Folic acid (FA) residue is a well-known and widely spread targeting ligand, or biovector, used as a component in engineering artificial nanosized and submicron particles (NSPs) to target various cells and treat a variety of diseases that are associated with FA (or folate) receptors (FR) overexpression. A particular place in the list of these diseases is held by various cancer types, for which overexpression of FR on the cell surface is often accompanied by a more severe disease course, increased resistance to the conventional chemotherapy, and poorer prognosis. The incorporation of albumin into NSPs has been shown to enhance their biocompatibility, give high compatibility with drug molecules, prolong their circulation, reduce thrombogenic activity, and improve their colloidal stability. Nowadays albumin-based NSPs with FA residue as a targeting agent are used for chemotherapy, photothermal and photodynamic therapy, combined therapy, visualization, and theranostics (also known as theragnostics) for various types of cancer: breast, cervical, ovarian, prostate, nasopharyngeal, gastric, colorectal, liver cancer, and brain tumors. A limited number of studies have also focused on the use of NSPs in rheumatoid arthritis treatment. In this review, we discuss the ways of FA-albumin conjugation and conjugation of FA to albumin-modified NSPs systems. An application of nanosized and submicron delivery systems on the base of serum albumin and FA for therapy and diagnostics is discussed.

Background/Objectives: Magnetic iron oxide nanoparticles (IONPs), human serum albumin (HSA) and folic acid (FA) are prospective components for hybrid nanosystems for various biomedical applications. The magnetic nanosystems FA-HSA@IONPs (FAMs) containing IONPs, HSA, and FA residue are engineered in the study. Methods: Composition, stability and integrity of the coating, and peroxidase-like activity of FAMs are characterized using UV/Vis spectrophotometry (colorimetric test using o-phenylenediamine (OPD), Bradford protein assay, etc.), spectrofluorimetry, dynamic light scattering (DLS) and electron magnetic resonance (EMR). The selectivity of the FAMs accumulation in cancer cells is analyzed using flow cytometry and confocal laser scanning microscopy. Results: FAMs (d_N~55 nm by DLS) as a drug delivery platform have been administered to cancer cells (human breast adenocarcinoma MCF-7 and MDA-MB-231 cell lines) in vitro. Methylene blue, as a model photosensitizer, has been non-covalently bound to FAMs. An increase in photoinduced cytotoxicity has been found upon excitation of the photosensitizer bound to the coating of FAMs compared to the single photosensitizer at equivalent concentrations. The suitability of the nanosystems for photodynamic therapy has been confirmed. Conclusions: FAMs are able to effectively enter cells with increased folate receptor expression and thus allow antitumor photosensitizers to be delivered to cells without any loss of their in vitro photodynamic efficiency. Therapeutic and diagnostic applications of FAMs in oncology are discussed.

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.