Delivering Complex Drugs With Nanotechnology-Based Solutions

May 1, 2013
Patricia Van Arnum

Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Pharmaceutical Technology, Pharmaceutical Technology-05-01-2013, Volume 2013 Supplement, Issue 3

Parenteral drug delivery offers a variety of challenges but also opportunities. The author examines recent developments in nanotechnology-based drug delivery and other advances in injection-based drug delivery.

ANDRZEJ WOJCICKI/Getty ImagesNanotechnology is an important area of research, particularly in certain therapeutic areas, such as anticancer therapies to control dosing and target drug delivery to the tumor site. A review of the literature shows several interesting developments in this field.

Superparamagnetic iron oxide nanoparticles

Swiss researchers have discovered a method that allows for the controlled release of an active agent on the basis of a magnetic nanovehicle. The research was conducted as part of the National Research Program “Smart Materials,” a cooperation between the Swiss National Science Foundation and the Commission for Technology and Innovation. The specific work was conducted by researchers at ETH Lausanne, the Adolphe Merkle Institute, and the University Hospital of Geneva in Switzerland.

The researchers demonstrated the feasibility of using a nanovehicle to transport drugs and release them in a controlled manner as explained in a Jan. 24, 2013 press release from the Swiss National Science Foundation. The nanocontainer used was a liposome with a diameter of 100 to 200 nm. The membrane of the vesicle was composed of phospholipids and the inside of the vesicle offered room for the drug. Superparamagnetic iron oxide nanoparticles (SPIONs) were integrated into the liposome membrane; the SPIONs become magnetic in the presence of an external magnetic field. Once they are in the field, the SPIONs heat up. The heat makes the membrane permeable, and the drug is released. The SPIONs also are a contrast agent in magnetic resonance imaging (MRI). A simple MRI shows the location of the SPION and allows for the release of the drug once it has reached the targeted spot (1, 2).

In their study, the researchers noted that liposomes have been characterized by cryogenic electron microscopy (CryoTEM) as well as in combination with nanoparticles in SPIONs incorporated inside the liposomal membrane. CryoTEM maintains the native state of the liposomes. The quick freezing of the sample immobilizes particles and liposomes exactly at their position in the suspension, which allows localization information to be extracted from the images. The researchers reported on the analysis of cryoTEM images of liposome-particle hybrids, including the estimation of the contrast transfer function (CTF) and electron dose as well as the correct positioning of the sample holder and tomography for accurate localization (1, 2).

Another challenge was to reach a temperature sufficiently high to open up the liposomes, according to the release. This problem was addressed by increasing the size of the SPION from 6 to 15 nm. The membrane of the vesicles had a thickness of only 4-5 nm. The researchers regrouped the SPION in one part of the membrane, which made the MRI detection easier. Before starting in-vivo tests, the researchers plan to study the integration of SPION into the liposome membrane in greater detail, according to the release.

Nanolipogels as drug-delivery vehicles

Researchers at Yale University developed nanolipogels as a new drug transport technology to deliver anticancer therapies. The nanolipogels are nanoscale, hollow, biodegradable spheres, which are capable of holding chemically diverse molecules, according to a July 15, 2012 press release by the National Science Foundation (NSF), which is providing funding for the research. The nanolipogels contained transforming growth factor (TGF-β) and interleukin-2 (IL-2). Specifically, the researchers developed nanoscale liposomal polymeric gels (i.e., nanolipogels) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers to deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines. The nanolipogel releasing TGF-β inhibitor and IL-2 significantly delayed tumor growth, increased survival of tumor-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration (3, 4).

“The cytokine can be thought of as a way to get reinforcements to cross the dry moat into the castle and signal for more forces to come in,” said Fahmy in the NSF release. “In this case, the reinforcements are T-cells, the body’s anti-invader ‘army.’ By accomplishing both treatment goals at once, the body has a greater chance to defeat the cancer,” he said.

An important aspect of the nanolipogels is their ability to “package” two completely different kinds of molecules--large, water-soluble proteins, such as IL-2, and smaller water-phobic molecules, such as the TGF-β inhibitor--into a single delivery vehicle, according to the NSF release. The outer shell of each nanolipogel is made from a biodegradable, synthetic lipid that degrades in a controlled manner, can encapsulate a drug-scaffolding complex, and is easy to form into a spherical shell. Each shell surrounds a matrix made from biocompatible, biodegradable polymers that are impregnated with the TGF-β inhibitor molecules. Those near-complete spheres are put in a solution containing IL-2, which gets entrapped within the scaffolding, a process called remote loading, according to the NSF release. The result is a nanoscale drug-delivery vehicle that is small enough to travel through the bloodstream but large enough to be entrapped for delivery to the tumor sites (3, 4).

Nanoparticles for protein synthesis

Researchers at the Massachusetts Institute of Technology (MIT) developed nanoparticles that can be controllably triggered to synthesize proteins. The hope is that particles could be used to deliver small proteins that kill cancer cells and eventually larger proteins such as antibodies that trigger the immune system to destroy tumors. The nanoparticles consist of lipid vesicles filled with the cellular machinery responsible for transcription and translation, including amino acids, ribosomes, and DNA caged with a photo-labile protecting group. These particles served as nanofactories capable of producing proteins including green fluorescent protein (GFP) and enzymatically active luciferase.

In vitro and in vivo protein synthesis was spatially and temporally controllable and could be initiated by irradiating micron-scale regions on the timescale of milliseconds (5).

The researchers designed the new nanoparticles to self-assemble from a mixture that includes lipids, which form the particles’ outer shells, plus a mixture of ribosomes, amino acids, and the enzymes needed for protein synthesis. Also included in the mixture are DNA sequences for the desired proteins. The DNA is trapped by DMNPE, which reversibly binds to it. This compound releases the DNA when exposed to ultraviolet light. In this study, particles were programmed to produce either GFP or luciferase. Tests in mice showed that the particles were successfully prompted to produce protein when UV light shone on them, according to an Apr. 9, 2012 MIT press release. Although more testing must be done to show that the nanoparticles can reach their intended destination in humans and that they can be used to produce therapeutic proteins, the research is an interesting start. The researchers are working on particles that can synthesize potential cancer drugs by targeting protein production that could be turned on only in the tumor, thereby avoiding side effects in healthy cells. The team also is working on new ways to activate the nanoparticles. Possible approaches include production triggered by acidity level or other biological conditions specific to certain body regions or cells, according to the MIT release.

Gold nanoparticles

Researchers at the University of Sydney in Australia, led by Nial Wheate, senior lecturer in the Faculty of Pharmacy, and researchers from the University of Strathclyde and the University of Glasgow in Scotland recently reported on delivering the anticancer drug cisplatin using gold-coated iron oxide nanoparticles for enhanced tumor targeting (6, 7). The researchers used this approach to overcome some challenges of cisplatin, namely poor bioavailability, severe dose-limiting side effects, and rapid development of drug resistance. The iron oxide core was coated in a protective layer of gold before the anticancer drug cisplatin was attached to the gold coating using spaghetti-like strings of polymer, according to a May 31, 2012 University of Sydney press release.

The iron oxide nanoparticles (FeNPs) were synthesised via a coprecipitation method before gold was reduced onto its surface (Au@FeNPs). Aquated cisplatin was used to attach {Pt(NH3)2} to the nanoparticles by a thiolated polyethylene glycol linker forming the desired product (Pt@Au@FeNP). The nanoparticles were characterized by dynamic light scattering, scanning transmission electron microscopy, UV visible spectrophotometry, inductively coupled plasma mass spectrometry, and electron probe microanalysis. Nanoparticle drug loading was found to be 7.9 × 10-4 moles of platinum per gram of gold. External magnets were used to show that the nanoparticles could be accumulated in specific regions and that cell-growth inhibition was localized to those areas (6, 7).

References

1. C. Bonnaud et al., IEEE Transaction on Magnetics 49 (1), 166-171 (2013).

2. P. Van Arnum, Pharm. Technol. Sourcing and Management, Feb. 6, 2013.

3. T. Fahmy et al., Nature Materials, online, DOI:10.1038/nmat3355, July 15, 2012.

4. P. Van Arnum, Pharm. Technol. Sourcing and Management, Aug. 1, 2012.

5. A. Schroeder et al, Nano Lett., online, DOI: 10.1021/nl2036047, Mar. 20, 2012.

6. P. Van Arnum, Pharm. Technol. Sourcing and Management, June 6, 2012.

7. N. Wheate et al., Inorg. Chimica Acta, online, DOI10.1016/j.ica.2012.05.012, May 30, 2012.