Enhanced Anti-Glioma Efficacy by Borneol Combined With CGKRK-Modified Paclitaxel Self-Assembled Redox-Sensitive Nanoparticles

Abstract

The serious therapeutic obstacles to glioma treatment include poor penetration across the blood-brain barrier (BBB) and low accumulation of therapeutic drugs at tumor sites. In this study, borneol combined with CGKRK peptide (a ligand of the heparan sulfate which overexpress on the glioma cells) modified paclitaxel prodrug self-assembled redoxresponsive nanoparticles (CGKRK-PSNPs) were hypothesized to enhance the BBB penetration ability and active tumor targeting efficiency, respectively. The resulting CGKRK-PSNPs possessed a spherical shape with a small particle size (105.61 ± 1.53 nm) and high drug loading for PTX (54.18 ± 1.13%). The drug release behavior proved that CGKRK-PSNPs were highly sensitive to glutathione (GSH) redox environment. The in vitro cell experiments suggested that CGKRK-PSNPs significantly increased the cellular uptake and cytotoxicity of U87MG cells, meanwhile CGKRK-PSNPs showed the low cytotoxicity against BCEC cells. Combined with borneol, CGKRK-PSNPs exhibited enhanced transportation across in vitro BBB model. In intracranial U87MG glioma-bearing nude mice, the higher accumulation of CGKRK-PSNPs combined with borneol was observed through real-time fluorescence image. Moreover, the in vivo anti-glioma results confirmed that CGKRK-PSNPs combined with borneol could improve the anti-glioma efficacy with the prolonged medium survival time (39 days). In conclusion, the collaborative strategy of CGKRK-PSNPs combined with borneol provided a promising drug delivery routine for glioblastoma therapy.

Therapeutics for Chemotherapy-Induced Peripheral Neuropathy: Approaches with Natural Compounds from Traditional Eastern Medicine

“…Notably, borneol transiently alters the permeability of the BBB, helping in drug delivery to the brain [ 162 , 163 , 164 , 165 , 166 ]. Multiple studies have shown that borneol treatment with chemotherapeutic agents could enhance the accumulation of the chemotherapeutic drug in the brain tissue and intracellular uptake, thereby improving the survival of glioma-bearing animals [ 167 , 168 , 169 , 170 ]. Borneol co-administered with temozolomide also enhanced anti-cancer efficacy of the drug against glioma by triggering mitochondrial dysfunction and ROS-induced DNA damage [ 171 ].…”

Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration

“…Active targeting can be obtained by decorating the surface of nanoparticles with substrates of transmembrane receptors overexpressed by cancer cells, such as albumin, folic acid, somatostatin or transferrin [ 81 ]. In this regard, the same type of self-assembled nanoparticles described above was functionalized on its surface with the CGKRK peptide (CGKRK-PSNPs), a ligand of the heparan sulfate, which overexpresses on the glioma cells membrane, in order to have an active targeting to the glioma site via heparan sulphate-mediated endocytosis ( Figure 13 b) [ 119 ]. The in vitro results were comparable to those obtained for Pep-PSNPs.…”

“…In this case the CGKRK-PSNPs were combined with borneol (Bor) when administered in vivo. Bor is a traditional Chinese medication used to transiently open the intercellular TJs at the BBB level, improving the permeation of drugs into the brain [ 119 ].…”

“…CGKRK-PSNPs were described as a strategy to specifically deliver the anticancer drug PTX into the brain to obtain an antiglioma effect. These nanoparticles were administered in vivo in combination with Bor, which can transiently slacken the TJs of the BBB and improve permeation into the brain of CGKRK-PSNPs [ 119 ]. However, this method is not considered very safe since the BBB is fundamental to maintain brain integrity and avoid damage caused by potentially toxic substances.…”

Recent Progress on the Synergistic Antitumor Effect of a Borneol-Modified Nanocarrier Drug Delivery System

“…The poor BBB penetration and low accumulation of therapeutic drugs at tumor sites are the major obstacles to achieving success glioma treatment. A previous study ( 98 ) investigated the efficiency of CGKRK peptide (a ligand of the heparan sulfate, which is overexpressed in glioma cells) modified paclitaxel prodrug self-assembled redox-responsive NPs (CGKRK-PSNPs) combined with borneol in glioma treatment. CGKRK was proved could target tumor cells and tumor neovascular through binding to the specific receptor heparan sulfate.…”