Ligand-targeted theranostic nanomedicines against cancer.
Ligand-targeted theranostic nanomedicines against cancer.
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DOI：
10.1016/j.jconrel.2016.01.002
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发表时间：
2016-10-28
期刊：
影响因子：
--
通讯作者：
Pasqualini R
中科院分区：
文献类型：
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作者：
Yao VJ;D'Angelo S;Butler KS;Theron C;Smith TL;Marchiò S;Gelovani JG;Sidman RL;Dobroff AS;Brinker CJ;Bradbury ARM;Arap W;Pasqualini R
纳米药物在癌症治疗方面具有巨大的潜力。尽管目前在临床试验中测试的大多数纳米药物使用的是简单的、生物相容性的脂质体纳米载体，但它们的广泛使用受到非特异性和低靶点浓度的限制，因此，与传统的全身化疗相比，不能提供实质性的临床优势。在过去的20年里，我们利用噬菌体上展示的组合肽文库，确定了肿瘤内皮细胞和血管周围细胞、肿瘤细胞、细胞外基质和基质细胞表面表达的特异性受体。这些研究证实了IL-11Rα、GRP78、EphA5等独特受体蛋白在肿瘤中差异过表达的观点，并为肿瘤特异性治疗药物提供了机会。通过使用与肿瘤特异性细胞表面受体结合的肽，可以精确和系统地递送治疗药物，如凋亡肽、自杀基因、成像染料或化疗药物，以减少肿瘤在体内的生长，而不损害健康细胞。鉴于基于肽的治疗方法的临床适用性，靶向递送装载治疗货物的纳米载体似乎是可行的。我们提出了一种功能化原始细胞的模块化设计，其中肿瘤靶向片段，如肽或重组人抗体单链可变片段（scFv），结合到脂质双分子层周围的硅基纳米载体核心，其中包含受保护的治疗cargo。功能化的原始细胞可以通过交换肿瘤靶向部分和/或治疗货物来定制特定的癌症亚型和治疗方案，或组合使用以创建独特的治疗药物。在这篇综述中，我们总结了利用组合噬菌体展示技术鉴定肿瘤特异性受体和利用抗体展示选择鉴定针对这些肿瘤特异性受体的重组人scfv。我们比较了不同类型的简单和复杂纳米载体的特点，并讨论了潜在的治疗货物类型和偶联策略。功能化原细胞的模块化设计可以提高纳米药物在未来癌症治疗中的有效性和安全性。模块化功能化的原始细胞通过肽配体或重组人单链可变片段靶向肿瘤，并在介孔硅核中嵌入显像或治疗剂。
Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20 years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. The modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy. The modular functionalized protocell is targeted to tumors via peptide ligands or recombinant human single chain variable fragments and contains imaging or therapeutic agents embedded in the mesoporous silica core.