Small, Smart, and LDLR-Specific Micelles Augment Sorafenib Therapy of Glioblastoma

Abstract

Targeted molecular therapy, for example, with sorafenib (SF) is considered as a new and potent strategy for glioblastoma (GBM) that remains hard to treat today. Several clinical trials with SF, as monotherapy or combination therapy with current treatments, have not met the clinical endpoints, likely as a result of the blood–brain barrier (BBB) and inferior GBM delivery. Here, we designed and explored small, smart, and LDLR-specific micelles to load SF (LDLR-mSF) and to improve SF therapy of GBM by enhancing BBB penetration, GBM accumulation, and cell uptake. LDLR-mSF with 2.5% ApoE peptide functionality based on poly­(ethylene glycol)-poly­(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate exhibited nearly quantitative SF loading, small size (24 nm), high colloidal stability, and glutathione-activated SF release. The in vitro and in vivo studies certified that LDLR-mSF greatly enhanced BBB permeability and U-87 MG cell uptake and caused 10.6- and 12.9-fold stronger anti-GBM activity and 6.0- and 2.5-fold higher GBM accumulation compared with free SF and non-LDLR mSF controls, respectively. The treatment of an orthotopic human GBM tumor model revealed that LDLR-mSF at a safe dosage of 15 mg of SF/kg significantly retarded tumor progression and improved the survival rate by inducing tumor cell apoptosis and inhibiting tumor angiogenesis. These small, smart, and LDLR-specific micelles provide a potential solution to enhance targeted molecular therapy of GBM.

Phenylboronic Acid-Functionalized Copolypeptides: Facile Synthesis and Responsive Dual Anticancer Drug Release

“…Sor as a kinase inhibitor can act on the RAF-MEK-ERK pathway that is often active in glioblastoma and closely associated with cell proliferation and tumor development. 25,26 Cur has been reported to affect reactive oxygen species and signal molecules like nuclear factor kappa B (NF-kB) as well as arrest the cell cycle at G2/M phase. 27 The introduction of Cur could overcome Sor resistance, and the simultaneous inhibition of ERK phosphorylation and NF-kB by Sor/Cur demonstrated synergistical anticancer effects in human hepatocellular carcinoma model.…”

“…have been developed or have entered clinical trials. − Here, the resultant PEG-PBPA diblock copolymer can self-assemble into nanoparticles in HEPES (pH 7.4) buffer, affording efficient co-encapsulation of both curcumin (Cur) and sorafenib tosylate (Sor) through dynamic boronic ester bonds, π–π stacking, and hydrophobic interactions (Scheme ). Sor as a kinase inhibitor can act on the RAF-MEK-ERK pathway that is often active in glioblastoma and closely associated with cell proliferation and tumor development. , Cur has been reported to affect reactive oxygen species and signal molecules like nuclear factor kappa B (NF-kB) as well as arrest the cell cycle at G2/M phase . The introduction of Cur could overcome Sor resistance, and the simultaneous inhibition of ERK phosphorylation and NF-kB by Sor/Cur demonstrated synergistical anticancer effects in human hepatocellular carcinoma model .…”

Introducing SuFEx click chemistry into aliphatic polycarbonates: a novel toolbox/platform for post-modification as biomaterials

“…63–66 Therefore, as long as a suitable combination of hydrophilic PEG chain segments and hydrophobic pFMCs can be identified, it is feasible to achieve self-assembly into micelles/vesicles, which will expectably enable drug delivery applications. 67–69 As shown in Scheme S6b (ESI†), pFMC-mPEG was synthesized by the SuFEx click reaction of pFMC and silyl ether-protected polyethylene glycol monomethyl ether (TBDMS-mPEG), which was verified by 1 H NMR and GPC (Fig. S16, ESI†).…”

Near infrared-activatable biomimetic nanogels enabling deep tumor drug penetration inhibit orthotopic glioblastoma

“…4a ). The enhanced BBB permeability through ApoE peptide functionalization was resulted from their high binding affinity with low density lipoprotein (LDL) receptors that were overexpressed in bEnd.3 cells 43 , 44 . Notably, NIR irradiation did not affect the transport of ARNGs across the mimic BBB layer (Supplementary Fig.…”