Targeted quantum dot conjugates for siRNA delivery
Targeted quantum dot conjugates for siRNA delivery
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DOI：
10.1021/bc060367e
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发表时间：
2007-09-01
影响因子：
4.7
通讯作者：
Bhatia, Sangeeta N.
中科院分区：
文献类型：
--
作者：
Derfus, Austin M.;Chen, Alice A.;Bhatia, Sangeeta N.
人类疾病如癌症的治疗通常涉及诊断工具和治疗方式的顺序使用。多功能平台将治疗和诊断成像功能结合在一辆车中，有望改变这种模式。特别是，基于纳米颗粒的多功能平台提供了改善药物制剂的药代动力学的潜力，同时提供了用于诊断成像和疾病靶向特征的附着位点。我们已经将这些原理应用于小干扰RNA（siRNA）治疗剂的递送，其中系统递送受到快速排泄和非靶向组织分布的阻碍。使用PEG化的量子点（QD）核心作为支架，siRNA和肿瘤归巢肽（F3）与颗粒表面上的官能团缀合。我们发现归巢肽是肿瘤细胞靶向内化所必需的，并且siRNA货物可以共附着而不影响肽的功能。使用EGFP模型系统，研究了缀合化学的作用，通过二硫键交联剂连接到颗粒的siRNA显示出比通过不可还原的硫醚键连接时更大的沉默效率。由于每个颗粒包含有限数量的附着位点，我们进一步探索了每个颗粒F3肽数量和siRNA数量之间的权衡，从而优化了配方。将这些F3/siRNA-QD递送至EGFP转染的HeLa细胞并从其内体截留中释放导致EGFP信号的显著敲低。通过设计针对治疗靶标（例如，癌基因）而不是EGFP，该技术可能最终适用于同时治疗和成像转移性癌症。
Treatment of human diseases such as cancer generally involves the sequential use of diagnostic tools and therapeutic modalities. Multifunctional platforms combining therapeutic and diagnostic imaging functions in a single vehicle promise to change this paradigm. in particular, nanoparticle-based multifunctional platforms offer the potential to improve the pharmacokinetics of drug formulations, while providing attachment sites for diagnostic imaging and disease targeting features. We have applied these principles to the delivery of small interfering RNA (siRNA) therapeutics, where systemic delivery is hampered by rapid excretion and nontargeted tissue distribution. Using a PEGlyated quantum dot (QD) core as a scaffold, siRNA and tumor-homing peptides (F3) were conjugated to functional groups on the particle's surface. We found that the homing peptide was required for targeted internalization by tumor cells, and that siRNA cargo could be coattached without affecting the function of the peptide. Using an EGFP model system, the role of conjugation chemistry was investigated, with siRNA attached to the particle by disulfide cross-linkers showing greater silencing efficiency than when attached by a nonreducible thioether linkage. Since each particle contains a limited number of attachment sites, we further explored the tradeoff between number of F3 peptides and the number of siRNA per particle, leading to an optimized formulation. Delivery of these F3/siRNA-QDs to EGFP-transfected HeLa cells and release from their endosomal entrapment led to significant knockdown of EGFP signal. By designing the siRNA sequence against a therapeutic target (e.g., oncogene) instead of EGFP, this technology may be ultimately adapted to simultaneously treat and image metastatic cancer.