Angiopep-2-conjugated poly(ethylene glycol)-<em>co</em>-poly(&epsilon;-caprolactone) polymersomes for dual-targeting drug delivery to glioma in rats

Abstract

The blood–brain barrier is a formidable obstacle for glioma chemotherapy due to its compact structure and drug efflux ability. In this study, a dual-targeting drug delivery system involving Angiopep-2-conjugated biodegradable polymersomes loaded with doxorubicin (Ang-PS-DOX) was developed to exploit transport by the low-density lipoprotein receptor-related protein 1 (LRP1), which is overexpressed in both blood–brain barrier and glioma cells. The polymersomes (PS) were prepared using a thin-film hydration method. The PS were loaded with doxorubicin using the pH gradient method (Ang-PS-DOX). The resulting PS were uniformly spherical, with diameters of ~135 nm and with ~159.9 Angiopep-2 molecules on the surface of each PS. The drug-loading capacity and the encapsulation efficiency for doxorubicin were 7.94%±0.17% and 95.0%±1.6%, respectively. Permeability tests demonstrated that the proton diffusion coefficient across the PS membrane was far slower than that across the liposome membrane, and the common logarithm value was linearly dependent on the dioxane content in the external phase. Compared with PS-DOX, Ang-PS-DOX demonstrated significantly higher cellular uptake and stronger cytotoxicity in C6 cells. In vivo pharmacokinetics and brain distribution experiments revealed that Ang-PS-DOX achieved a more extensive distribution and more abundant accumulation in glioma cells than PS-DOX. Moreover, the survival time of glioma-bearing rats treated with Ang-PS-DOX was significantly prolonged compared with those treated with PS-DOX or a solution of free doxorubicin. These results suggested that Ang-PS-DOX can target glioma cells and enhance chemotherapeutic efficacy.

Vinorelbine cationic liposomes modified with wheat germ agglutinin for inhibiting tumor metastasis in treatment of brain glioma

“…Surgical treatment, radiotherapy and chemotherapy are the most common method to treat glioma. Unfortunately, it is difficult to completely remove all the tumor cells for the infiltrative growth and the blurred boundary to normal brain tissue [33]. As a promising treatment, chemotherapy plays a crucial role in the prognosis after surgical treatment.…”

Peptide based drug delivery systems to the brain

“…Significant amount (47%) of drug released within two minutes after HIFU irradiation, causing apoptosis of tumour cells [106]. Methoxypolyethylene glycol (MPEG) and methoxypoly (ethylene glycol)-b-polycaprolactone (PCL) NPs, conjugated with angiopep-2 (CTFFYGGSRGKRNNFKTKRY) peptide with encapsulation efficiency of more than 95% showed higher in vivo accumulation in the brain [107].…”

Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke

“…The coupling efficiency of Angiopep-2 and PGP to PAMAM NPs was determined as described previously. 32 The drug loading efficiency (LE) and entrapment efficiency (EE) of Angiopep-2-PGP-STA-PEG-PAMAM NPs was assayed by UltiMate® 3000 DGLC HPLC. LE and EE were calculated by the following equations:…”