bulletin cover story Nanophase Ceramics for Improved Drug Delivery: Current Opportunities and Challenges by Lei Yang, Brian W. Sheldon and Thomas J. Webster Introduction After more than a decade of research and development, nanotechnology has reshaped the traditional thinking (or lack thereof) of using ceramics for drug delivery. Although drug delivery has been a poly- mer-dominated field, the blossoming of nanotechnology means that ceramic materials are now showing much promise for numerous drug delivery applications. Typically, nanotechnology is defined as the use of materials and systems whose structures and com- ponents exhibit novel and significantly changed properties when control is gained at the nanoscale (spe- cifically, <100 nm or <10–7 m).1 For ceramics, this means fabricating ceramics whose grain or particle sizes are within the range of 1 nm to 100 nm). Nanophase ceramics already have been widely used in a broad spectrum of biomedical applications, and now drug delivery is one of the fastest emerging and developing arenas for nano- ceramics, drawing increasing attention over the past few years. Indeed, research- ers are realizing that the extraordinary characteristics of nanophase ceramics (including size, structural advantages, highly active surfaces, unique physical and chemical properties and ease of modification) suggest that they can be excellent platforms for drug transportation and controlled prolonged release compared with polymeric platforms. The advances nanophase ceramics are making in drug delivery seem to promise that these materials will solve many of today’s challenging medical problems. lassifications based on their architectural differences, C the nanophase ceramics reviewed below can be placed into two general categories: nanoparticles and nanoscaffolds. Alhough increasingly popular, both of these categories of multifunctional drug delivery system are still in their infancy. On the other hand, analyses of the potential risks of using nanophase ceramics as drug carriers are often omitted. Therefore, the last part of the article discusses the challenges that nanophase ceramics face when compared to polymeric drug delivery systems. Also, ilt also should be note that although this article con- centrates only on ceramic materials, the potential and development of hybrid or composite ceramic–polymer drug delivery systems that incorporate the benefits from other types of materials should not be neglected. Ceramic nanoparticles Particulate drug carriers (as opposed to two-dimensional coatings or three-dimensional scaffolds) have a variety of advantages for use in drug delivery and are probably the most common ceramic drug delivery platforms today. 24 American Ceramic Society Bulletin, Vol. 89, No. 2 Particulate carriers can easily trans- a dual ability: it can tar- port drug entities in volume-confined get tumor cells and release administration routes (such as blood embedded doxorubicin – a vessels, the digestive tract, across cell DNA-interacting antican- membranes, etc.) and, thus, can deliver cer drug – in responses to drugs in minimally invasive methods temperature changes above just as their polymeric counterparts. 34.4°C.3 Particulate carriers also possess large However, all of the above surface area-to-volume (or surface benefits are generally true (a) area-to-mass) ratios that allow for a for polymers too, and are high drug payload and a prolonged associated primarily with drug-release profile. Another plus is their nano size. So, how are that from a process and production nanoparticles of ceramics dif- point of view, particulate materials are ferent from polymers in terms also easy to fabricate and inexpensive of drug delivery? Ceramic to produce, especially in terms of mass nanoparticles possess several production. unique properties compared Advances in nanotechnology have with polymeric or metallic further strengthened these advantages nanoparticles. by providing ultrasmall particles of First, ceramic nanopar- high purity and extremely high surface ticles usually have longer bio- area-to-volume ratios as well as afford- degradation times, a property able fabrication processes with a high crucial to diffusion-controlled (b) control of particle size, morphology or drug release kinetics. Slowly porosity. Nanoscale drug-carrying par- degradable – or even close ticles can enhance endocytosis of drugs to nondegradable – ceramic by target cells and can also facilitate matrices can retain drugs for deeper penetration into capillaries and longer times after adminis- through fenestrations to, ultimately, tration. In these cases, drug enhanced cellular uptake. release is dependent on con- For example, studies have shown centration gradients and can that nanoparticles with sizes from 10 be prolonged. nm to 70 nm in diameter can penetrate Second, unlike polymers, capillaries, and those with sizes 70 nm ceramic nanoparticles in to 200 nm have the most prolonged aqueous conditions gener- circulation time compared with other ally do not swell or change sizes.2 High surface area-to-volume porosity and are more stable ratios of nanoparticles and their associ- when variations in pH or (c) ated high surface activities can further temperature are encountered. improve drug-loading efficiencies and For instance, the small swell- Fig. 1. Hollow calcium phosphate nanospheres stability. These means that medical ing ratios of ceramics prevent (a) before and (b) after ultrasonic applications. professionals can achieve better drug the release of a burst of drugs (c) Release profiles of amylose from the hollow control and sustained release. – a problem commonly seen calcium phosphate nanospheres under vari- Moreover, nanotechnology offers in hydrogels, such as poly(2- ous applied ultrasonic power densities: (1) no ultrasonic application; (2) continuous ultrasonic various novel approaches to control hydroxyethyl methacrylate) treatment (150 W); (3) 1-min treatment of ultra- drug transportation throughout the (pHEMA) drug-delivery sound (150 W) between an interval of 1.5 min; body, whereby pharmaceuticals can be systems. (4) continuous ultrasonic treatment (100 W); released in precise, timely, targetable Third, and possibly and (5) continuous ultrasonic treatment (50 W). or environment-responsive manners. the most intriguing of all, (Modified from Ref. 10) For example, a thermosensitive nano- properly fabricated ceramic gel with the ability to target tumors nanoparticles can possess the biocompatibility even before releasing was developed recently.3 The poly(N- same chemistry, crystalline structure drugs. In addition, the nanoparticles isopropylacrylamide-co-propyl acrylic and size as the constituents of targeted can be engineered with favorable elec- acid) nanogel, conjugated with an tissues (e.g., various types of calcium trical (e.g., ferroelectrical and diaelec- arginine-glycine-aspartic acid (RGD) phosphate in bone). Their fabrication tric properties), mechanical (e.g., pizeo- containing peptide and transferin, has enhances the material’s bioactivitiy and electrical properties, ultrahigh hardness, American Ceramic Society Bulletin, Vol. 89, No. 2 25 Nanophase ceramics for improved drug delivery More interestingly, researchers Table 1. Representative ceramic nanoparticle for drug-delivery applications have designed and fabricated calcium Ceramics Structural feature Applications phosphate nanoparticles that achieve Calcium phosphate Hollow apatite nanospheres On–off drug release con trolled by sonication10, 11 the on–off delivery of drugs triggered Apatite nanocrystals Enhancing protein adsorption and prolong desorption37 by programmable external forces, such Nanocomposites Enhancing gene transfer and controlling the extent of gene as ultrasonic vibration with a spe- transfer42 cific power density. As an example, Iron oxides Nanoparticles Magnetic liposomes for BMP delivery;39 Drug release one group has developed a type of controlled by magnetic heating;4; Multi-functional hydroxyapatite-like hollow nanospheres drug carriers with capacities of imaging and targeting (sizes 145 ± 20 nm) that can collapse Ferrofluids Colloidal solutions of iron oxide surrounded by coatings and transform to pin-shaped HA-like of targeting molecules for delivery of drugs41 nanocrystallites under ultrasonic treat- Silica Nanoparticles Photosensitizer for photodynamic therapy (PDT)24, 25 ment.10 Knowing this, the group suc- Hollow nanospheres Enhance drug loading capacity13 cessfully encapsulated drugs in the hol- Hollow nanotubes Improve drug loading capacity and biocompatibility of low structures that were then triggered drug delivery system;14 Gene delivery43 by ultrasound. A drug release study of Titania Nanotubes Enhance drug loading capacity and prolong drug release30 these HA nanospheres using amylose Alumina Hollow nanoshells Drug loading agents15 as a drug model revealed that the drug Calcium carbonate Hollow spheres Drug release vectors and diagnostic markers16 release rates can be controlled by alter- 2+ 3+ – Layered double Anionic nanoclays (M 1-xM x(OH)2) Highly efficient, bio-resorbable drug and gene delivery ing ultrasound power density to collapse m– 26, 27 hydroxides (LDH) (A )x/m·nH2O; M: Metal cations platforms various amounts of nanospheres (Fig. and A: Interlayer anions 1).10, 11 Various versions of hollow nano- etc.), magnetic (e.g., superparamagnetic Several recent examples of nano- structures composed of other ceramic properties) and optical (e.g., photother- phase ceramics used as novel drug materials also have