Transformative Materials for Interfacial Drug Delivery

Abstract

Drug delivery systems (DDS) are designed to temporally and spatially control drug availability and activity. They assist in improving the balance between on-target therapeutic efficacy and off-target toxic side effects. DDS aid in overcoming biological barriers encountered by drug molecules upon applying them via various routes of administration. They are furthermore increasingly explored for modulating the interface between implanted (bio)medical materials and host tissue. Here, an overview of the biological barriers and host-material interfaces encountered by DDS upon oral, intravenous, and local administration is provided, and material engineering advances at different time and space scales to exemplify how current and future DDS can contribute to improved disease treatment are highlighted.

Introduction

Drug delivery systems (DDS) aim to improve therapeutic efficacy and reduce side effects. DDS offers several advantages over conventional free drug formulations. They can, for instance, protect unstable drugs, or aid in increasing the aqueous solubility of highly hydrophobic drugs. They furthermore help to control drug distribution and activation, thereby improving the pharmacokinetics and target site accumulation of small molecules.^[^1-3^] Traditional examples in this regard are coated tablets or capsules that protect drugs from low pH or digestive enzymes in the stomach, or pegylated nanoparticles (NP) that are routinely used to encapsulate small molecule chemotherapeutics to increase their circulation half-life and tumor accumulation. DDS can be sub-categorized into systems that assist in better controlling the temporal aspects of drug activation and systems that help to spatially guide drug molecules to certain organs or pathological sites within the body (Figure 1).

Depending on the route of administration, drugs and DDS encounter multiple biological barriers. Oral delivery is, for example, hampered by the harsh acidic conditions in the stomach and by poor permeability across the intestinal epithelium. Upon intravenous (IV) delivery, nano- and micro-DDS delivery suffer from rapid clearance by the mononuclear phagocyte system, as well as from the structural integrity of vascular endothelium. For local administration, the presence of mucus, for example, in the airways and the vaginal tract, can lead to inefficient drug delivery. These and other biological barriers impede DDS performance and therapeutic efficacy.^[^4-7^] Other than biological barriers, patient adherence to medication is often an overlooked barrier, which must be taken into consideration while designing DDS. Different approaches to overcome this barrier are highlighted in detail by Baryakova et al.^[⁸^]

To promote drug delivery across biological barriers, it is important to look at barriers not as hurdles, but as targetable, interactive, and adaptive interfaces. Interfacial drug delivery can be achieved in various different ways, and upon different routes of application (as well as via DDS integration in implants), with the overarching goal of temporally and spatially enhancing drug delivery and drug activity.^[^9-11^] Novel materials and methods for interface modulation open up new directions for transformative DDS development and improved DDS performance.^[¹²^]

In this perspective, we discuss the biological barriers and in vivo interfaces that DDS encounter upon oral, IV, and local administration. We furthermore highlight recent advances in DDS engineering and bio-material interface modulation, which are together resulting in radical improvements in temporally and spatially targeted drug treatment.

Transformative Materials for Interfacial Drug Delivery_Figure2 — Drug delivery systems for modulating interfaces upon oral application. A) Schematic showing the key interfaces associated with oral drug delivery. B) Self-orienting microneedle applicator (SOMA) mimicking the shape of a tortoise localizes to the bottom of the stomach and autonomously orients its microneedles to mediate maximally efficient transepithelial drug delivery. In a pig model, SOMA efficiently delivered mRNA nanoparticles encoding for the Cre-recombinase to produce tdTomato fluorescence. Reproduced with permission.[36] Copyright 2022, Elsevier Inc. C) Mucoadhesive patches can be released from enterically coated capsules in the basic environment of the small intestine, followed by adhesion to mucus and subsequent intra-mucus drug payload release. In mice, micelles coated with mucoadhesive polymer enabled higher retention and enhanced curcumin (green) delivery to the small intestine. Reproduced with permission.[47] Copyright 2022, Elsevier B.V.. D) Negatively charged silica nanoparticles bind to integrin on intestinal epithelial cells, activate the myosin light chain kinase, and trigger the opening of tight junctions. Mice treated with anionic silica nanoparticles create cell clusters where the tight junction protein ZO-1 (red) is absent, indicating the opening of epithelial tight junctions in the dashed white area. Reproduced with permission.[55] Copyright 2019, Springer Nature. E) Prebiotics like inulin can be loaded in gel-based DDS to enhance drug delivery to microbiota and promote CD8+ T cell responses when combined with checkpoint blockade cancer immunotherapy in mice bearing CT26 colon carcinoma. Reproduced with permission.[58] Copyright 2021, Springer Nature.

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Prachi Desai, Anshuman Dasgupta, Alexandros Marios Sofias, Quim Peña, Robert Göstl, Ioana Slabu, Ulrich Schwaneberg, Thomas Stiehl, Wolfgang Wagner, Stefan Jockenhövel, Julia Stingl, Rafael Kramann, Christian Trautwein, Tim H. Brümmendorf, Fabian Kiessling, Andreas Herrmann, and Twan Lammers, Transformative Materials for Interfacial Drug Delivery, Adv. Healthcare Mater. 2023, 2301062, © 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH, DOI: 10.1002/adhm.202301062