Inducing a Transient Increase in Blood–Brain Barrier Permeability for Improved Liposomal Drug Therapy of Glioblastoma Multiforme

Abstract

The blood–brain barrier (BBB) selectively controls the passage of endogenous and exogenous molecules between systemic circulation and the brain parenchyma. Nanocarrier-based drugs such as liposomes and nanoparticles are an attractive prospect for cancer therapy since they can carry a drug payload and be modified to improve targeting and retention at the desired site. However, the BBB prevents most therapeutic drugs from entering the brain, including physically restricting the passage of liposomes and nanoparticles. In this paper, we show that a low dose of systemically injected recombinant human vascular endothelial growth factor induces a short period of increased BBB permeability. We have shown increased delivery of a range of nanomedicines to the brain including contrast agents for imaging, varying sizes of nanoparticles, small molecule chemotherapeutics, tracer dyes, and liposomal chemotherapeutics. However, this effect was not uniform across all brain regions, and permeability varied depending on the drug or molecule measured. We have found that this window of BBB permeability effect is transient, with normal BBB integrity restored within 4 h. This strategy, combined with liposomal doxorubicin, was able to significantly extend survival in a mouse model of human glioblastoma. We have found no evidence of systemic toxicity, and the technique was replicated in pigs, demonstrating that this technique could be scaled up and potentially be translated to the clinic, thus allowing the use of nanocarrier-based therapies for brain disorders.

Multifunctional temozolomide-loaded lipid superparamagnetic nanovectors: dual targeting and disintegration of glioblastoma spheroids by synergic chemotherapy and hyperthermia treatment

“…[35] Besides TfR targeting, which promotes the increase of nanoparticle crossing through the BBB by transcellular pathway, other approaches have been proposed to transiently and safely increase the BBB permeability and the consequent paracellular transport of nanoparticles/compounds to the brain. The most relevant examples include the injection of recombinant human vascular endothelial growth factor, [36] the use of focused ultrasound, [37] and the magnetothermal stimulation. [38] In this context, AbLMNV represents a multifunctional nanoplatform, that can be locally accumulated with a static magnetic field, it is able to promote dual targeting towards both the endothelial cells of the BBB and the GBM cells, and, finally, it induces significant temperature increment when exposed to an AMF; in principle, the nanoparticle heating could be exploited, transiently, for promoting the BBB crossing, and, chronically, for GBM treatment.…”

Considering the Experimental Use of Temozolomide in Glioblastoma Research

“…[A,B]. Based on: (A) https://www.lgcstandards-atcc.org/; (B) https://www.phe-culturecollections.org.uk/; (C) [93]; (D) [94]; (E) [95]; (F) [96]; (G) [97]; (H) [98]; (I) [99]; (J) [100]; (K) [101]; (L) [102]; (M) [103]; (N) [104]; (O) [105]; (P) [106]; (Q) [107]; (R) [108]; (S) [109]; (T) [110]; (U) [111]; (V)[112]; (W)[113]; (X)[114]; (Y)[115]; (Z)[116]; (Aa)[117]; (Bb)[118]; (Cc)[119]; (Dd)[120]; (Ee)[121]; (Ff)[122]; (Gg)[70]; Hh)[123]; (Ii)[124]; (Jj)[125]; (Kk)[126] …”

Development of Novel Therapeutics Targeting the Blood–Brain Barrier: From Barrier to Carrier

“…On the other hand, transient opening of the BBB, by means of physical force or chemicals, has been explored to enhance BBB penetration of drugs with promising results in animal studies and clinical trials. [ 33–35 ] Evidence also suggests that the BBB is an active player to regulate the influx and efflux of molecules and cells between the brain and blood. [ 36 ] This defines another important role of the BBB: as a transport carrier to mediate communication between two sides of the BBB.…”