Development of ion-dependent microscale secretory granules for nanomedical applications

ELOI PARLADÉ; HECTOR LOPEZ LAGUNA; PATRICIA ÁLAMO,; ERIC VOLTA DURAN; JULIETA M. SANCHEZ; NAROA SERNA; UGUTZ UNZUETA ,; RAMON MANGUES; ANTONIO VILLAVERDE; ESTHER VÁZQUEZ

Santander

Conferencia; 3rd International Conference on Nanomaterials Applied to Life Sciences 2022; 2022

Universidad de Cantabria

Diverse medical practices including drug delivery or vaccination can benefit from biocompatible materials with the ability to release peptides in a time-prolonged way. Ideally, the delivered molecules should be self-contained as chemically homogenous entities to prevent the necessity of potentially toxic scaffolds or hold matrices. In nature, peptidic hormones are self-stored in protein-only secretory granules formed by the reversible coordination of Zn2+ and histidine residues [1]. Inspired by this concept and through the controlled addition of divalent cations at physiological concentrations, polyhistidine-tagged proteins can be clustered in form of chemically pure and mechanically stable micron-scale particles that act as secretory granules [2]. The construction of these granules was initially studied with 12 different proteins (engineered and non-engineered) acting as building blocks; monitoring the respective precipitation dynamics, release rates, and testing the functionality of the released particles, for example, as selective labelling agents of cancer cells in a CXCR4+ mouse model of human colorectal cancer. Under physiological conditions, Zn-based granules act as self-disintegrating protein depots for the progressive release of the forming polypeptide. However, to assess whether and how other biocompatible ions would serve as molecular glue-like agents we then tested the the cationic forms of Zn, Ca, Mg and Mn, individually and in combination. In vivo disintegration patterns of a set of such depots was investigated upon subcutaneous administration in mice, where Ca2+ and Zn2+ were deemed as particularly good promoters of time-prolonged protein leakage [3]. In summary, short histidine tags allow the packaging of structurally and functionally dissimilar polypeptides, which supports the proposed fabrication method as a powerful protocol extensible to diverse clinical scenarios in which slow protein drug delivery is required.