α-Aminoisobutyric Acid-Containing Amphipathic Helical Peptide-Cyclic RGD Conjugation as a Potential Drug Delivery System for MicroRNA Replacement Therapy in Vitro

Abstract

Replacement therapy with tumor suppressive microRNA (TS-miRNA) might be the next-generation oligonucleotide therapy; however, a novel drug delivery system (DDS) is required. Recently, we developed the cell-penetrating peptide, model amphipathic peptide with α-aminoisobutyric acid (MAP­(Aib)), as a carrier for oligonucleotide delivery to cells. In this study, we examined whether a modified MAP­(Aib) analogue, MAP­(Aib)-cRGD, could be a DDS for TS-miRNA replacement therapy. MIR145-5p, a representative TS-miRNA especially in colorectal cancer, was selected. The MAP­(Aib)-cRGD dose was adjusted for MIR145-5p delivery to cells using peripheral blood mononuclear cells and degradation analysis. AlexaFluor488-labeled MIR145-5p incorporation into cells and negative regulation of MIR145-5p-targeting genes demonstrated MAP­(Aib)-cRGD’s functionality as a miRNA DDS. Treating MIR145-5p with MAP­(Aib)-cRGD also revealed various anticancer effects, such as cell viability, invasion inhibition, and apoptosis induction in WiDr cells. Altogether, these findings suggest that MAP­(Aib)-cRGD could be a DDS for TS-miRNA replacement therapy, but in vivo investigations are required.

Delivery of Anti-miRNA-221 for Colorectal Carcinoma Therapy Using Modified Cord Blood Mesenchymal Stem Cells-Derived Exosomes

“…However, the biggest challenge to developing miRNA therapeutics is designing a miRNA delivery vector to prevent the degradation of nuclease and the escape of drug molecules from endocytosis ( Xie et al, 2018 ). Furthermore, the dilemma of a miRNA drug delivery system lies in its potential immune stimulation and the lack of target specificity for the lesion ( Taniguchi et al, 2019 ).…”

Formulation, Characterization and Evaluation against SH-SY5Y Cells of New Tacrine and Tacrine-MAP Loaded with Lipid Nanoparticles

“…Cell-penetrating peptides (CPPs) are mostly used in combination with NPs as targeting ligands, and are facilitating drug delivery through endocytosis or passive transport. One example of efficient drug delivery is the model amphipathic peptide (MAP), presenting 72 h half-life in human serum [ 25 , 26 ] and an enhanced capability to deliver a wide range of compounds such as peptides, siRNA and oligonucleotides [ 27 , 28 , 29 ]. MAP is a cell penetrating peptide with 18 amino acid residues (KLALKLALKALKAALKLA), presenting repetitive blocks of cationic residue (lysine) and two hydrophobic residues (alanine and leucine), which confer an amphipathic a-helix structure crucial to interact with membrane surfaces and facilitate endocytosis [ 30 ].…”

PTBP1‐targeting microRNAs regulate cancer‐specific energy metabolism through the modulation of PKM1/M2 splicing

“…Recently, MIR34a-5p (MRX34) was selected as a therapeutic tool in various solid tumors; a phase I study (NCT01829971) was conducted 74 and terminated due to immune-related adverse events; the suitability of the drug delivery system was questioned. 75 Nonetheless, we suggest that the organ-specificity of MIR34a-5p…”

“…We should also consider organ‐specificity in the context of clinical applications. Recently, MIR34a‐5p (MRX34) was selected as a therapeutic tool in various solid tumors; a phase I study (NCT01829971) was conducted 74 and terminated due to immune‐related adverse events; the suitability of the drug delivery system was questioned 75 . Nonetheless, we suggest that the organ‐specificity of MIR34a‐5p should also be considered; the organ‐distribution of the particular miRNA in healthy conditions should also be factored in, to maximize the effectiveness of the treatment and to avoid potential side effects.…”