Development of transferrin functionalized poly(ethylene glycol)/poly(lactic acid) amphiphilic block copolymeric micelles as a potential delivery system targeting brain glioma

Abstract

The aim of present study is to conceive a biodegradable poly(ethylene glycol)-polylactide (PEG-PLA) copolymer nanoparticle which can be surface biofunctionalized with ligands via biotin-avidin interactions and used as a potential drug delivery carrier targeting to brain glioma in vivo. For this aim, a new method was employed to synthesize biotinylated PEG-PLA copolymers, i.e., esterification of PEG with biotinyl chloride followed by copolymerization of hetero-biotinylated PEG with lactide. PEG-PLA nanoparticles bearing biotin groups on surface were prepared by nanoprecipitation technique and the functional protein transferrin (Tf) were coupled to the nanoparticles by taking advantage of the strong biotin-avidin complex formation. The flow cytometer measurement demonstrated the targeting ability of the nanoparticles to tumor cells in vitro, and the fluorescence microscopy observation of brain sections from C6 glioma tumor-bearing rat model gave the intuitive proof that Tf functionalized PEG-PLA nanoparticles could penetrate into tumor in vivo.

Novel multi-biotin grafted poly(lactic acid) and its self-assembling nanoparticles capable of binding to streptavidin

“…Although several studies have reported self-assembling NPs with attached biotin to the end of PLA via PEG or pluronic spacer, 5,6,10,12,13,[16][17][18] no study has reported more than one biotin incorporated into one PLA molecule to enhance its binding and potential targeting to streptavidin. In this study, three biotins were linked to one PLA with step by step graft reaction.…”

“…Biotin/(Strept)avidin are the most popular molecules used to ascribe it bioactivity. Although several studies have reported conjugating biotin with PEGblock-PLA or pluronic-block-PLA materials, which selfassemble into NPs and target to steptavidin in vitro, 5,6,10,12,13,[16][17][18] problems still exist: (1) no more than one biotin is attached to one PLA molecule, which limits the combination of NPs with streptavidin and their targeting function, and (2) the MW of PEG used is generally higher than 3800 in order to receive good protein resistance and self-assembly function of NPs. PEG cannot degraded in the body although it expresses low toxicity, 19 which limits applications of NPs.…”

“…For example, biotin-graft-PLA NPs can be used to target to acute and chronic inflammatory tissue, where selectins are localized and carefully regulated expressed by conjugation with biotinylated sialyl-Lewis X , a highly specific receptor for selectin via streptavidin arm, so as to reduce the gastrointestinal side effects such as ulcer caused by anti-inflammatory drugs. 32 Similarly NPs can target to brain glioma by conjugation with biotinylated transferrin, a monomeric glycoprotein with receptor that is overexpressed in brain capillary endothelium and at the surface of proliferating cells such as brain tumor cells, especially glioblastoma multiforme, 16 via a streptavidin arm. In addition, due to the appearance of biotin on outside biotin-graft-PLA NPs and the encapsulation for hydrophobic fluorescent naproxen and pyrene, the application of NPs in vivo detection system by way of fluorescent and optical imaging methods would be expected.…”

Recent advances in PEG–PLA block copolymer nanoparticles

“…Due to the hydrophilic chain of PEG, it can stay longer in the nasal cavity and facilitate nanoparticles through cell transit. Moreover, after linking modifiers of special biological activity in the PEG-PLA chain end, such as peptide, amino acid, and protein, [57][58][59] drugs in PEG-PLA nanoparticles can enter the brain through the blood-brain barrier.…”

Transferrin receptor-targeted vitamin E TPGS micelles for brain cancer therapy: preparation, characterization and brain distribution in rats

“…1 year) has not been significantly improved. The reduced efficacy of brain cancer chemotherapy is mainly attributed to the existence of blood-brain barrier (BBB), which limits the penetration of drug molecules into brain given systemically (Ren et al, 2010). Another obstacle is blood-tumor barrier (BTB), which hampers drug accumulation and uptake, results in poor drug accumulation in brain tumor (Cui et al, 2013).…”