Opportunities and Challenges of Switchable Materials for Pharmaceutical Use

Abstract

Switchable polymeric materials, which can respond to triggering signals through changes in their properties, have become a major research focus for parenteral controlled delivery systems. They may enable externally induced drug release or delivery that is adaptive to in vivo stimuli. Despite the promise of new functionalities using switchable materials, several of these concepts may need to face challenges associated with clinical use. Accordingly, this review provides an overview of various types of switchable polymers responsive to different types of stimuli and addresses opportunities and challenges that may arise from their application in biomedicine.

Keywords: controlled drug-release systems; smart materials; stimuli-sensitive polymers; switchable polymers.

Figure 16

Enzymatic cleavage for disassembly of carrier systems. (A) Cleavage of cephalosporine junction by bacterial β-lactamase for hydrogel destruction. Reprinted with permission from [215]. Copyright 2022, American Chemical Society. (B) Cleavage of azobenzene-linked poly(ethylene glycol)-b-poly(styrene) (PEG-N=N-PS) amphiphilic copolymer causing micellar disassembly by azoreductase in the presence of NADPH. Reprinted with permission from [219]. Copyright 2013, American Chemical Society. (C) Cleavable amphiphilic peptide (Arg-His-(Gly-Phe-Lue-Gly)₃ (RH-(GFLG)₃) with GFLG sequences sensitive to intracellular cathepsin B. Reprinted from [228]; licensed under Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/), © 2022 by the authors.

Figure 1

Schematic illustration of switchable drug-release systems. The release of therapeutics is triggered from a model drug carrier by exposure to the respective stimulus/stimuli, including temperature, enzymes, light, ultrasound, magnetic field, or small molecules such as glucose.

Figure 2

Schematic structure of selected thermoresponsive polymers that show an LCST. PNIPAAm: poly(N-isopropylacrylamide), PDEAAm: poly(N,N-diethylacrylamide), PDMAEMA: poly[2-(dimethylamino)ethyl methacrylate], PVME: poly(vinyl methyl ether), PEO-PPO-PEO: poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) with the international nonproprietary name Poloxamer, PVCL: poly(N-vinylcaprolactam), PAOx: poly(2-alkyl-2-oxazoline).

Figure 3

(A) Schematic illustration of the structure and switching capability of shell-crosslinked micelles from block copolymers of polymethyl methacrylate and poly(N-isopropylacrylamide-co-N-acryloxysuccinimide). (B,C) Temperature-controlled alteration of drug release from the micelles in aqueous solution was accompanied with shift in the particle size distribution upon heating. Reprinted from [55], © 2022 Elsevier B.V. All rights reserved, with permission from Elsevier.

Figure 4

Curcumin release from crosslinked thermoresponsive poly(N-isopropylacrylamide-co-N-methylolacrylamide) fibers. (A) Fiber mesh prepared via electrospinning. (B) Release pattern at 37 °C. (C) Stepwise release pattern at alternating temperatures. Reprinted from [56], © 2022 Elsevier B.V. All rights reserved, with permission from Elsevier.

Figure 5

On-demand release pulse or on-demand release initiation from shape memory tubes (SMT), which switch due to heat (direct exposure or indirectly through NIR light) to smaller inner diameters and expel a hydrogel loaded with the protein of interest. Data originating from [72], © 2022 Elsevier B.V. All rights reserved, with permission from Elsevier.

Figure 6

Chemical structures of selected photochromic molecules. (A) Moieties shifting their hydrophobicity/hydrophilicity balance and/or orientation upon irradiation. (B) Exemplary moieties that undergo photocleavage/photocoupling upon irradiation.

Figure 7

Azobenzene-based photoswitches combined with upconversion nanoparticles (UCNP; NaYF₄:Tm,unYb functionalized with polyacrylic acid (PAA)) to release doxorubicin after dissociation of surface-bound DNA strands. (a) Principles of the assembly of components to form the particle cores. (b) Surface conjugation of TAT and HA coating. (c) HA-mediated cell binding and subsequent endocytosis. LA_AZO/LC_AZO: DNA strand with AZO moieties; LB: DNA strand; DOX: doxorubicin intercalated between the DNA strands; HA: anionic hyaluronic acid for triggered endocytosis; HAase: hyaluronidase; TAT: nuclear localization peptide. Reprinted with permission from [93], © 2022 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 8

Dissociation of vesicles after photocleavage of nitrobenzyl (NB) moieties. (A) Cleavage of NB linker in amphiphilic shell causes dissociation of polymersome and compound release (hydrophobic dye). Used with permission of Royal Society of Chemistry, from [99]; permission conveyed through Copyright Clearance Center, Inc. (B) Cleavage of nitrobenzyl succinate side chain induces pH-dependent charge repulsion between polyethyleneimine (PEI) segments and micelle dissociation for compound release. Reprinted from [83]; licensed under Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/), © 2022 by the authors.

Figure 9

Magnetically induced drug-release system combining effects of hyperthermia and drug action. (A) Scheme of mesoporous silica particles with a mixed coating of PEG-SPION and PNIPAAm chains, the latter collapsing upon heating via alternating magnetic fields (AMF). (B) Temperature dependency of levofloxacin release in vitro. (C) In vitro release of levofloxacin at 37 °C with and without application of AMF. (D,E) Concept and data for the eradication of E. coli biofilms in vitro by hyperthermia vs. hyperthermia + levofloxacin (L) release. Reprinted from [147]; licensed under Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/), © 2022 by the authors.

Figure 10

Stepwise shape-recovery and release of copper sulfate as a model compound from temperature-sensitive amorphous SMP networks from poly[(methyl methacrylate)-co-(butyl acrylate)]. High-intensity focused ultrasound (HIFU) was applied as non-contact stimulus that indirectly creates heat. Modified with permission of Royal Society of Chemistry, from [73]; permission conveyed through Copyright Clearance Center, Inc.

Figure 11

Schematic illustration of pH levels in the body (A) in the gastrointestinal tract and (B) at the cell level (a prototypical mammalian cell).

Figure 12

pH-triggered drug-delivery systems for doxorubicin (DOX) based on cleavable bonds in different positions based on (A,B) hydrazone and (C,E) imine links. (A) Scheme of DOX coupling to hyperbranched double-hydrophilic block copolymer (PEO-hb-PG-DOX), its micellar assembly, and intracellular drug release. (B) DOX release profiles under different pH conditions. Reprinted with permission from [190]. Copyright 2012, American Chemical Society. (C) Scheme of DOX coupling to dextran (dex) and proposed mode of action of ~23 nm-sized particulate aggregates. (D) pH-dependent DOX release in vitro. (E) Tumor volume of B16F10 melanoma-grafted BALB/c mice treated with free DOX, DOX-dextran nanoparticles, or PBS as control. Reprinted from [192]. Copyright 2017, with permission from Elsevier.

Figure 13

Illustrative scheme of mRNA-loaded micelle sensitive to environmental pH due to cleavable amide bonds. Vehicle formation includes covalent crosslinking of CAA (cis-aconitic anhydride) and pLL (poly(L-lysine)) in micelle cores and electrostatic interaction between mRNA and pLL. Reprinted from [196]; licensed under Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/), © 2022 by the authors.

Figure 14

Designer polyplexes comprising polycations built from charged artificial oligomers with efficient siRNA-binding capability, and grafting with PEG for shielding and with folate for receptor-mediated cellular uptake. siRNA can be bound in polyplexes of defined size via ionic interaction and can be used as conjugate with an endosomolytic peptide (herein, influenza peptide Inf7). Adapted with permission from [199], Copyright © 2022 American Chemical Society.

Figure 15

pH-sensitive nanogels from poly(2-aminoethyl methacrylate hydrochloride)-2,4-dimethylmaleic anhydride (PAMA–DMMA) with charge conversion. (A) Scheme of proposed action of PAMA–DMMA nanogels that are negatively charged in the blood, leak into tumor sites due to the EPR effect, and experience charge conversion to positive charge in the acidic tumor environment, which may enhance cellular internalization. (B) pH-dependent cumulative DOX release profiles from the PAMA–DMMA nanogels in vitro. (C) Cell viability of MDA-MB-435s cells after incubation with DOX-loaded PAMA–DMMA and free DOX at the same DOX concentration. Reprinted with permission from [203], 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 17

Main principles of glucose sensing for on-demand insulin release via enhanced diffusivity out of hydrogel matrices. (A) pH-responsive polymer hydrogels including glucose oxidase (GOx) as sensor, which oxidizes glucose to gluconic acid, causing a pH change, and thus, swelling of the network. (B) Competitive binding of free glucose to Con A leads to network loosening. (C) Covalent binding of glucose to boronic acid leads to netpoint destruction and gel–sol phase transition. Various systems based on these principles have been reported, some of which include a second network structure with covalent links not shown here for didactic reasons.

Figure 18

Schematic concepts of responsive release systems with switches based on antigen–antibody affinity. (A,B) Hydrogels network architectures resulting in (A) non-reversible and (B) reversible responses (gel swelling) upon exposure to the antigen (here rabbit IgG was used as antigen). Reprinted with permission from [265]. Copyright 2009, Wiley Periodicals, Inc. (C,D) Permeation pattern of a drug through an antigen–antibody membrane in response to the (C) absence and (D) presence of a target antigen. Reprinted with permission from Springer Nature Customer Service Center GmbH: Springer Nature [264], Copyright © 2022, The Society of Polymer Science, Japan.