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

Abstract

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.

Engineered elastin-like polypeptides: An efficient platform for enhanced cancer treatment

“…Moreover, the concrete guest residue and peptide length of ELPs need to be optimized for drug delivery to different tumor types. Sarangthem V indicated that increased molecular weight of AP1-ELPs contributes to better tumor penetration and retention in 4T1 tumor-bearing mice ( Sarangthem et al, 2020 ). Kuna M also demonstrated that the increased molecular weight of ELPs had longer plasma half-lives and higher total renal accumulation ( Kuna et al, 2018 ).…”

Multifunctional elastin-like polypeptide nanocarriers for efficient miRNA delivery in cancer therapy

“…In a previous study, we demonstrated the potential of micelle-forming multivalent targeting based AP1-ELP (A86) polymers, emphasizing their heightened binding activity, rapid cellular entry, and efficient processing within the interleukin-4 receptor (IL-4R)-dependent endocytic pathway across diverse cancer cell lines [ 44 ]. Exclusively, A86 exhibited superior tumor penetration and substantial retention within tumor tissues while also mitigating non-specific accumulation in critical organs in a murine model with 4T1 allografted tumors.…”