Abstract
Materials that respond to endogenous stimuli are being leveraged to enhance spatiotemporal control in a range of biomedical applications from drug delivery to diagnostic tools. The design of materials that undergo morphological or chemical changes in response to specific biological cues or pathologies will be an important area of research for improving efficacies of existing therapies and imaging agents, while also being promising for developing personalized theranostic systems. Internal stimuli-responsive systems can be engineered across length scales from nanometers to macroscopic and can respond to endogenous signals such as enzymes, pH, glucose, ATP, hypoxia, redox signals, and nucleic acids by incorporating synthetic bio-inspired moieties or natural building blocks. This Review will summarize response mechanisms and fabrication strategies used in internal stimuli-responsive materials with a focus on drug delivery and imaging for a broad range of pathologies, including cancer, diabetes, vascular disorders, inflammation, and microbial infections. We will also discuss observed challenges, future research directions, and clinical translation aspects of these responsive materials.
Highlights
Materials that respond to endogenous stimuli are being leveraged to enhance spatiotemporal control in a range of biomedical applications from drug delivery to diagnostic tools
CX-072 enzyme-activatable antibody−drug conjugate PK1, pHPMA-GFLG-Dox conjugate PK2, pHPMA-GFLG-Dox conjugate with galactosamine targeting PNU166945, pHPMA-GFLG-Paclitaxel congugate Paclitaxel conjugate of poly(L-glutamic acid), lysosomal enzyme-mediated release (CT-2103/Xyotax/Opaxio) Adcetris, Brentuximab vedotin, VC peptide-linked CD30 antibody−drug conjugate computed X-ray tomography (CT)-2106-degradable conjugate of poly(L-glutamic acid), lysosomal enzyme-mediated camptothecin release DSTA4637S, anti-S. aureus antibody linked to antibiotic dmDNA31 through VC peptide linker Genexol-pm, mPEG-PDLLA-formulated Paclitaxel
Nucleic acid-responsive materials as diagnostic tools or therapeutic formulations that perform in vivo are complex systems requiring accurate characterization, the opportunity for precise programming of behavior makes them attractive targets for future research
Summary
Tuning the rate or location of drug delivery in the body helps to reduce adverse effects to large doses of therapeutics.[29−31] High doses are required in non-formulated or non-targeted systems in order to overcome pharmacological inefficiencies, but those come with increased toxicity or other side effects. Delivery systems of all sizes for drugs and imaging agents help avoid these problems by increasing spatial control (Figure 1) For macroscale systems this can be achieved through using local administration routes combined with materials or devices to retain the active agents at a particular site.[1,2] Another route to achieve spatial control is through particle design parameters such as size, shape, and stiffness, which can help particulate systems avoid immune recognition and localize to certain organs.[11,32] The ideal design approach would begin with a product profile with the desired target pathology and efficacy defined; this would determine how to proceed when choosing a route of administration and formulation dimension characteristics (conjugate, nanoparticle, microparticle, or macroscale depot). Long anisotropic particles such as tubular polymersomes,[64,65] peptide nanofibers,[66−69] and carbon nanotubes[70] can make significant differences in cell uptake biodistribution and treatment efficacy
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