Multivalent Targeting Based Delivery of Therapeutic Peptide using AP1-ELP Carrier for Effective Cancer Therapy

Abstract

Elastin-like polypeptide (ELP)-based drug delivery has been utilized for various applications including cancer therapies for many years. Genetic incorporation of internalization ligands and cell-targeting peptides along with ELP polymer enhanced tumor accumulation and retention time as well as stability and activities of the drug conjugates. Herein, we described a unique delivery system comprised of genetically engineered ELP incorporated with multiple copies of IL-4 receptor targeting peptide (AP1) periodically and proapoptotic peptide (KLAKLAK)2 referred to as AP1-ELP-KLAK. It triggered thermal-responsive self-assembly into a nanoparticle-like structure at physiological body temperature and stabilized its helical conformation, which is critical for its membrane-disrupting activities. Increased IL-4 receptor specific cellular internalization was associated with the enhanced cytotoxic effect of (KLAKLAK)2 peptide. Additionally, multivalent presentation of targeting ligands by AP1-ELP-KLAK significantly enhanced intratumoral localization and prolonged the retention time compared to ELP-KLAK, non-targeted control. Systemic administration of AP1-ELP-KLAK significantly inhibited tumor growth by provoking cell apoptosis in various tumor xenograft models without any specific organ toxicity. Thus, our newly designed AP1-ELP-KLAK polymer nanoparticle is a promising candidate for effective cancer therapy and due to the simple preparative procedures of ELPs, this platform can be used as a good carrier for tumor-specific delivery of other therapeutics.

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

“…Previously, we reported that [AP1-V12]6, ELP-based polymer consisting of six repeats of AP1 increased binding avidity and affinity towards IL-4R. The polymer was highly localized to IL-4R-expressing tumor tissue after intravenous injection and was retained up to 24 h. Moreover, [AP1-V12]6 showed higher accumulation in the liver and kidney, which may be attributed to its lower molecular weight [34,35]. Thus, various multivalentbased AP1-ELP polypeptides containing random repetitions of IL-4R-targeting peptide with different molecular weights were generated.…”

“…Protein samples were diluted to 25 μM in PBS and filtered through a 0.2-μm Whatman syringe filter (GE Healthcare, Amersham, UK) to remove impurities. The CD spectra were measured at the different temperatures of 20,25,30,35,40,50, and 60 °C in a 0.1-cm path length cell. The spectra were recorded from 180 to 260 nm at a scan speed of 50 nm/min.…”

“…(A) TEM images of A38, A60, A86, and A100 at 37 °C, scale bars, 100 nm. (B) Circular dichroism spectra of polypeptides were taken at different temperatures(20,25,30,35,40, 50, and 60 °C). Data are represented as mean ± SD (n = 3).…”

Genetically Engineered Elastin-based Biomaterials for Biomedical Applications

“…Thus, these new chimeric AP1-ELP-KLAK NPs enhanced tumor accumulation and retention time, thus making them promising candidates for effective cancer therapy. Due to the simple preparative procedures of these ELRs, this platform could also be used as a good carrier for tumor-specific delivery of other therapeutic agents [54].…”

Application of dual targeting drug delivery system for the improvement of anti-glioma efficacy of doxorubicin

“…Therefore, IL-4R-based tumor targeting drug delivery could be used for the treatment of several tumors. CRKRLDRNC peptide (AP1 peptide), selected through the phage-display technology, was reported to selectively bind to IL-4R [ 28 ]. Herein, we developed DOX-loaded nanoparticles and decorated on its surface with AP1 peptide for both glioma cells and angiogenesis dual targeting delivery of doxorubicin.…”