Modular Nanotransporters for Targeted Intracellular Delivery of Drugs: Folate Receptors as Potential Targets

Abstract

The review is devoted to a subcellular drug delivery system, modular nanotransporters (MNT) that can penetrate into target cells and deliver a therapeutic into their subcellular compartments, particularly into the nucleus. The therapeutics which need such type of delivery belong to two groups: (i) those that exert their effect only when delivered into a certain cell compartment (like DNA delivered into the nucleus); and (ii) those drugs that are capable of exerting their effect in different parts of the cells, however there can be found a cell compartment that is the most sensitive to their effect. A particular interest attract such cytotoxic agents as Auger electron emitters which are known to be ineffective outside the cell nucleus, whereas they possess high cytotoxicity in the vicinity of nuclear DNA through the induction of non-reparable double-strand DNA breaks. The review discusses main approaches permitting to choose internalizable receptors permitting both recognition of target cells and penetration into them. Special interest attract folate receptors which become accessible to blood circulating therapeutics after malignant transformation or on activated macrophages which makes them an attractive target for both several oncological and inflammatory diseases, like atherosclerosis. In vitro and in vivo experiments demonstrated that MNT is a promising platform for targeted delivery of different therapeutics into the nuclei of target cells.

Modular Nanotransporters for Nuclear-Targeted Delivery of Auger Electron Emitters

“…These features of FRs made them a widely exploited target (Lu and Low, 2012; Xie et al, 2016; Srinivasarao and Low, 2017). The list of diseases with abnormal cells characterized by overexpression and/or accessibility of FRs includes several types of cancer and a group of diseases that are characterized by inflammation, e.g., rheumatoid arthritis, atherosclerosis, and Crohn’s disease (Slastnikova et al, 2015, 2017b). …”

“…This review focuses on MNT delivery of AEEs; delivery of photosensitizers and other molecules by MNTs has been reviewed earlier (Sharman et al, 2004; Glover, 2012; Simoes et al, 2015; Slastnikova et al, 2015; Ulasov et al, 2018). …”

Development and evaluation of a new modular nanotransporter for drug delivery into nuclei of pathological cells expressing folate receptors

“…One promising approach to provide this is the use of lesion-specific surface cell receptors or antigens as a target for therapeutics 1. Folate receptors (FRs), which are frequently overexpressed and accessible to blood-circulating agents either upon malignant transformation of the cell or upon activation of macrophages in contrast to their negligible exposure to the blood pool in normal tissues and non-activated macrophages, are among the best known and recognized types of these target antigens;1–4 FRs are prospective surface receptors for targeting numerous diseases, mainly several types of cancer and a broad group of significant inflammatory conditions including, but not limited to, rheumatoid arthritis,5,6 atherosclerosis,7 Crohn’s disease,8 and some other conditions.…”

Targeted delivery of in situ PCR-amplified Sleeping Beauty transposon genes to cancer cells with lipid-based nanoparticle-like protocells

“…Then, the protocells were modified with two active targeting moieties. One is folic acid (FA) containing polyethylene glycol-distearoylphosphatidylethanolamine (FA-PEG-DSPE), which enables the FA motif to be exposed on the surface of the protocells for increasing the cellular uptake of transposons gene [16]. Another is dexamethasone (DEX), which was embedded in the hydrophobic bilayer and employed as a nuclear localization signaling molecule for improving the nuclear translocation of transposons to favor the insertion of transgenes into the host genome [17].…”