Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China.
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China.
Eur J Nucl Med Mol Imaging. 2024 Oct;51(12):3532-3544. doi: 10.1007/s00259-024-06793-9. Epub 2024 Jun 13.
PURPOSE: Fluorescence imaging-guided surgery has been used in oncology. However, for tiny tumors, the current imaging probes are still difficult to achieve high-contrast imaging, leading to incomplete resection. In this study, we achieved precise surgical resection of tiny metastatic cancers by constructing an engineering erythrocyte membrane-camouflaged bioprobe (AR-M@HMSN@P). METHODS: AR-M@HMSN@P combined the properties of aggregation-induced emission luminogens (AIEgens) named PF3-PPh (P), with functional erythrocyte membrane modified by a modular peptide (AR). Interestingly, AR was composed of an asymmetric tripodal pentapeptide scaffold (GGKGG) with three appended modulars: KPSSPPEE (A6) peptide, RRRR (R4) peptide and cholesterol. To verify the specificity of the probe in vitro, SKOV3 cells with overexpression of CD44 were used as the positive group, and HLF cells with low expression of CD44 were devoted as the control group. The AR-M@HMSN@P fluorescence imaging was utilized to provide surgical guidance for the removal of micro-metastatic lesions. RESULTS: In vivo, the clearance of AR-M@HMSN@P by the immune system was reduced due to the natural properties inherited from erythrocytes. Meanwhile, the A6 peptide on AR-M@HMSN@P was able to specifically target CD44 on ovarian cancer cells, and the electrostatic attraction between the R4 peptide and the cell membrane enhanced the firmness of this targeting. Benefiting from these multiple effects, AR-M@HMSN@P achieved ultra-precise tumor imaging with a signal-to-noise ratio (SNR) of 15.2, making it possible to surgical resection of tumors < 1 mm by imaging guidance. CONCLUSION: We have successfully designed an engineered fluorescent imaging bioprobe (AR-M@HMSN@P), which can target CD44-overexpressing ovarian cancers for precise imaging and guide the resection of minor tumors. Notably, this work holds significant promise for developing biomimetic probes for clinical imaging-guided precision cancer surgery by exploiting their externally specified functional modifications.
目的：荧光成像引导手术已应用于肿瘤学领域。然而，对于微小肿瘤，当前的成像探针仍然难以实现高对比度成像，导致切除不完全。在本研究中，我们通过构建一种工程红细胞膜伪装的生物探针（AR-M@HMSN@P），实现了对微小转移性癌症的精确手术切除。
方法：AR-M@HMSN@P 结合了一种名为 PF3-PPh（P）的聚集诱导发光（AIEgens）的特性，并通过模块化肽（AR）修饰功能化的红细胞膜。有趣的是，AR 由一个不对称的三肽基五肽支架（GGKGG）组成，带有三个附加的模块：KPSSPPEE（A6）肽、RRRR（R4）肽和胆固醇。为了在体外验证探针的特异性，我们使用过表达 CD44 的 SKOV3 细胞作为阳性组，并用 CD44 低表达的 HLF 细胞作为对照组。我们利用 AR-M@HMSN@P 的荧光成像为微转移病灶的切除提供手术指导。
结果：在体内，由于从红细胞中继承的天然特性，AR-M@HMSN@P 被免疫系统清除的速度降低。同时，AR-M@HMSN@P 上的 A6 肽能够特异性靶向卵巢癌细胞上的 CD44，而 R4 肽与细胞膜之间的静电吸引增强了这种靶向的牢固性。得益于这些多重作用，AR-M@HMSN@P 实现了超精准的肿瘤成像，信噪比（SNR）达到 15.2，使得通过成像引导切除肿瘤<1mm 成为可能。
结论：我们成功设计了一种工程化荧光成像生物探针（AR-M@HMSN@P），它可以靶向过表达 CD44 的卵巢癌进行精确成像，并指导微小肿瘤的切除。值得注意的是，这项工作为利用外部指定的功能修饰开发用于临床成像引导的精准癌症手术的仿生探针提供了重要的启示。
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