ed the significance of NO synthesis in the retention of DOX in cancer cells and have located that NO inhibits P-gp’s activity by nitration with the critical tyrosine residues in its chemical structure (Chegaev et al., 2011). In additional research, NO donating DOX prodrugs have been actively delivered to MDR cancer cells by light-induced NO release (stimuli responsive intelligent delivery) and also a folic acid immobilized carrier (active targeting) (Gazzano et al., 2018) for enhanced spatial handle release. DOX has been derivatized with 4-nitro-3-(trifluoromethyl)aniline to impart Coccidia drug photosensitivity. The photosensitive prodrug, when excited with visible light (wavelength 400 nm), releases NO in tumors (Chegaev et al., 2017). 3.three. Mitochondrial targeting for MDR reversal ALK6 custom synthesis mitochondria carry out a central function in cancer cell multiplication and metastasis (Farnie et al., 2015). As cancer cells create MDR, the consumption of ATP increases manyfold. To meet these improved needs, MDR cancer cells have greater mitochondrial membrane prospective, much more mitochondrial bulk, and larger metabolic prices (Henkenius et al., 2017). The dysfunctional mitochondria alter cellular metabolism inside the cells, thus playing a crucial function in anti-apoptotic defense mechanisms in cancer cells (Griguer and Oliva, 2011). The extra polarized mitochondria are an appealing target to counter MDR in cancer cells (Galluzzi et al., 2006). Nevertheless, penetrating the mitochondria is challenging, since their internal hydrophobic membrane acts as a barrier for the diffusion of the therapeutic moieties. Lipid-conjugated cationic peptides can cross this barrier (Fernndez-Carneado et al., a 2005). Cationic molecules are attracted towards the hyperpolarized mitochondrial membrane potential. 1 such lipid-conjugated cationic peptide was created by Horton and co-workers, that have utilized arginine (A) and lysine (L) to impart a good charge around the conjugate; meanwhile, phenylalanine (P) and cyclohexyl alanine (C) supply the required hydrophobicity for membrane permeation. The peptide with all the amino acid sequence (CACLCACL) has demonstrated the highest mitochondrial internalization in MCF-7 BC cell lines (Horton et al., 2008). Lately, Czupiel and co-workers have explored the anti-mitochondrial and ultimately P-gp inhibiting ability of vitamin E succinate modifiedTable 5 List of numerous ligands utilized for site-specific delivery of chemotherapeutic agents and P-gp inhibitors in drug-resistant BC.Ligand Nanoformulation Therapeutic positive aspects Reference Pan et al. (2020)The targeted mesoporous silica NPs demonstrated superior internalization by the MDA-MB-231 cells in vitro. Actively targeted NPs Hyaluronic QUE and DO co-loaded accumulated inside the acid PLGA-polyethyleneimine breast tumor and NPs lungs. Hyaluronic QUE and DOX co-loaded HA-mediated targeting acid D–tocopheryl showed superior therapeutic activity, polyethylene glycol such as a two.95-fold succinate micelles decline inside the IC50 worth, accumulation of DOX in the nuclei, and increased apoptosis. Hyaluronic PTX-loaded DThe micelles exhibited acid high internalization -tocopheryl and cytotoxicity in polyethylene glycol MCF-7/ADR cells in succinate micelles vitro and in vivo. Transferrin receptor 1-mediated endocytosis The conjugate 7pep Transferrin receptor-1demonstrated high targeted 7pep-conjuselectivity for tumor gated hybrid peptide cells, with 72.two four.six composed of an inhibition within the extracellular signalxenografts in vivo. regulated kinase inhibit