Applications of Diels-Alder Chemistry in Biomaterials and Drug Delivery.

Recent studies, leveraging click chemistry reactions, have significantly advanced the fields of biomaterials and drug delivery. Of these click reactions, the Diels-Alder cycloaddition is exceptionally valuable for synthetic organic chemistry and biomaterial design, as it occurs under mild reaction conditions and can undergo a retrograde reaction, under physiologically relevant conditions, to yield the initial reactants. In this review, potential applications of the Diels-Alder reaction are explored within the nexus of biomaterials and drug delivery. This includes an emphasis on key platforms such as polymers, nanoparticles, and hydrogels which utilize Diels-Alder for drug delivery, functionalized surfaces, bioconjugation, and other diverse applications. Specifically, this review will focus on the use of Diels-Alder biomaterials in applications of tissue engineering and cancer therapies, while providing a discussion of the advantages, platforms, and applications of Diels-Alder click chemistry.

Near-Infrared Induced miR-34a Delivery from Nanoparticles in Esophageal Cancer Treatment.

Current nucleic acid delivery methods have not achieved efficient, non-toxic delivery of miRNAs with tumor-specific selectivity. In this study, a new delivery system based on light-inducible gold-silver-gold, core-shell-shell (CSS) nanoparticles is presented. This system delivers small nucleic acid therapeutics with precise spatiotemporal control, demonstrating the potential for achieving tumor-specific selectivity and efficient delivery of miRNA mimics. The light-inducible particles leverage the photothermal heating of metal nanoparticles due to the local surface plasmonic resonance for controlled chemical cleavage and release of the miRNA mimic payload. The CSS morphology and composition result in a plasmonic resonance within the near-infrared (NIR) region of the light spectrum. Through this method, exogenous miR-34a-5p mimics are effectively delivered to human squamous cell carcinoma TE10 cells, leading to apoptosis induction without adverse effects on untransformed keratinocytes in vitro. The CSS nanoparticle delivery system is tested in vivo in Foxn1nu athymic nude mice with bilateral human esophageal TE10 cancer cells xenografts. These experiments reveal that this CSS nanoparticle conjugates, when systemically administered, followed by 850 nm light emitting diode irradiation at the tumor site, 6 h post-injection, produce a significant and sustained reduction in tumor volume, exceeding 87% in less than 72 h.

Controlled Degradation of Polycaprolactone Polymers through Ultrasound Stimulation.

This study describes the development of an ultrasound-responsive polymer system that provides on-demand degradation when exposed to high-intensity focused ultrasound (HIFU). Diels-Alder cycloadducts were used to crosslink polycaprolactone (PCL) polymers and underwent a retro Diels-Alder reaction when stimulated with HIFU. Two Diels-Alder polymer compositions were explored to evaluate the link between reverse reaction energy barriers and polymer degradation rates. PCL crosslinked with isosorbide was also used as a non-Diels-Alder-based control polymer. An increase of HIFU exposure time and amplitude correlated with an increase of PCL degradation for Diels-Alder-based polymers. Ultrasound imaging during HIFU allowed for real-time visualization of the on-demand degradation through cavitation-based mechanisms. The temperature surrounding the sample was monitored with a thermocouple during HIFU stimulation; a minimal increase in temperature was observed. PCL polymers were characterized using Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), optical profilometry, and mechanical testing. PCL degradation byproducts were identified by mass spectrometry, and their cytocompatibility was evaluated in vitro. Overall, this study demonstrated that HIFU is an effective image-guided, external stimulus to control the degradation of Diels-Alder-based PCL polymers on-demand.