolly DC
影响因子：
13.3
作者：
Lee, Jeong Yu;Kim, Jin-Ho;Nam, Yoon Sung
通讯作者：
Nam, Yoon Sung
影响因子：
14.9
作者：
Crinelli, R;Bianchi, M;Magnani, M
通讯作者：
Magnani, M