Folate-Targeted Anticancer Drug Delivery via a Combination Strategy of a Micelle Complex and Reducible Conjugation

Abstract

Conjugation of various active targeting ligands to the surface of nanocarriers to realize specific recognition by the corresponding receptors localized on the membrane of the cancer cells has provided a powerful means toward enhanced cancer therapy. Folic acid (FA) is one of the most used targeting ligands due to the overexpressed FA receptors in many cancer cell lines. However, conjugation of hydrophobic FA to the surface of nanocarriers usually alters the hydrophilic/hydrophobic balance of the stabilized nanoparticles, leading to their thermodynamic instability and subsequent formation of aggregates, which apparently compromises the in vivo long circulation and minimized side effects of nanocarriers. The currently leading strategy to overcome this issue is to incorporate a protecting hydrophilic stealth that can be deshielded to expose the targeting ligand at the desired tumor site, which generally involves multistep chemical modifications, conjugations, and purifications. To develop a simple alternative toward FA-mediated enhanced anticancer drug delivery, a combination strategy of micelle complex and reducible conjugation was reported in this study. FA was first conjugated to the terminus of the hydrophilic block of a reduction-sensitive miktoarm star-shaped amphiphilic copolymer, PCL3-SS-POEGMA1, with the previously optimized star structure by click coupling via a reducible disulfide link. The resulting PCL3-SS-POEGMA1-SS-FA was further mixed with the parent PCL3-SS-POEGMA1 to afford a micelle complex with both reducibly conjugated and relatively low amount of FA-targeting ligands toward excellent FA-mediated targeted drug delivery without compromised salt stability in vitro and in vivo. Therefore, the combined strategy developed herein provides a simple and powerful means to promote FA-mediated anticancer drug delivery.

Excretable, ultrasmall hexagonal NaGdF4:Yb50% Nanoparticles for bimodal imaging and radiosensitization

“…In several reported studies, folate-conjugated drug delivery systems have shown signi cant nuclear uptake. [80][81][82] Folic-acid modi ed silica nanoparticles (FAMSNs) with 100 nm diameter have been observed to accumulate in both the nuclei and the cytoplasm, while unmodi ed MSNs were found only in the cytoplasm, which con rmed the role of folic acid receptors in the nuclear uptake. [81] Presence of folic acid receptor α (FRα) in the nuclear membrane has been reported.…”

Excretable, ultrasmall hexagonal NaGdF4:Yb50% nanoparticles for bimodal imaging and radiosensitization

“…In several reported studies, folate-conjugated drug delivery systems have shown significant nuclear uptake (Goren et al 1949 ; Porta et al 2013 ; Wang et al 2020 ). Folic acid-modified silica nanoparticles (FAMSNs) with 100 nm diameter have been observed to accumulate in both the nuclei and the cytoplasm, while unmodified MSNs were found only in the cytoplasm, which confirmed the role of folic acid receptors in the nuclear uptake (Porta et al 2013 ).…”

Excretable, ultrasmall hexagonal NaGdF4:Yb50% Nanoparticles for bimodal imaging and radiosensitization

“…In several reported studies, folate-conjugated drug delivery systems have shown signi cant nuclear uptake. [71][72][73] Folic-acid modi ed silica nanoparticles (FAMSNs) with 100 nm diameter have been observed to accumulate in both the nuclei and the cytoplasm, while unmodi ed MSNs were found only in the cytoplasm, which con rmed the role of folic acid receptors in the nuclear uptake. [72] Presence of folic acid receptor α (FRα) in the nuclear membrane has been reported.…”