Sims Jessica D, Hwang Jae Youn, Wagner Shawn, Alonso-Valenteen Felix, Hanson Chris, Taguiam Jan Michael, Polo Richard, Harutyunyan Ira, Karapetyan Gevorg, Sorasaenee Karn, Ibrahim Ahmed, Marban Eduardo, Moats Rex, Gray Harry B, Gross Zeev, Medina-Kauwe Lali K
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Daegu Gyeongbuk Institute of Science & Technology, Daegu, Republic of Korea.
J Control Release. 2015 Nov 10;217:92-101. doi: 10.1016/j.jconrel.2015.08.046. Epub 2015 Aug 31.
Water-soluble corroles with inherent fluorescence can form stable self-assemblies with tumor-targeted cell penetration proteins, and have been explored as agents for optical imaging and photosensitization of tumors in pre-clinical studies. However, the limited tissue-depth of excitation wavelengths limits their clinical applicability. To examine their utility in more clinically-relevant imaging and therapeutic modalities, here we have explored the use of corroles as contrast enhancing agents for magnetic resonance imaging (MRI), and evaluated their potential for tumor-selective delivery when encapsulated by a tumor-targeted polypeptide. We have found that a manganese-metallated corrole exhibits significant T1 relaxation shortening and MRI contrast enhancement that is blocked by particle formation in solution but yields considerable MRI contrast after tissue uptake. Cell entry but not low pH enables this. Additionally, the corrole elicited tumor-toxicity through the loss of mitochondrial membrane potential and cytoskeletal breakdown when delivered by the targeted polypeptide. The protein-corrole particle (which we call HerMn) exhibited improved therapeutic efficacy compared to current targeted therapies used in the clinic. Taken together with its tumor-preferential biodistribution, our findings indicate that HerMn can facilitate tumor-targeted toxicity after systemic delivery and tumor-selective MR imaging activatable by internalization.
具有固有荧光的水溶性卟吩能与肿瘤靶向性细胞穿透蛋白形成稳定的自组装体，并且在临床前研究中已被探索用作肿瘤光学成像和光致敏的试剂。然而，激发波长的组织穿透深度有限限制了它们的临床适用性。为了研究它们在更具临床相关性的成像和治疗方式中的效用，在此我们探索了卟吩作为磁共振成像（MRI）的造影剂的用途，并评估了其被肿瘤靶向性多肽包封时肿瘤选择性递送的潜力。我们发现一种锰金属化的卟吩表现出显著的T1弛豫缩短和MRI造影增强，其在溶液中因颗粒形成而被阻断，但在组织摄取后产生可观的MRI造影。细胞内吞而非低pH促成了这一点。此外，当由靶向多肽递送时，卟吩通过线粒体膜电位丧失和细胞骨架破坏引发肿瘤毒性。与临床中使用的当前靶向疗法相比，蛋白质 - 卟吩颗粒（我们称之为HerMn）表现出更高的治疗效果。结合其肿瘤优先的生物分布，我们的研究结果表明HerMn在全身递送后可促进肿瘤靶向毒性，并可通过内化激活肿瘤选择性MR成像。
