A Multifunctional Porous Silicon Nanocarrier for Glioblastoma Treatment

Abstract

Clinical treatment of glioblastoma (GBM) remains a major challenge because of the blood−brain barrier, chemotherapeutic resistance, and aggressive tumor metastasis. The development of advanced nanoplatforms that can efficiently deliver drugs and gene therapies across the BBB to the brain tumors is urgently needed. The protein "downregulated in renal cell carcinoma" (DRR) is one of the key drivers of GBM invasion. Here, we engineered porous silicon nanoparticles (pSiNPs) with antisense oligonucleotide (AON) for DRR gene knockdown as a targeted gene and drug delivery platform for GBM treatment. These AON-modified pSiNPs (AON@pSiNPs) were selectively internalized by GBM and human cerebral microvascular endothelial cells (hCMEC/D3) cells expressing Class A scavenger receptors (SR-A). AON was released from AON@pSiNPs, knocked down DRR and inhibited GBM cell migration. Additionally, a penetration study in a microfluidic-based BBB model and a biodistribution study in a glioma mice model showed that AON@pSiNPs could specifically cross the BBB and enter the brain. We further demonstrated that AON@pSiNPs could carry a large payload of the chemotherapy drug temozolomide (TMZ, 1.3 mg of TMZ per mg of NPs) and induce a significant cytotoxicity in GBM cells. On the basis of these results, the nanocarrier and its multifunctional strategy provide a strong potential for clinical treatment of GBM and research for targeted drug and gene delivery.

Angiopep-2-Functionalized Lipid Cubosomes for Blood–Brain Barrier Crossing and Glioblastoma Treatment

“…Using an innovative microfluidic BBB/GBM organ-on-a-chip model, the ability of our developed cubosomes to cross the BBB tight monolayer and then the uptake into glioblastoma U87 cells was investigated under physiological flow conditions. The microfluidic model was developed using a previously reported method , with slight modifications, as presented in Figure A. This model is designed to closely mimic the physiological complexity of the BBB .…”

“…To further assess the permeability of the developed cubosomes across the BBB and the subsequent uptake into brain cancer cells, we used a μBBB-GBM model, which was previously developed and validated by previous studies. , …”

“…To further assess the permeability of the developed cubosomes across the BBB and the subsequent uptake into brain cancer cells, we used a μBBB-GBM model, which was previously developed and validated by previous studies. 50,59 In brief, two-step photolithography and soft lithography techniques were used to make the polydimethylsiloxane (PDMS) replicas of the microfluidic devices (Figure S2), which were then cured at 80 °C and punctured to make flow ports and medium reservoirs. A brief exposure to oxygen plasma in a plasma cleaner, 1 min for the PDMS and 3 min for the glass coverslips, was employed to bond the PDMS to the glass coverslips.…”

Recent Advances in Nanotherapeutics for Neurological Disorders

“…Engineered porous silicon nanoparticle conjugated antisense oligonucleotides as a targeted drug delivery system for the clinical treatment of glioblastoma have been attempted . Glioblastoma is an aggressive tumor that originates in the brain.…”

“…The ability of the proposed antisenseloaded nanocarrier to penetrate the BBB network was demonstrated using a microfluidic-based BBB model and xenograft mouse models (Figure 2). 22 The size of the nanocarrier is essential for improving cancertargeting efficiency and biodistribution. Liaw et al have demonstrated the effect of nanocarrier size on brain tumor targeting efficiency and BBB penetrating capability.…”