# Folate-Functionalized Albumin-Containing Systems: Non-Covalent vs. Covalent Binding of Folic Acid

## TL;DR

This review compares covalent and non-covalent binding of folate to albumin in nano/submicron particles for drug delivery and targeting in disease treatment.

## Contribution

The paper provides a detailed analysis of binding methods and structural modifications of albumin in folate-functionalized systems.

## Key findings

- Covalent and non-covalent binding methods affect the stability and targeting efficiency of folate-albumin systems.
- Albumin's conformational state and amino acid residues are crucial for effective folate binding and functionality.
- Binding conditions and physicochemical methods influence the formation and performance of folate-albumin-NSPs.

## Abstract

Nano- and submicron particles (NSPs) with folate for targeting are actively used for the treatment and diagnosis of cancer and inflammatory diseases. Albumin-containing systems have enhanced biocompatibility, circulation time, and colloidal stability, which are important for medical applications. The outstanding binding properties of albumin allow the transport of numerous therapeutic and/or imaging agents. This review summarizes multiple aspects of binding a folate residue (or folic acid) to NSPs and the functioning of folate-albumin-NSPs. Special attention in the review is given to the types of bonds between folic acid and albumin, i.e., covalent and non-covalent, and to the confirmation and quantification of binding by different physicochemical methods. The process of binding, the qualitative and quantitative characteristics of binding and forming product, and its functioning are interconnected with the binding conditions; thus, an analysis of reaction conditions is provided. For the proper functioning of folate-albumin-NSPs, the state of albumin within them is important; thus, considerable focus in the review is placed on the features of structure modification of serum albumin in folate-albumin binding, i.e., the amino acid residues involved in this process and the conformational state of the protein. The stability and the functioning of the protein within folate-albumin-NSPs are discussed. Also, the effectiveness of targeting by folate is viewed as dependent on many characteristics of folate-albumin-NSPs, particularly on the peculiarities of binding between the folic acid residue and albumin. Furthermore, the authors discussed and suggested solutions concerning the shortcomings highlighted in the studies devoted to obtaining folate-modified albumin-containing NSPs.