Mehdi’s Blog

Post 4:

Intro:

Made up of oxides, carbides, phosphates, metal carbonates, and metalloids such as calcium, titanium, silicon, etc., ceramic nanoparticles provide an alternative source material from traditional organic polymers. Thomas et. al. say that ceramic nanoparticles are among some of the best carriers of drugs, genes, proteins, and other common uses for nanoparticles. This is because of developed techniques that have been able to control to an extent the size range, surface properties, porosity, surface area to volume ratio, and other characteristics that make ceramic nanoparticles suitable for use as drug delivery systems.

Some background:

Ceramic nanoparticles are those materials whose properties lie between metals and non-metals. As a results, they have low electrical and thermal conductivity (like non-metals), high elastic modulus (like metals), and resistance to corrosive environments. Like all the materials we’ve covered, these properties are a result of the strong ionic bonds between the molecules that make up a ceramic. Right away, ceramic nanoparticles have an advantage in that they can easily be prepared in the right size, shape, and porosity. Ceramics also have high stability, high loading capacity, easy incorporation of hydrophobic and hydrophilic systems, and do not undergo swelling or changes in porosity with change in pH.

SEM image of Silica raspberry particles

Because this article reviews several inorganic materials, I will focus on one ceramic that we briefly mentioned in class: calcium phosphates, such as hydroxyapatite. In class, we learned that calcium phosphates are natural and found in calcified vertebrate tissues. In particular, hydroxyapatite has a similar chemical structure to bone mineral, and as a result has high biocompatibility. We classified it as an osteoconductive and osteointegrative material, which means that it is very bioactive and has an affinity for proteins and bone cells that allows it to integrate and adhere to bone material. According to Thomas et. al., calcium phosphates have advantages in that they can deliver drugs in minimally invasive ways (such as orally or through inhalation), are easy to formulate, take longer to biodegrade (calcify and conduct bone tissues), are stable under temperature and pH variations, can have enhanced bioavailability and compatibility during formulation, and most importantly, possess the same chemistry, crystalline structure, and size as their most commonly targeted tissue: bone. Though other materials such as tricalcium phosphates are used, their properties are distinct: based on different ratios of calcium to phosphate, the physical and mechanical properties of these ceramics shifts from amorphous to crystalline, stable to unstable at room temperature, and rapid to slow hydrolysis. Thus, hydroxyapatite is considered the best choice for sustained drug delivery.

Methods of Synthesis:

Hydroxyapatite nanoparticle structures: SEM and TEM

Because they are crystalline ceramics, Hydroxyapatites are most commonly synthesized through wet chemical precipitation from solution. As we learned in class, precipitation is the simple chemical reaction that produces crystal growth. The reaction of calcium hydroxide with hydrogen phosphates yields nanocrystals of hydroxyapatite. But as we learned in class, crystallization is highly vulnerable to changes in reaction conditions. These can be used to our advantage: through careful control of pH, reaction temperature, reactant addition rate, and other factors, produces specific desired nanoparticles of sizes typically under 100nm.

Another method of synthesis is shared by lipid nanoparticles: surfactant based emulsion. Through this, two immiscible liquids such as water and oil are agitated under the presence of an amphiphilic surface-active agent to disperse the water phase into an oil phase. This causes the formation of reverse micelle microdroplets that provide geometrically restricted regions for the synthesis of nano-phase materials. The microemulsion of of aqueous cyclohexane and phosphoric acid with the organic phase of calcium nitrate and surfactant produced hydroxyapatite particles between 30 to 50nm with needle and spherical morphologies. While it produces excellent morphology with little agglomeration, microemulsion results in low yields.

A final method I will discuss is the sol-gel process, a soft chemistry path that converts metal alkoxides into amorphous gels through hydrolysis and condensation reactions. These are then turned into ceramics by heating at low temperatures. Benefits of the sol-gel method compared to conventional techniques is a higher chemical and structural homogeneity, because there is molecular-level mixing of the calcium and and phosphorous precursors. The main disadvantage is the side hydrolysis of phosphates.

Applications of Calcium Phosphate in Drug Delivery:

As we discussed in class, hydroxyapatite finds its best uses in the treatment of bone diseases such as osteoporosis. This is due to its uniquely crystalline structure and its natural associations with bone tissue, as I mentioned earlier. Slowly, hydroxyapatite formulations are being explored for the treatment of cancer and other diseases as well. Delivery systems of hydroxyapatite particles are able to extend drug release do it the material’s low degradation rate and high biocompatibility. Furthermore, hydroxyapatite is easily linked with other materials that can reinforce its therapeutic effects and drug release. Previous work has shown that Amoxicillin loaded iron doped particles or superparamagnetic iron hydroxyapatite  nanoparticles possess excellent biocompatibility. Furthermore, they cause greater osteoblastic cell proliferation when exposed to a static magnetic field. As we discussed in class, hydroxyapatite makes for ideal scaffolding material because of its high integrative ability. As a result, super-paramagnetic responsive nanofibrous scaffolds have been shown to produce accelerated bone formation in rabbits. Hydroxyapatite can be combined with magnetite or silica to create pH responsive, “smart” drug delivery systems. Similarly, nanoparticles can be grafted with poly(N-isopropylacrylamide) to produce thermal-responsive, smart delivery systems with enhanced bioactivity.

Biomimetic Hydroxyapatite-containing composite Nano-fibrous scaffolds for bone tissue engineering

These examples are just a few related to one class of inorganic nanoparticles of a large group of materials that holds exciting potential for the field of drug delivery. Thomas et al. says it best: “Ceramic nanoparticles hold the promise of better, safer, and cost- effective drug delivery agents in future of biomedical science.”

Thomas, Shindu C. et. al. “Ceramic Nanoparticles: Fabrication Methods and Applications in Drug Delivery.” Current Pharmaceutical Design, vol 21, 2015.

Hi everyone, welcome to my blog #3.

Given that our two lectures this week concerned a) nanoparticles and b) patenting, I thought I’d look into a curious situation in the current scientific community over a development in nanoparticle synthesis: the use of the PRINT technique.

PRINT, or Particle Replication in Non-wetting Templates, was a clever idea implemented by the DeSimone research group at UNC Chapel Hill. In order to better determine the shape of their synthesized nanoparticles, they used a 3D printed elastomeric mold comprised of a low surface energy perfluoropolyether network. This allowed scientists to, for the first time, produce with control monodisperse and shape- and stereo- specific nanoparticles.

To recap: traditional polymeric nanoparticles are made from the sonication of mixed solvents. This is an inexpensive technique, but what scientists save in money they lack in control.  Sonication results most often in basic spherical nanoparticles. Sometimes, and often randomly, other basic shapes can be achieved through combinations of different materials, temperatures, pH, and solvents. But an increasing body of literature points to the advantages of formulating specific or complex shapes for certain targets: rod-shaped nanoparticles extravasate into tumors better than spherical nanoparticles. But there is little literature about a reliable way to formulate specific polymeric nanoparticle shapes. Even what literature exists concerns specific molecules, and is not easily generalized. Certain nanocarriers currently achievable are liposomes, dendrimers, micelles, and polymeric particles.

Instead the PRINT technique uses a template to produce exact sizes, shapes, compositions, and surface functionality. This was revolutionary, because it allowed precise loading of delicate cargos in formations, shapes, and functionalities that would maximize their extravasation into tumors. Scientists in the DeSimone group used elastomeric solids that enabled high-resolution imprint lithography, applying a technique commonly used in microelectronics. PRINT is analogous to the mass production technologies used to create nanoscale devises, transistors, and microprocessors. Thus, it is a truly engineered drug delivery approach, providing scientists simultaneous control over every parameter that influences succesful drug delivery. Further, the lithography of PRINT allows for replications of the master template in order to create homogenous and monodisperse particles. The master template also allows complete control over particle shape. Geometries such as spheres, cylinders, discs, and toroids can now be reliable formulated with precise ratios.

The matrix formulation is also successful with a variety of organic materials, including albumin, hydrogels, PLLA, PLGA, and more. This formulation can be carefully altered in order to control such specific characteristics as porosity, texture, and modulus of the particle. Further, because it is highly compatible, PRINT is open to straightforward incorporation of cargo: hydrophilic or hydrophoboic, biologicals, peptides, proteins, oligonucleotides, siRNA, contrast agents, radiotracers, and fluorophores. Even more, the exact concentrations of such cargos can be chosenfor specific needs, since PRINT doesn’t rely on the trapping of particles during fabrications, as in the case with liposomes and micelles. Finally, surface functionalization can be modified through the matrix composition or postfunctionalization with moieties: surfaces accommodate targeting peptides, antibodies, aptamers, avidin/biotin complexes, cationic/anionic charges, and “stealth” PEG chains for steric stabilization.

The DeSimone group claims that theirs is the only current technology that can independently design and control each of these attributes to create truly engineered nanocarriers for drug therapies. For the first time, nanoparticles can deliver drugs with precises paramters of bioavailability, biodistribution, and targeting. There is enormous potential. So what did the DeSimone group do? Put a lock on any use of PRINT outside of their lab. For the duration of the patent, from 2007 until this year (they are trying to currently extend), only the DeSimone group has access to PRINT technology.

Their exact claims are rather interesting: as we now know, inventors take liberties in the “claims” section of the patent. Here, they can stretch the “uses and implications” of their invention as much as they which—given that others may contest exact nuances later. Some of the claims made by the DeSimone group are that their patent explored the idea of a method that forms a nanoparticle from “a patterned template and a substrate,” “disposing a volume of liquid material in…the patterned template” or a “plurality of recessed areas,” and “forming one or more particles by…contacting [a] patterned template surface with the substrate.”

Labs around the world that might want access to such technology to explore the implications of drug delivery are still left trying to approximate the current techniques for formulating specific nanoparticles, which have experienced little progress aside from DeSimone’s PRINT technology. The patent has also prevented other labs from testing the limits of this technology; we do not know yet if it is sustainable, although some suspect that in practice, such a technique would end up far more expensive than current sonicating techniques. Overall, there continues to remain a small gap in the literature concerning the issue of nanoparticle shape. While most labs have gotten around the problem by working with materials that already have defined and useful shapes, or else settling for spherical nanoparticles that have a lower rate of extravasation. There is much work to be done in determining a cost efficient and easy way to manipulate the shapes of nanoparticles and take advantage of the full potential of nanoparticle drug therapeutics.

Gratton, Stephanie E.A.. “Nanofabricated Particles for engineered drug therapies: A preliminary biodistribution study of PRINT nanoparticles.” Journal of Controlled Release, 2007.