Time-Prolonged Release of Tumor-Targeted Protein-MMAE Nanoconjugates from Implantable Hybrid Materials.

Naroa Serna,Antonio Villaverde,Ugutz Unzueta,Ramón Mangues,Isolda Casanova,Annabel García-León,Alejandro Sánchez-Chardi,Aïda Falgàs,Carlos Martínez-Torró,Yáiza Núñez,Esther Vazquez

doi:10.3390/pharmaceutics14010192

Abstract

The sustained release of small, tumor-targeted cytotoxic drugs is an unmet need in cancer therapies, which usually rely on punctual administration regimens of non-targeted drugs. Here, we have developed a novel concept of protein–drug nanoconjugates, which are packaged as slow-releasing chemically hybrid depots and sustain a prolonged secretion of the therapeutic agent. For this, we covalently attached hydrophobic molecules (including the antitumoral drug Monomethyl Auristatin E) to a protein targeting a tumoral cell surface marker abundant in several human neoplasias, namely the cytokine receptor CXCR4. By this, a controlled aggregation of the complex is achieved, resulting in mechanically stable protein–drug microparticles. These materials, which are mimetics of bacterial inclusion bodies and of mammalian secretory granules, allow the slow leakage of fully functional conjugates at the nanoscale, both in vitro and in vivo. Upon subcutaneous administration in a mouse model of human CXCR4+ lymphoma, the protein–drug depots release nanoconjugates for at least 10 days, which accumulate in the tumor with a potent antitumoral effect. The modification of scaffold cell-targeted proteins by hydrophobic drug conjugation is then shown as a novel transversal platform for the design of slow releasing protein–drug depots, with potential application in a broad spectrum of clinical settings.

Highlights

Reaching time-sustained drug delivery upon a single-dose administration is of paramount clinical relevance in pathologies, such as cancer, that require steady levels of the drug at the target organs over significant periods of time [1–4]
The technologies of protein clustering based on divalent cations rely on histidine-rich peptides overhanging from engineered proteins [22]
We have explored this hypothesis by cross-linking the anticancer drug MMAE with the tumor-targeted functional protein T22-GFP-H6

Summary

Introduction

Reaching time-sustained drug delivery upon a single-dose administration is of paramount clinical relevance in pathologies, such as cancer, that require steady levels of the drug at the target organs over significant periods of time [1–4]. A diversity of materials organized as drug-holding matrices are under development, aiming to achieve the progressive time-sustained release of the payload drug [5]. Such dynamic depots are usually based on biocompatible, polymeric materials with fibrous architectures that hold the embedded drug in inner spaces, aiming for either passive or stimuli-based release [5–9]. Reaching steady drug levels is difficult for the small-molecular-weight cytotoxic agents used in the chemotherapy of cancer. This is due to their poor retention in such scaffolding depots and because of the renal clearance of the drug below approximately 7 nm [10–13]

Methods

Results

Conclusion