Author: R. Loch Macdonald
The Nobel Prize-winning theoretical physicist Richard Feynman is often credited with conceptualizing the future field of nanotechnology in his 1959 lecture, “There’s plenty of room at the bottom,” during the American Physical Society meeting at the California Institute of Technology. The field came closer to reality in 1981 with the invention of the scanning tunneling microscope. It is interesting to note that the term nanotechnology may have first been used in 1974 by Norio Taniguchi, then later independently recoined in 1981 by Eric Drexler.1
One definition of nanotechnology encompasses designing and making materials, machines, and things that are between 1 and 100 nm in size.2 This is around the size of viruses and deoxyribonucleic acid (DNA). DNA is a few nm in diameter, and a human chromosome up to 85 nm long. Nanomaterials may be metals, organic molecules, or a combination. The advantages of, for example, nanoparticles are the increase in surface area to volume compared to larger structures like microparticles.
Some nanomaterials preferentially permeate tumor vasculature or can be targeted to tumors or specific tissues by coating the particle with a molecule or antibody specific to the target. In addition, a hollow nanoparticle can be loaded with hundreds of drug molecules. Some nanoparticle coatings can also prolong the half-life of a drug and favorably alter its pharmacokinetic and pharmacodynamic profile.3 Thus, nanoparticle formulations of drugs may lead to less toxicity, higher tumor exposure, and more optimal pharmacokinetics.
In practice, nanotechnology has generated drug delivery systems and contrast agents that selectively deliver high concentrations of chemotherapeutic drugs or contrast agents for enhanced antineoplastic efficacy and better imaging. Some examples approved by the Food and Drug Administration include superparamagnetic iron oxide crystals coated with dextran or carboxydextran that are selectively taken up in liver cells and are approved for liver imaging to detect liver metastases. Nanoparticle chemotherapy delivery systems are approved for breast cancer and acute lymphocytic leukemia.
Many of the same chemicals and principles continue to be used for drug delivery on a micrometer scale. For example, 5-fluorouracil- containing microparticles made of poly (DL-lactide-co-glycolide) have been injected into the brain around the resection cavity of patients with malignant gliomas in order to release the drug at high concentrations while avoiding systemic complications.6 The limitations of this delivery are the need to inject the microparticles into the brain and the need for the microparticles to diffuse through the brain’s extracellular space for millimeters in order to target all of the remaining tumor cells.
On the other hand, drugs injected into the brain are reabsorbed into the systemic circulation so that some exposure would then occur diffusely in the brain by a systemic route, depending on blood-brain barrier permeability and efflux systems.4 Furthermore, malignant brain tumors are not a self-limited disease.
An ideal disease for direct, local single administration of a sustained-release, biodegradable drug delivery system would be a disease originating in a preformed body cavity that is self-limited and for which an existing treatment exists, but which is suboptimal due to systemic dose-limiting toxicity.
Figure 1: Scanning electron microscopy (A, D) and Raman spectroscopy (B, C, E, F) of fresh nimodipine (A - C) microparticles, or the same formulations after storage at 30-35°C for 30 days (D - F). Formulation 00447-108 showed no change in morphology or spectroscopy demonstrating stability necessary for clinical development (scale bar = 20 ?m). Red is nimodipine, green is poly(DL-lactide-co-glycolide), and blue is epoxy in Raman spectroscopy B and E. Red is nimodipine form 1, green is amorphous nimodipine, and blue is nimodipine form 2 in Raman spectroscopy C and F. Intracisternal application of the nimodipine microparticles in a paste-like formulation mixed with hyaluronic acid (G).
Reasoning along these lines, we formulated nimodipine in a biodegradable matrix delivery system for sustained release after intraventricular or intracisternal injection in patients with aneurysmal subarachnoid hemorrhage (SAH). Nimodipine has a known safety profile in humans and demonstrated efficacy in improving outcome after SAH. The hypothesis was that this would deliver high concentrations of nimodipine to the perivascular space to reduce angiographic vasospasm, cortical spreading ischemia, microcirculatory dysfunction, impaired autoregulation, capillary transit time heterogeneity, and microthrombosis, processes suggested to contribute to delayed cerebral ischemia after SAH.5 Systemic concentrations would be low, avoiding dose-limiting hypotension.
Only single administration would be required if the microparticles were engineered to release the drug over 21 days. The size range of the particles was 20 to 100 micrometers, since smaller microparticles could be cleared away by macrophages and larger ones could be difficult to inject. Preclinical toxicity studies were conducted as well as the effects on angiographic vasospasm in a dog model of SAH. Nimodipine microparticles were mixed with a low-viscosity hyaluronic acid buffer for intraventricular injection, or a high-viscosity one for intracisternal injection (Figure 1).
These studies permitted opening an Investigational New Drug Application in the United States and approval from Health Canada to conduct the NEWTON study (Phase 1/2, a multicenter, controlled, randomized, open-label, dose escalation, safety, tolerability, and pharmacokinetic study comparing EG-1962 and nimodipine in patients with aneurysmal SAH, NCT01893190, www.clinicaltrials. gov). This study assesses safety, tolerability, and pharmacokinetics of nimodipine microparticles in cohorts of 12 patients (randomized to nimodipine microparticles and no oral nimodipine [n = 9] versus oral nimodipine [n = 3]). Two cohorts (100 mg, 200 mg doses) have been completed, and preliminary plasma pharmacokinetics show sustained plasma nimodipine concentrations over 21 days after administration of nimodipine microparticles. No treated patients experienced hypotension, whereas 50% of controls experienced dose-limiting hypotension. Top-line results from the NEWTON study of this novel, unique, sustained-release nimodipine formulation are anticipated next year.
- Gribbin J, Gribbin M: Richard Feynman: A life in science. Boston, Dutton, 1997.
- Kim GH, Kellner CP, Hickman ZL, et al. A phase I clinical trial of tiopronin, a putative neuroprotective agent, in aneurysmal subarachnoid hemorrhage. Neurosurgery. 2010;67:182-185.
- Hrkach J, Von HD, Mukkaram AM, et al. Preclinical development and clinical translation of a PSMAtargeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med. 2012;4:128ra39.
- Lin JH. CSF as a surrogate for assessing CNS exposure: an industrial perspective. Curr Drug Metab. 2008;9:46-59.
- Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014;10:44-58.
- Menei P, Capelle L, Guyotat J, et al. Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of malignant glioma: a randomized phase II trial. Neurosurgery. 2005;56:242-248.