Chemical Conjugation in Drug Delivery Systems

Abstract

Cancer is one of the diseases with the highest mortality rate. Treatments to mitigate cancer are usually so intense and invasive that they weaken the patient to cure as dangerous as the own disease. From some time ago until today, to reduce resistance generated by the constant administration of the drug and improve its pharmacokinetics, scientists have been developing drug delivery system (DDS) technology. DDS platforms aim to maximize the drugs' effectiveness by directing them to reach the affected area by the disease and, therefore, reduce the potential side effects. Erythrocytes, antibodies, and nanoparticles have been used as carriers. Eleven antibody-drug conjugates (ADCs) involving covalent linkage has been commercialized as a promising cancer treatment in the last years. This review describes the general features and applications of DDS focused on the covalent conjugation system that binds the antibody carrier to the cytotoxic drug.

Keywords: biomolecules; carriers; covalent bioconjugation; drug delivery systems; linkers.

FIGURE 1

Drug delivery system (DDS) components.

FIGURE 2

(A) Biotinylation reagents general structure. The reagent shown is NHS-LC-biotin, (B) a streptavidin-biotin technique using RBC as a carrier.

FIGURE 3

Conjugation of Escherichia coli L-asparaginase-II (ASNase) with copies of glycophorin A-binding peptide (ERY1). (A) Chemical conjugation between Lys residues of ASNase and peptide ERY1 using SMCC as a linker, (B) high-affinity binding of ASNase to erythrocytes through chemical conjugation of several copies of glycophorin A–binding peptide (ERY1).

FIGURE 4

Strategies of conjugation for DDS based on the modified nanoparticle surface.

FIGURE 5

(A) General liposome formation. (B) The general structure of DDS is based on functionalized liposomes.

FIGURE 6

Pegylation of L-asparaginase to obtain a nanotherapeutic product Oncaspar^®.

FIGURE 7

(A) Structures of the drug (MMAE) and mAb-drug conjugate. (B) Conjugation of the humanized anti-hapten monoclonal antibody (mAb) h38C2 through nucleophilic lysine with β-lactam derivatives (i.e., β-lactam functionalized monomethyl auristatin F (MMAF).

FIGURE 8

General structures of ADC’ are approved by the FDA. (A) Adcetris^®, Polivy^®, Padcev^®, and Tivdak^®. (B) Kadcyla^®. (C) Besponsa^® and Mylotarg^®. (D) Enhertu^®. (E) Blenrep^®. (F) Trodelvy^®. (G) Zynlonta^®. All linkers are highlighted in red.

FIGURE 9

(A) Lipid-Lipid and lipid-oligosaccharide conjugates. (B) Oligosaccharide-steroid conjugates: Steroid-carbohydrate conjugates by multicomponent conjugation (MCC) of oligosaccharide to steroidal isocyanides. The most important covalent bond between entities is highlighted in red.

FIGURE 10

Peptide-peptide and carbohydrate peptide conjugation. (A) The final product of diastereoselective multicomponent ligation (MCL) of peptide and sugar residues to chiral bifunctional building blocks, (B) final product of MLC of urea-peptide, a lipid, and aminoribosyl-5-C-glycyludrine. The most important covalent bond between entities is highlighted in red.

FIGURE 11

Peptide-steroid conjugation. Multicomponent conjugation (MCC) of two peptide fragments previously linked to the steroid to construct a unique N-steroidal cyclopeptide.

FIGURE 12

Peptide-steroid and peptide-lipid conjugates. (A) Solid phase ligation (SPL) of lipids and steroids by resin-bound peptide (RBP) using on-resin Ugi reaction, (B) double ligation by Ugi reaction, (C) SPL of lipids, biotinylated steroids by RBP using on-resin Ugi azide reaction. The most important covalent bond between entities is highlighted in red.

FIGURE 13

(A) Peptide-steroid and peptide-lipid conjugates. Products of simultaneous cyclization and lipidation of peptides by Ugi and Passerini reactions. (B) The pattern of the product was obtained using resin Ugi-smiles macrocyclization and ligation.

FIGURE 14

Protein immobilization, labeling, and glycoconjugate (A) Ugi-derived polymer-supported glycoenzyme; (B) final products from multicomponent conjugation (MCC) to polymeric support (see Panel (A)) and fluorescent label (rhodamine B) and carbohydrate (β-D-glucosides) using Ugi reaction; (C) multicomponent immobilization (MCI) of horseradish peroxidase (HRP) on a polysaccharide-coated gold electrode; (D) site-selective protein labeling at Tyr residue by Mannich type MCC; (E). Site-selective protein labeling at only one Lys residue by Cu-catalyzed A3 coupling MCC. The most important covalent bond between entities is highlighted in red.

FIGURE 15

Final products obtained from protein immobilization, labeling, and glycoconjugate through (A) multicomponent conjugation (MCC) of oxo-functionalized capsular polysaccharide (CP) to nonactivated diphtheria (DT) and tetanus toxoids (TT); (B) hydrazide-activated DT and TT (DDa or TTa), and (C) MCC of two CPs to hydrazide-activated TT for the obtention of multivalent glycoconjugate vaccines. The most important covalent bond between entities is highlighted in red.