Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells

Abstract

BackgroundEffective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells.MethodsMagnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured in vivo with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed ex vivo with fluorescence imaging.ResultsWe found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells.ConclusionThe therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives.

Maghemite Functionalization for Antitumor Drug Vehiculization

“…In another interesting investigation functionalized dendrimers which may in effect pass over the BBB and concentrate within malignant glioma cells have been prepared. It was determined that dendrimers with sizes smaller than 11.7 -11.9 nm, which were delivered to the patient in a intravenous way, were capable of crossing pores of the blood-brain tumor barrier, and bigger dendrimers could not do it (Sarin et al, 2008).…”

Dendrimer-based magnetic resonance imaging agents for brain cancer

“…. . [140], rhodamine [92,93], quantum dots [141], etc, for more accurate and sensitive multi-modal imaging [41]. Often, fluorescent imaging enables the precise delineation of tumor margins and hence more complete resection of the tumor during surgery.…”

“…The BBTB often contains large pores, which make the BBB more permeable to nanosized macromolecules than the endothelial barrier in the microvasculature of most normal tissues. In order to probe the pore size in the BBTB of brain tumors, Sarin et al [92,93] labelled PAMAM dendrimers of generation 5 to 8 with Gd-DTPA at the terminals, and investigated their transport in brain tumors in mouse models using dynamic contrast-enhanced magnetic resonance imaging. The size of the G 7 dendrimers bearing Gd-DTPA functions was 11 ± 1 nm, and that of the G 8 dendrimers was 13 ± 1 nm.…”

Recent Advances in RNA Interference Therapeutics for CNS Diseases

“…In the future, targeting the brain after systemic delivery may be possible. Alternatively, researchers may be able to take advantage of the impaired BBB in some neurological diseases, allowing for diffusion of viruses, drugs, and other small molecules into the brain that are delivered systemically [67,170]. 3) Duration of silencing.…”