Nanobiotechnology-Based Strategies for Crossing the Blood–Brain Barrier

Kewal K Jain

Disclosures

Nanomedicine. 2012;7(8):1225-1233. 

In This Article

Nanobiotechnology-Based Delivery of Therapeutics for Brain Tumors Across the BBB

The application of anticancer drugs and gene therapy for malignant brain tumors may involve direct introduction into the tumor at the time of surgery. Some of the techniques used for facilitating the transport of systemically administered therapeutic substances across the BBB by forcibly opening the BBB involve damage to the BBB, which is not desirable, considering that the brain tumor may already have caused some damage. Several strategies based on nanobiotechnology can be used to facilitate delivery of chemotherapy across the BBB to reach brain tumors without damaging the membrane.

Treatment of glioblastoma multiforme (GBM), the most malignant primary brain tumor, is a challenge for therapy. Several strategies utilize NPs for the targeted delivery of therapeutics to GBM, including gene therapy.[25]

Nanobiotechnology for Gene Transfer Across the BBB

Viral vectors have limitations for gene therapy of brain tumors by systemic administration due to the difficulty in crossing the BBB. Several NPs have been used as vectors for gene therapy of the brain, for example liposomes, lipid NPs, polymer NPs and dendrimers, among others. PAMAM dendrimers can hold DNA in cavities and act as nonimmunogenic vectors for in vivo gene transfer. The combination of a gene and NP with a surfactant coating can facilitate gene transfer in the brain across the BBB.

Nonviral plasmid DNA can be delivered to the brain via a transvascular route by receptor-mediated transcytosis across the BBB following intravenous administration of DNA encapsulated within Trojan horse liposomes. Intravenous RNAi gene therapy using Trojan horse liposomes has been shown to result in a 90% increase in survival time in mice with intracranial brain tumors.[26]

LipoBridge Technology

LipoBridge contains short-chain oligoglycerolipids, which can temporarily and reversibly open tight junctions to facilitate the transport of drugs across the BBB and into the CNS.[27] LipoBridge itself forms a clear suspension of NPs in water and can solubilize or stabilize some drugs, it is nonimmunogenic and is excreted unmetabolized. It has been demonstrated in several laboratories that intracarotid injections of a simple mixture of LipoBridge and model compounds or pharmaceutical actives can deliver these actives into one or both hemispheres of the brain, enabling increased concentration in a selected hemisphere. They can be administered orally as well as intravenously. LipoBridge has been used to administer anticancer drugs for brain cancer in animals. Clinical studies of its safety in humans are in progress.

Nanoparticulate Formulations of Chemotherapeutics

NP formulations of chemotherapeutic agents may be helpful for the treatment of malignant brain tumors. Coating PBCA or PLGA NPs with polysorbate 80 or poloxamer 188 facilitates their use for transport of cytostatics such as doxorubicin across the BBB. NP-mediated delivery of doxorubicin to rats bearing intracranial glioblastoma increased the survival times and led to a complete tumor remission in 20–40% of the animals.[28] This method of drug delivery targeted to the tumor reduces the cardiotoxicity and testicular toxicity of doxorubicin.

NP Delivery Across the BBB for Imaging & Therapy of Brain Tumors

A nanoprobe has been designed that can cross the BBB and specifically target brain tumors in a genetically engineered mouse model, by using in vivo magnetic resonance and biophotonic imaging, as well as histologic and biodistribution analyses.[29] The nanoprobe is made of an iron oxide NP coated with a biocompatible PEG-grafted chitosan copolymer, to which a tumor-targeting agent, chlorotoxin (a small peptide isolated from scorpion venom), and a near-infrared fluorophore are conjugated. The particles, measuring approximately 33 nm in diameter, have a very low toxicity profile with no evidence of damage to the BBB and sustained retention in tumors. This NP platform has potential uses for the diagnosis and treatment of a variety of brain tumors. The fluorescent NPs improve the contrast between the tumor tissue and the normal tissue in both MRI and optical imaging during surgery, which is important because the survival of patients with brain tumors is directly related to the amount of tumor that can be removed. Peptide–NP conjugates, described in the previous section, can also be used to deliver imaging agents and anticancer drugs to brain tumors.

PLA NPs for Controlled Delivery of BCNU to Brain Tumors

1,3-bis-2-chloroethyl-1-nitrosourea (BCNU)-loaded biodegradable PLA NPs have been combined with Tf, an iron-transporting serum glycoprotein, which binds to receptors expressed on the surfaces of glioma cells.[30] In vitro drug release studies have demonstrated that BCNU-loaded PLA NPs show certain sustained release characteristics. The biodistribution of Tf-coated NPs, investigated by 99Tc-labeled single photon emission computed tomography showed that the surface-containing Tf PLA NPs were concentrated in the brain and no radioactive foci could be found outside the brain. Inhibition of tumor growth in the C6 tumor-bearing animal model showed that BCNU-loaded PLA NPs had stronger cytotoxicity and prolonged the average survival time of rats. In contrast to the BCNU wafer approach, the stereotactic method of delivery used in this study may be useful in the development of a new method for delivery of chemotherapy to malignant brain tumors.

NP-Based Targeted Delivery of Chemotherapy Across the BBB

Technologies based on NPs have been used for targeted delivery of anticancer drugs across the BBB. Nanosystems should have ligands that bind to receptors on the endothelium of blood vessels to facilitate their crossing of the BBB by receptor-mediated endocytosis.

G-Technology, described perviously, has been applied to anticancer drugs as it improves the targeted delivery to brain tumors after systemic administration and reduces adverse effects. Glutathione PEGylated liposomal doxorubicin (2B3–101) is in Phase I/II clinical trials in patients with brain cancer.

The ideal anticancer drug delivery system for GBM should have an extra component to target the tumor across the blood–brain tumor barrier in addition to crossing the BBB. An intravenously administered polymeric nanobioconjugate containing a biodegradable, as well as nonimmunogenic polymalic acid, has been used for the delivery of a mAb targeting the tumor cells as well as antisense oligonucleotides to block the synthesis of laminin-411, a protein involved in angiogenesis.[31] This is a promising strategy for the treatment of GBM. The concept of 'whole-process targeting' for brain tumors for nanodrug delivery systems consists of a series of overall targeted drug delivery strategies aimed at key points in the development of these tumors.[32] A multicomponent nanoconstruct can combine a number of functions to facilitate drug delivery for brain tumors. The concept of targeted drug delivery to GBM across the BBB by combining mAb with the Trojan horse approach is shown in Figure 2.

Figure 2.

A concept of targeted drug delivery to glioblastoma multiforme across the blood–brain barrier.
A NP combined with a mAb for R crosses the BBB into the brain by the Trojan horse approach. The NP, with a ligand targeting the BBB (dark triangle), traverses the BBB by receptor-mediated transcytosis. The ligand (light triangle) docks on a cancer cell receptor and the NP delivers its anticancer payload to the cancer cell in GBM.
BBB: Blood–brain barrier; GBM: Glioblastoma multiforme; mAb: Monoclonal antibody; NP: Nanoparticle; R: Receptor.

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