Co-Opting Host Receptors for Targeted Delivery of Bioconjugates-From Drugs to Bugs

Abstract

Bioconjugation has allowed scientists to combine multiple functional elements into one biological or biochemical unit. This assembly can result in the production of constructs that are targeted to a specific site or cell type in order to enhance the response to, or activity of, the conjugated moiety. In the case of cancer treatments, selectively targeting chemotherapies to the cells of interest limit harmful side effects and enhance efficacy. Targeting through conjugation is also advantageous in delivering treatments to difficult-to-reach tissues, such as the brain or infections deep in the lung. Bacterial infections can be more selectively treated by conjugating antibiotics to microbe-specific entities; helping to avoid antibiotic resistance across commensal bacterial species. In the case of vaccine development, conjugation is used to enhance efficacy without compromising safety. In this work, we will review the previously mentioned areas in which bioconjugation has created new possibilities and advanced treatments.

Keywords: antibiotics; antibody–drug conjugates; bioconjugation; conjugated vaccines; drug delivery; nanoparticles; targeted vaccines; vaccines.

Figure 1

Schematic of targeted conjugate vaccines. (a) A plasmid encoding a protein subunit conjugate is transfected into mammalian cells which secrete the fusion protein for subsequent purification and administration as a vaccine. Modeled after HA targeting to Xcr1 on DCs [44]. (b) A plasmid encoding a peptide carrier and capsular PS synthases is transformed into an oligosachride transferase (OTase)—engineered strain of E. coli which assembles the glycoconjugate which is subsequently purified for use as a vaccine. Modeled after production of a Kp capsular PS-Pa exotoxin A glycoconjugate vaccine [46]. (c) NPs are chemically activated to facilitate conjugation of Ag; loaded NPs are then administered as the vaccine. Modeled after activated amines to conjugate Pfs25 and generate a malaria vaccine [47]. (d) Glycoconjugate vaccines produced by chemically activating a peptide carrier, linking the purified components, and administering the conjugate as a vaccine. Modeled after generation of the meningitis vaccine [45]. (e) A plasmid encoding a targeted protein subunit conjugate that is anchored to an OMP is transformed into bacteria which are administered as a live vaccination. The conjugate protein is trafficked to the OM and cleaved from the OMP anchor. Modeled after CR-targeted Ts Ag, produced by the engineered Salmonella vaccine strain [52]. (f) A plasmid encoding an OMP-anchored conjugate (lacking a cleavage site) is expressed in bacteria, effectively targeting the whole bacterial cell to immune cells when administered as a vaccine. Modeled after targeting Ft to CRs [51].