Effects of molecular weight and structural conformation of multivalent-based elastin-like polypeptides on tumor accumulation and tissue biodistribution

Nanotheranostics

article

Vijaya Sarangthem¹  Bo-Yeon Seo¹  Aena Yi¹  Young-Jin Lee¹  Sun-Ha Cheon¹  Sang Kyoon Kim³  Thoudam Debraj Singh⁴  Byung-Heon Lee¹  Rang-Woon Park¹ 

[1] Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University;Department of Pathology, All India Institute of Medical Sciences;Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation;Department of Medical Oncology Lab., All India Institute of Medical Sciences

关键词: multivalent;    size-dependent;    tumor targeting;    IL-4 receptor;    ELP;    biodistribution;   

DOI  :  10.7150/ntno.39804

学科分类：大气科学

来源: Ivyspring International Publisher

【 摘 要 】

In order to improve clinical outcomes for novel drug delivery systems, distinct optimization of size, shape, multifunctionality, and site-specificity are of utmost importance. In this study, we designed various multivalent elastin-like polypeptide (ELP)-based tumor-targeting polymers in which multiple copies of IL-4 receptor (IL-4R)-targeting ligand (AP1 peptide) were periodically incorporated into the ELP polymer backbone to enhance the affinity and avidity towards tumor cells expressing high levels of IL-4R. Several ELPs with different molecular sizes and structures ranging from unimer to micelle-forming polymers were evaluated for their tumor accumulation as well as in vivo bio-distribution patterns. Different percentages of cell binding and uptake were detected corresponding to polymer size, number of targeting peptides, or unimer versus micelle structure. As compared to low molecular weight polypeptides, high molecular weight AP1-ELP showed superior binding activity with faster entry and efficient processing in the IL-4R-dependent endocytic pathway. In addition, in vivo studies revealed that the high molecular weight micelle-forming AP1-ELPs (A86 and A100) displayed better tumor penetration and extensive retention in tumor tissue along with reduced non-specific accumulation in vital organs, when compared to low molecular weight non-micelle forming AP1-ELPs. It is suggested that the superior binding activities shown by A86 and A100 may depend on the multiple presentation of ligands upon transition to a micelle-like structure rather than a larger molecular weight. Thus, this study has significance in elucidating the different patterns underlying unimer and micelle-forming ELP-mediated tumor targeting as well as the in vivo biodistribution.

【 授权许可】

CC BY-NC