Crossing the Blood-Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology

Abstract

The blood-brain barrier (BBB) constitutes a microvascular network responsible for excluding most drugs from the brain. Treatment of brain tumors is limited by the impermeability of the BBB and, consequently, survival outcomes for malignant brain tumors remain poor. Nanoparticles (NPs) represent a potential solution to improve drug transport to brain tumors, given their small size and capacity to target tumor cells. Here, we review the unique physical and chemical properties of NPs that aid in BBB transport and discuss mechanisms of NP transport across the BBB, including paracellular transport, carrier-mediated transport, and adsorptive- and receptor-mediated transcytosis. The major types of NPs investigated for treatment of brain tumors are detailed, including polymeric NPs, liposomes, solid lipid NPs, dendrimers, metals, quantum dots, and nanogels. In addition to their role in drug delivery, NPs can be used as imaging contrast agents and can be conjugated with imaging probes to assist in visualizing tumors, demarcating lesion boundaries and margins, and monitoring drug delivery and treatment response. Multifunctional NPs can be designed that are capable of targeting tumors for both imaging and therapeutic purposes. Finally, limitations of NPs for brain tumor treatment are discussed.

Keywords: blood-brain barrier; drug delivery; nanoparticle; tumor.

Figure 1

NPs can exploit several transport mechanisms to cross the BBB. Their small size is advantageous for paracellular transport across the TJs. Carrier-mediated transport takes advantage of endogenous BBB transporters needed for entry of molecules for homeostasis and neuronal health. Adsorptive-mediated transport processes occur via favorable interactions between the surfaces of NPs and the endothelial membrane, while receptor-mediated processes stem from recognition of a ligand on the NP by a membrane receptor. Membrane invagination results in internalization of the NPs into clathrin-coated pits or caveolae before exiting into the target tissue.

Figure 2

Dendrimers are NPs whose building blocks extend out in generations from a central core. The surfaces of these tree-like structures can be conjugated with a number of functional ligands that can target BBB and tumor receptors and carry chemotherapeutic drugs.

Figure 3

Transport of GNPs to tumor cells. (A) Gold NPs carrying the chemotherapeutic agent doxorubicin and the TAT peptide can cross the BBB through paracellular transport and AMT to reach tumor cells. The GNPs accumulate at the tumors via the enhanced permeability and retention effect. (B) After internalization by the tumor cell, the GNPs are transported into lysosomes, where doxorubicin is released from its hydrazone linkage by the acidic microenvironment. The doxorubicin enters the nucleus and damages DNA by acting as an intercalator, resulting in apoptosis of tumor cells. (C) GNPs improve paracellular transport across the BBB by decreasing the level of phosphorylated PKCζ, an enzyme required for the proper association between ZO-1 and occluding at the tight junctions of endothelial cells.