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.