Folate receptor‐targeted aminoglycoside‐derived polymers for transgene expression in cancer cells

Abstract

Targeted delivery of anticancer therapeutics can potentially overcome the limitations associated with current chemotherapeutic regimens. Folate receptors are overexpressed in several cancers, including ovarian, triple‐negative breast and bladder cancers, making them attractive for targeted delivery of nucleic acid therapeutics to these tumors. This work describes the synthesis, characterization and evaluation of folic acid‐conjugated, aminoglycoside‐derived polymers for targeted delivery of transgenes to breast and bladder cancer cell lines. Transgene expression was significantly higher with FA‐conjugated aminoglycoside‐derived polymers than with Lipofectamine, and these polymers demonstrated minimal cytotoxicty. Competitive inhibition using free folic acid significantly reduced transgene expression efficacy of folate‐targeted polymers, suggesting a role for folate receptor‐mediated uptake. High efficacy FA‐targeted polymers were employed to deliver a plasmid expressing the TRAIL protein, which induced death in cancer cells. These results indicate that FA‐conjugated aminoglycoside‐derived polymers are promising for targeted delivery of nucleic acids to cancer cells that overexpress folate receptors.

Bifunctionally engineered polyethylenimines as efficient DNA carriers and antibacterials against resistant pathogens

“…Buffering capacity plays an important role, which actually depicts the release of vector-pDNA complexes in the cytoplasm after endocytosis. 38–40 Here, in the present study, after conjugation of aminoglycoside with bPEIs, the buffering capacity of the resulting conjugates decreased as compared to bPEI. It is quite evident from Figure 4 that the PEI-streptomycin conjugates required lower volume of 0.1 N HCl to bring a change in pH from 10.0 to 3.0 as compared to bPEI.…”

“…Since the aminoglycosides have already been approved by FDA, researchers have further incorporated modifications to enable them to carry genetic therapeutics inside the cells effectively and exhibit high levels of transgene expression. [33][34][35][36][37] Besides, these carriers also offer an added advantage of taking care of any infection during immunity compromising treatment of patients. Most of the aminoglycosides possess abundant hydroxyl and amino functionalities attached to sugar moieties which are amenable to modification/derivatization.…”

Functional Nanomedicines for Targeted Therapy of Bladder Cancer

“…Two mechanisms of FA uptake have been identified: 1) reduced folate carrier (RFC1) promotes endocytosis of folic acid in a reduced form by cells and 2) high-affinity folate receptor recognizes folic acid and promotes its oxidation by cells through receptor mediation. Folic acid that enters the cell through this pathway is released into the cytoplasm through endosomal acidification ( Godeshala et al, 2016 ). FR has been shown to be overexpressed in a number of human tumor types, including triple-negative breast cancer, ovarian cancer, and non-small cell lung cancer.…”

Strategies for the enhanced intracellular delivery of nanomaterials

“…Thus, modifying the surface of nanomaterials with particular ligands is one way to improve their cellular uptake and endosomal escape [39]. Table 2 summarizes receptors targeted in this approach, including CD31, integrin b3 and transferrin [122], TLR2, TLR3 and TLR9 [123], avb3 integrin [119], transferrin [124], EGFR [125], CD44 [126], IGFR [127],FcRn [128], CD163 [129], biotin [130], folate [131], and vitamin B 12 [132].…”