Breaking the selectivity-uptake trade-off of photoimmunoconjugates with nanoliposomal irinotecan for synergistic multi-tier cancer targeting
Breaking the selectivity-uptake trade-off of photoimmunoconjugates with nanoliposomal irinotecan for synergistic multi-tier cancer targeting
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DOI：
10.1186/s12951-019-0560-5
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发表时间：
2020-01-02
影响因子：
10.2
通讯作者：
Huang, Huang-Chiao
中科院分区：
文献类型：
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作者：
Liang, Barry J.;Pigula, Michael;Huang, Huang-Chiao
背景光免疫疗法涉及通过抗体缀合物靶向递送光敏剂（即，光免疫缀合物，PIC），随后光活化以选择性杀死肿瘤。PIC选择性和PIC摄取之间的权衡是限制光免疫疗法功效的主要缺点。尽管有充分的证据表明，光免疫疗法与化疗结合时最有效，但设计纳米载体以共同递送PIC和化疗药物仍然是一个未满足的需求。为了克服这些挑战，我们开发了一种新型的光免疫缀合物纳米脂质体（PIC-Nal），其包含三种临床使用的药剂：抗表皮生长因子受体（anti-EGFR）单克隆抗体西妥昔单抗（Cet）、苯并卟啉衍生物（BPD）光敏剂和伊立替康（IRI）化疗剂。结果首先使用碳二亚胺化学将BPD光敏剂与Cet以6：1的摩尔比连接以形成PIC。通过无铜点击化学促进PIC缀合到纳米脂质体伊立替康（Nal-IRI）上，这产生平均尺寸为158.8 +/-15.6 nm的单分散PIC-Nal-IRI。PIC-Nal-IRI对EGFR过表达的上皮性卵巢癌细胞具有高度选择性，在低EGFR表达细胞中的蓄积减少2至6倍。PIC与Nal-IRI的成功偶联使OVCAR-5细胞中的PIC摄取和光免疫治疗功效提高了高达30%。此外，PIC-Nal-IRI通过独特的三向机制（即，EGFR下调、线粒体去极化和DNA损伤）。越来越明显的是，最有效的癌症治疗将涉及靶向多个非重叠途径的联合治疗，同时最大限度地减少副作用。纳米技术结合光化学提供了一个独特的机会，同时提供和激活多种药物，靶向所有主要区域的癌细胞质膜，细胞质和细胞核。PIC-Nal-IRI提供了一种有前途的策略，可以克服选择性摄取权衡，提高光免疫治疗的疗效，并实现多层癌症靶向。可控的药物区室化、容易的表面改性和高度的临床相关性共同使得PIC-Nal-IRI非常有价值，值得在活体动物中进行进一步研究。
Background Photoimmunotherapy involves targeted delivery of photosensitizers via an antibody conjugate (i.e., photoimmunoconjugate, PIC) followed by light activation for selective tumor killing. The trade-off between PIC selectivity and PIC uptake is a major drawback limiting the efficacy of photoimmunotherapy. Despite ample evidence showing that photoimmunotherapy is most effective when combined with chemotherapy, the design of nanocarriers to co-deliver PICs and chemotherapy drugs remains an unmet need. To overcome these challenges, we developed a novel photoimmunoconjugate-nanoliposome (PIC-Nal) comprising of three clinically used agents: anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab (Cet), benzoporphyrin derivative (BPD) photosensitizer, and irinotecan (IRI) chemotherapy. Results The BPD photosensitizers were first tethered to Cet at a molar ratio of 6:1 using carbodiimide chemistry to form PICs. Conjugation of PICs onto nanoliposome irinotecan (Nal-IRI) was facilitated by copper-free click chemistry, which resulted in monodispersed PIC-Nal-IRI with an average size of 158.8 +/- 15.6 nm. PIC-Nal-IRI is highly selective against EGFR-overexpressing epithelial ovarian cancer cells with 2- to 6-fold less accumulation in low EGFR expressing cells. Successful coupling of PIC onto Nal-IRI enhanced PIC uptake and photoimmunotherapy efficacy by up to 30% in OVCAR-5 cells. Furthermore, PIC-Nal-IRI synergistically reduced cancer viability via a unique three-way mechanism (i.e., EGFR downregulation, mitochondrial depolarization, and DNA damage). Conclusion It is increasingly evident that the most effective therapies for cancer will involve combination treatments that target multiple non-overlapping pathways while minimizing side effects. Nanotechnology combined with photochemistry provides a unique opportunity to simultaneously deliver and activate multiple drugs that target all major regions of a cancer cell-plasma membrane, cytoplasm, and nucleus. PIC-Nal-IRI offers a promising strategy to overcome the selectivity-uptake trade-off, improve photoimmunotherapy efficacy, and enable multi-tier cancer targeting. Controllable drug compartmentalization, easy surface modification, and high clinical relevance collectively make PIC-Nal-IRI extremely valuable and merits further investigations in living animals.