Cationic liposomes loaded with proapoptotic peptide D-(KLAKLAK)(2) and Bcl-2 antisense oligodeoxynucleotide G3139 for enhanced anticancer therapy.
Cationic liposomes loaded with proapoptotic peptide D-(KLAKLAK)(2) and Bcl-2 antisense oligodeoxynucleotide G3139 for enhanced anticancer therapy.
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DOI：
10.1021/mp900006h
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发表时间：
2009-05
影响因子：
4.9
通讯作者：
Torchilin VP
中科院分区：
文献类型：
--
作者：
Ko YT;Falcao C;Torchilin VP
使用寡核苷酸或肽等大分子治疗剂治疗癌症需要能够细胞内渗透的有效递送系统，并且还可能受益于使用具有不同作用机制的治疗剂的组合。考虑到这种可能性，我们构建了负载促凋亡肽D-(KLAKLAK)2和bcl-2反义寡脱氧核苷酸G3139的阳离子脂质体，并确定促凋亡大分子在单一阳离子脂质体中的组合是否可以增强抗肿瘤功效。利用交替电荷相互作用来捕获相反电荷的大分子。首先将聚阳离子肽D-(KLAKLAK)2与聚阴离子寡脱氧核苷酸G3139缩合以获得总体带负电荷的肽/寡脱氧核苷酸复合物。然后将复合物包埋到 DOTAP/DOPE 阳离子脂质体 (CL) 中。这种连续的电荷相互作用确保了 D-(KLAKLAK)2 和 G3139 的有效捕获，并具有高负载效率 (50%) 和容量 (7.5 wt%)。与单独负载 G3139 的 CL 相比，用负载 D-(KLAKLAK)2/G3139 的 CL 对小鼠黑色素瘤 B16(F10) 进行体外治疗，通过刺激诱导凋亡 (Caspase 3/7) 活性介导，抗肿瘤功效显着增强。在 B16(F10) 小鼠异种移植物中瘤内注射负载 D-(KLAKLAK)2/G3139 的 CL 也可抑制肿瘤生长，并增强细胞凋亡活性。因此，促凋亡肽D-(KLAKLAK)2和反义寡核苷酸G3139在阳离子脂质体中的组合增强了凋亡/抗肿瘤功效，并可能为癌症治疗提供有前景的工具。
The treatment of cancer using macromolecular therapeutics such as oligonucleotides or peptides requires efficient delivery systems capable of intracellular penetration and may also benefit from use of a combination of therapeutics with different mechanisms of action. With this possibility in mind, we constructed cationic liposome loaded with the proapoptotic peptide, D-(KLAKLAK)2 and the bcl-2 antisense oligodeoxynucleotide, G3139, and determined whether the combination of the proapoptotic macromolecules in a single cationic liposome can enhance antitumor efficacy. Advantage was taken of alternating charge interaction to entrap macromolecules of opposite charge. The polycationic pepetide D-(KLAKLAK)2 was first condensed with the polyanionic oligodeoxynucleotide G3139 to obtain overall negatively charged peptide/oligodeoxynucleotide complexes. The complexes were then entrapped into DOTAP/DOPE cationic liposomes (CL). This sequential charge interaction ensured efficient entrapment of D-(KLAKLAK)2 and G3139 with a high loading efficiency (50 %) and capacity (7.5 wt%). In vitro treatment of mouse melanoma B16(F10) with CL loaded with D-(KLAKLAK)2/G3139 led to significantly enhanced antitumor efficacy, mediated by stimulated induction of apoptotic (Caspase 3/7) activity, when compared to CL loaded with G3139 alone. Intratumoral injection of CL loaded with D-(KLAKLAK)2/G3139 in B16(F10) mice xenograft also led to suppressed tumor growth associated with enhanced apoptotic activity. Thus, the combination of proapoptotic peptide D-(KLAKLAK)2 and antisense oligonucleotide G3139 in a cationic liposome led to enhanced apoptotic/antitumor efficacy and may provide a promising tool for cancer treatment.
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影响因子：
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