Tumor-targeting nanocomplex delivery of novel tumor suppressor RB94 chemosensitizes bladder carcinoma cells in vitro and in vivo
Tumor-targeting nanocomplex delivery of novel tumor suppressor RB94 chemosensitizes bladder carcinoma cells in vitro and in vivo
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DOI：
10.1158/1078-0432.ccr-07-1951
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发表时间：
2008-04-01
影响因子：
11.5
通讯作者：
Chang, Esther H.
中科院分区：
文献类型：
--
作者：
Pirollo, Kathleen F.;Rait, Antonina;Chang, Esther H.
目的：RB 94是RB 110的截短形式，对迄今为止测试的所有肿瘤类型（包括膀胱癌）具有增强的肿瘤抑制效力和活性。然而，将编码RB 94的基因特异性地有效地全身递送至肿瘤是作为抗癌治疗剂的临床应用的障碍。我们开发了一种全身给药的纳米脂质体DNA递送系统，其特异性靶向原发性和转移性疾病。通过这种纳米复合物递送的RB 94在体外和体内对膀胱癌化疗敏感的能力进行了评估。纳米复合物是由阳离子脂质体包封的RB 94质粒，其表面用肿瘤靶向部分装饰，转铁蛋白（Tf/Lip/RB 94）或抗转铁蛋白受体单链抗体片段（TfRScFv/Lip/RB 94）。通过XTT测定在体外评估复合物对人膀胱癌HTB-9细胞对化疗药物的增敏能力。结果：Tf/Lip/RB 94转染HTB-9细胞后，在体外对化疗药物有明显的增敏作用。通过免疫组织化学和PCR在原位膀胱肿瘤模型中显示了复合物的肿瘤特异性。此外，在携带皮下HTB-9肿瘤的小鼠中，全身给予的Tf/Lip/RB 94或TfRScFv/Lip/RB 94加吉西他滨的组合导致显著的抗肿瘤作用。（P < 0.0005）肿瘤生长抑制/消退和诱导凋亡。利用肿瘤-靶向纳米复合物以特异性地将有效的肿瘤抑制剂RB 94有效地递送至肿瘤具有作为更有效的治疗方式的潜力，泌尿生殖系统和其他癌症。
Purpose: RB94, a truncated form of RB110, has enhanced tumor suppressor potency and activity against all tumor types tested to date including bladder carcinoma. However, efficient, systemic delivery of the gene encoding RB94 specifically to tumors, is an obstacle to clinical application as an anticancer therapeutic. We have developed a systemically given, nanosized liposome DNA delivery system that specifically targets primary and metastatic disease.The ability of RB94, delivered via this nanocomplex, to sensitize bladder carcinoma to chemotherapy in vitro and in vivo was assessed.Experimental Design: The nanocomplex is an RB94 plasmid encapsulated by a cationic liposome, the surface of which is decorated with a tumor-targeting moiety, either transferrin (Tf/Lip/RB94) or an antitransferrin receptor single-chain antibody fragment (TfRScFv/Lip/ RB94). The ability of the complex to sensitize human bladder carcinoma HTB-9 cells to chemotherapeutics was assessed in vitro by XTTassay. In vivo tumor specificity and efficacy were tested in mice carrying HTB-9 tumors by PCR and tumor growth inhibition, respectively.Results: Transfection withTf/Lip/RB94 significantly sensitized HTB-9 cells to chemotherapeutic agents in vitro. Tumor specificity of the complex was shown in an orthotopic bladder tumor model by immunohistochemistry and PCR. Moreover, in mice bearing subcutaneous HTB-9 tumors, the combination of systemically given Tf/Lip/RB94 orTfRScFv/Lip/RB94 plus gemcitabine resulted in significant (P < 0.0005) tumor growth inhibition/regression and induction of apoptosis.Conclusions: Use of our tumor-targeting nanocomplex to specifically deliver the potent tumor suppressor RB94 efficiently to tumors has potential as a more effective treatment modality for genitourinary and other cancers.