Penetration of blood–brain barrier and antitumor activity and nerve repair in glioma by doxorubicin-loaded monosialoganglioside micelles system

Abstract

For the treatment of glioma and other central nervous system diseases, one of the biggest challenges is that most therapeutic drugs cannot be delivered to the brain tumor tissue due to the blood–brain barrier (BBB). The goal of this study was to construct a nanodelivery vehicle system with capabilities to overcome the BBB for central nervous system administration. Doxorubicin as a model drug encapsulated in ganglioside GM1 micelles was able to achieve up to 9.33% loading efficiency and 97.05% encapsulation efficiency by orthogonal experimental design. The in vitro study demonstrated a slow and sustainable drug release in physiological conditions. In the cellular uptake studies, mixed micelles could effectively transport into both human umbilical vein endothelial cells and C6 cells. Furthermore, biodistribution imaging of mice showed that the DiR/GM1 mixed micelles were accumulated sustainably and distributed centrally in the brain. Experiments on zebrafish confirmed that drug-loaded GM1 micelles can overcome the BBB and enter the brain. Among all the treatment groups, the median survival time of C6-bearing rats after administering DOX/GM1 micelles was significantly prolonged. In conclusion, the ganglioside nanomicelles developed in this work can not only penetrate BBB effectively but also repair nerves and kill tumor cells at the same time.

Antibodies can be Spontaneously Loaded onto Monosialoganglioside Micelles Containing Oncological Drugs

“…On the other hand previously reports by owner and others shows that GM1 micelles were able to load and release oncological drugs such as Paclitaxel and Doxorubicine and moreover that the complex were able to cross brain blood barrier [12,13,29]. In these experimental conditions we also shown that GM1-IgG complex retain the capability of load drugs such as Ptx or Doxo, although it is necessary to follow a specific sequence in order to obtain stable GM1-IgG -drug complexes.…”

“…It is well known that antibodies are therapeutically useful molecules by themselves, capable of producing direct pharmacological effects, such as blocking the interaction of a receptor with a ligand, interfering with a multimerization process or activating receptor internalization or apoptosis of target cells with numerous intermediate cell modulation options [9,28]. The incorporation of antibodies into micellar structure could be considered as a strategy for improvement in the pharmacokinetic and biodistribution properties of the antibodies, which often do not achieve the effectiveness sought by low plasma halflife or because they do not reach the tumor tissues; variables in which GM1 micelles could offer substantial advantages such as crossing the blood-brain barrier and entering the brain [29]. This encapsulation of IgG into micelles of GM1 also could be used for improving the biodistribution by facilitating selective tumor accumulation through enhanced permeability and retention (EPR) effect [28][29][30].…”

“…The incorporation of antibodies into micellar structure could be considered as a strategy for improvement in the pharmacokinetic and biodistribution properties of the antibodies, which often do not achieve the effectiveness sought by low plasma halflife or because they do not reach the tumor tissues; variables in which GM1 micelles could offer substantial advantages such as crossing the blood-brain barrier and entering the brain [29]. This encapsulation of IgG into micelles of GM1 also could be used for improving the biodistribution by facilitating selective tumor accumulation through enhanced permeability and retention (EPR) effect [28][29][30].…”

Development of functional docetaxel nanomicelles for treatment of brain glioma

“…Chemotherapy for brain glioma still faces challenging difficulty due to the low penetration of most anticancer drugs into the inside of the BBB [17]. In fact, many chemotherapeutic drugs that are effective to cancers are unable to treat brain glioma due to restriction of the BBB [18]. To solve this problem, functional nanomedicines have drawn much attention in the latest years [19,20].…”

Zebrafish (Danio rerio) model as an early stage screening tool to study the biodistribution and toxicity profile of doxorubicin-loaded mixed micelles

“…The zebrafish transparency during the larval stage and the fluorescent properties of DOX provide advantages for in vivo visualization and could serve as a valuable tool for identifying tissue-specific distribution. DOX could be tracked even when is encapsulated into nanocarriers using fluorescence-based techniques without any other fluorescence labels (Zou et al, 2017).…”