Enhanced blood brain barrier permeability and glioblastoma cell targeting via thermoresponsive lipid nanoparticles

Abstract

Thermoresponsive targeting is used to deliver therapeutic agents at hyperthermic conditions (39-45 °C). However, available thermoresponsive drug delivery systems (TDDS), including liposomes, have a complex method of preparation involving toxic solvents and reagents. The objective of this in vitro study was to prepare and characterize thermoresponsive lipid nanoparticles (TLN) for treating glioblastoma, the most aggressive brain tumor whose treatment is limited by a low blood brain barrier (BBB) permeability of drugs. Thermoresponsive lipids were prepared by mixing liquid and solid fatty acids (0.1 : 1 to 2 : 1 ratio) and lipid mixtures exhibiting a solid-liquid phase transition at 39 °C were identified by plotting melting point against liquid contents. TLN were prepared by a hot melt encapsulation method using mono- or double-surfactant systems. TLN showed desirable size (<270 nm), zeta potential (-35 to -50 mV), spherical morphology and stability by FTIR studies. In the drug release studies, paclitaxel release was slow at 37 °C, however, it was released abruptly at 39 °C due to the faster diffusion rate from liquid state nanoparticles. During cytotoxicity studies, the unloaded TLN were non-toxic whereas paclitaxel loaded TLN showed higher cytotoxicity to glioblastoma cells at 39 °C (69% cell viability after one hour) compared to 37 °C (82% cell viability). The TLN showed higher permeability across an in vitro model of BBB at 39 °C due to a deformable liquid state which can squeeze through the tight junctions of the BBB. In conclusion, this study demonstrated that the TLN can be used as a safe and effective alternative to traditional TDDS with higher potential to target glioblastoma cells across the BBB.

Establishment of a Human iPSC- and Nanofiber-Based Microphysiological Blood–Brain Barrier System

“…46,47,63 We demonstrated that our BBB model had positive barrier functions to block PTX and BTZ transportation to work on the GBM cells underneath, which is similar to the limited therapeutic effects of PTX and BTZ on GBM in vivo. 64,65 Our results also demonstrated that a lower dose of PTX and BTZ had a slight effect on the TEER value of the BBB model, with a short time period of administration, whereas a higher dose significantly affected the BBB integrity. During the AD progression, BBB plays an important role in regulating the dynamic balance of A β in the brain.…”

Stimuli-responsive lipid-based magnetic nanovectors increase apoptosis in glioblastoma cells through synergic intracellular hyperthermia and chemotherapy

“…The ability of LMNVs to cross an in vitro BBB model was preliminarily investigated (Fig. 6), as previously reported in the literature 44. Briefly, two-compartment BBB models consisting of porous scaffolds (with pores of 3 μm diameter) were used to culture brain endothelial cells (BEC) at high confluence.…”

Immunoengineering in glioblastoma imaging and therapy

“…Multifunctionalized theragnostic systems have various abilities ranging from tumor targeting and cell penetration to real time monitoring. Specifically, to further enhance BBB permeability and targeting of GBM, nanoparticles could also be responsive to different stimuli such as pH (Tao et al, ), redox (X. Zhu et al, ), temperature (Rehman et al, ; Turabee, Jeong, Ramalingam, Kang, & Ko, ), magnets and ultrasound (Raucher, Dragojevic, & Ryu, ). In this section, we outline recent examples of novel and advanced nanosystem for GBM multimodal therapy and imaging.…”