Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry

Abstract

Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes. Through metabolic engineering, bioorthogonal groups can be tagged onto cell membranes, which selectively attach to cargos with paired groups via bioorthogonal reactions. Due to its simplicity, high efficiency, and specificity, bioorthogonal chemistry has demonstrated great application potential in drug delivery. On the one hand, bioorthogonal reactions improve therapeutic agent delivery to target sites, overcoming off-target distribution. On the other hand, nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions, providing approaches to developing multi-functional drug delivery systems (DDSs). In this review, we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups. We then highlight recent breakthroughs in developing active targeting DDSs to tumors, immune systems, or bacteria by bioorthogonal chemistry, as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs (biomimetic DDSs, cell-based DDSs, bacteria-based and phage-based DDSs) and hydrogels. Finally, we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery. We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.

Bioorthogonally Assisted Phototherapy: Recent Advances and Prospects

“…In case of the pyridazine product, a ten‐fold decrease in the IC 50 value was observed upon light irradiation (IC 50 1.92 μM (tetrazine) vs 0.212 μM (pyridazine)), enabling PDT on HeLa cells with metabolically bioorthogonalized DNA using 5‐vinyl‐2′‐deoxyuridine (VdU) (Figure 2a). Active targeting of overexpressed receptors (e.g., with aptamers, antibodies peptides or folates) enable precise delivery of PSs to tumor sites [45] . Nevertheless, these conjugates are moderately taken up by normal cells as most cancer‐associated receptors are not solely expressed on cancer cells.…”

Bioorthogonally Assisted Phototherapy: Recent Advances and Prospects

“…Active targeting of overexpressed receptors (e.g., with aptamers, antibodies peptides or folates) enable precise delivery of PSs to tumor sites. [45] Nevertheless, these conjugates are moderately taken up by normal cells as most cancer-associated receptors are not solely expressed on cancer cells. To circumvent this problem, dual receptor targeting was applied by Ng et al [46] In their recent work, a biotinylated BODIPY-tetrazine derivative (2) was internalized concurrently with a BCN-conju- gated epidermal growth factor receptor (EGFR)-targeting cyclic peptide.…”

Reversible Polymer–Protein Functionalization by Stepwise Introduction of Amine-Reactive, Reductive-Responsive Self-Immolative End Groups onto RAFT-Derived Polymers

“…For both variants, as it is often the case in the generation of reversible reductive-responsive protein–polymer conjugates, the presence of available sulfhydryl groups on the protein surface is an essential prerequisite. Therefore, the protein must either carry a nondimerized cysteine in native form, as in the case of BSA, , or they are artificially generated by chemical modification, whereby also biorthogonal click chemistry approaches are very helpful. − Another possibility is to install free cysteines by genetic engineering . However, these procedures are often very complex and ultimately lead to the fact that even after reductive release of the protein, parts of the modification still remain on the protein surface and can restrict its function.…”