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bulletin cover story Nanophase for Improved 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, 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 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, Cthe nanophase ceramics reviewed below can be placed into two general categories: 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– 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 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 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 . 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 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 ’s bioactivitiy and electrical properties, ultrahigh ,

American Ceramic Society Bulletin, Vol. 89, No. 2 25 Nanophase ceramics for improved drug delivery

More interestingly, researchers Table 1. Representative ceramic 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 adsorption and prolong desorption37 by programmable external forces, such Enhancing gene transfer and controlling the extent of gene as ultrasonic vibration with a spe- transfer42 cific power density. As an example, Iron Nanoparticles Magnetic for BMP delivery;39 Drug release one group has developed a type of controlled by magnetic heating;4; Multi-functional -like hollow nanospheres drug carriers with capacities of imaging and targeting (sizes 145 ± 20 nm) that can collapse Ferrofluids Colloidal of iron 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 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: 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 been highlighted mal effects, electroluminescence, etc.) delivery platforms are summarized in in recent studies. All of these have properties rarely seen in polymeric or Table 1. Most significantly, calcium one thing in common: They have an metallic nanoparticles. phosphates have been widely studied extremely high drug-loading capac- due to their biocompatibility, tailor- ity and time-delayed release behavior Controlling the release able bioabsorbability and bioactivity. (pulse or discrete release) compared Medical professionals often seek a Calcium phosphates have been used as with bulk nanopheres. For example, specific drug-release profile pattern. novel delivery carriers for antibiotics studies have shown that hollow silica Drug delivery patterns can be divided (e.g., gentamicin sulphate, flomoxef into either continuous or discrete (“on- , tetracycline, etc.), anti-inflam- nanospheres are capable of entrapping off”).2 Nanotechnology can be used to matory agents (e.g., salicylic acid, indo- an eightfold increased quantity of drug control drug delivery in each category. methacin), analgesic and anticancer species compared with silica nano- 12 For example, medical professionals drugs (e.g., mercaptopurine, ), spheres. Another study revealed that in cases, such as diabetes therapy and growth factors (e.g., bone morphologi- hollow silica nanospheres had a time- inflammation suppression after surgery, cal , transforming growth fac- delayed multiple-stage release profile prefer continuous but time-delayed drug tors β (TGF-β), etc.), proteins (e.g., (including an initial burst release for 20 delivery followed by a stable release I and osteocalcin) and genes minutes, a prolonged steady release up profile rather than initial drug-burst (e.g., DNA).5, 6 to 10 hours and a final fast release for 13 release.4 Conversely, for discrete deliv- Nanotechnology-derived calcium another 2 hours). ery, such as a drug release to phosphates also have successfully Hollow silica nanospheres have pio- cells or pathogen sites, a burst release maintained a sustained and steady drug neered such research and have been of drugs at a designated time is often release over time. A bovine serum albu- fabricated into well-controlled shapes desirable. min-loaded calcium-deficient hydroxy- and sizes by using templates or self- Researchers are taking this a step apatite system revealed a single-stage templating molecules.12, 13 Other studies further, targeting the drug to specific slow-release profile in which only about on hollow ceramic for sites, such as pathogens, specific tissues 55 percent of the BSA released during drug-delivery purposes include magnetic or cells. This targeting ability is highly the first 8 hours and an additional 35 silica nanotubes,14 nanoshell alumina desirable (and challenging) because it percent after 90 hours.7 Recent stud- spheres15 and calcium carbonate nano- increases drug efficiency and decreases ies have also indicated that the drug- spheres16 (Fig. 2). toxic side effects. Because of their release kinetics could be further con- extraordinary characteristics, ceramic trolled by tailoring calcium phosphate Perfect for multifunctions nanoparticles have considerable poten- nanoparticle , surface area and Besides applications in controlled tial to tackle these challenges. calcium-to-phosphorus ratios.8, 9 drug release, a new trend is to use ceram-

26 American Ceramic Society Bulletin, Vol. 89, No. 2 (a) (b) ic nanoparticles as advanced multifunc- tional platforms for diagnostic imaging and therapeutic pur- poses. As an exam- ple, magnetic iron oxide nanoparticles (including magnetite

γ-Fe2O3, magnetite

Fe3O4 and associated compounds, also (c) known as superpara- (d) magnetic ION) have been actively studied for these purposes. can be real- ized by biochemi- cally modifying such drug carriers to specifically bind to target cells, or more directly, by using Fig. 2. (a) Hollow siliceous nanospheres (Adopted from Ref. 12.); (b) magnetic porous hollow nanotubes external measures to (Adopted from Ref. 14.); (c) hollow alumina nanospheres (Adopted from Ref. 15.); and (d) hollow - move drug carriers ate nanospheres (Adopted from Ref. 16.). to the pathological sites. Monoclonal (such as increased without releasing any drug. tosensitizer carriers due to their pho- anti-HER2, anti-VEGF McAb, etc.) In summary, coupled with their tostability, easily controlled size, shape and peptide sequences (such as the extraordinary magnetic properties for and monodispersity and appropriate HIV-Tat peptide) have been conju- enhancing magnetic imag- pore sizes (0.5 nm – 1 nm) for gated to ION to target them to tumors, ing and ability to damage cancer cells diffusion and drug retention.24 Typical myocardial infarctions or beta-amyloid through magnetic thermal effects,22,23 ceramic materials for PDT applica- plaques.17 A specific example is that ION-rendered drug-delivery systems tions are silica-based nanoparticles. A ION conjugated with the synapotagmin can be made to be multifunctional to recent systematic study demonstrated I protein can target apoptotic tumor image, sense, diagnose and treat various that silica-based nanoparticles, approxi- cells. These cells express anionic phos- diseases. mately 30 nm in size) successfully pholipids that specifically bind to the Finally, there are two fast-emerging entrapped a photosensitizing anticancer protein.18 topics toward using ceramic nanopar- drug (2-devinyl-2-(1-hexyloxyethyl) In the case of applying external forc- ticles in drug delivery worth further pyropheophorbide) and can be synthe- es to target drug delivery, an external attention. One is photodynamic ther- sized by hydrolysis. These drug-doped magnetic field is applied to guide ION- apy (PDT) and the other is nanoscale nanoparticles revealed high aqueous 1 conjugated drugs to specific sites after layered double hydroxides (LDHs). stability, efficient generation of O2, intravenous delivery of the particles. PDT is an emerging method for the active uptake by tumor cells and, most This technique has reached clinical treatment of various diseases, including importantly, significant damage to trials for cancer therapy.19 Similarly, oncological, cardiovascular, dermato- tumor cells after photoirradiation.25 several recent studies using ION to logical and ophthalmic diseases. PDT LDHs refer to a class of anionic treat bone diseases (such as osteopo- involves the uptake of a photosensitizer layered ceramic materials (or anionic rosis, osteoarthritis, bone cancer, etc.) (such as silica) by pathological tissue, nanoclays) made of charged metal proposed a strategy of delivering ION- such as tumor tissue, followed by pho- hydroxide layers and charge-balancing based drug systems to osteoporosis sites toirradiation. The photoirradiation trig- hydrate gallery anions. The metallic 20,21 1 2+ 2+ by using a directional magnetic field. gers singlet oxygen ( O2) formation as a cations in the LDHs can be Mg , Zn , Here, the idea can be taken a step result of the combined action of excited Ni2+, Cu2+, Al3+, Fe3+, etc., and the 2– – further. By directing magnetic nanopar- photosensitizers and molecular oxygen, interlayer anions can be CO3 , NO3 , 1 24 2– 26 ticles to the pores of osteoporotic bone, and the O2 induces cellular death. SO4 or other anionic species. bone strength can be immediately Ceramic nanoparticles are ideal pho- LDHs are bioresorbable and have a

American Ceramic Society Bulletin, Vol. 89, No. 2 27 Nanophase ceramics for improved drug delivery

Ceramic nanoscaffolds for drug (a) delivery and tissue regeneration Like their nanoparticle counterparts, nanotechnology-created ceramic scaf- folds have also demonstrated great potential for controlled drug delivery. These ceramic scaffolds were initially designed as supportive architectures to control and direct cellular behavior by creating a biomimetic environment. Examples are calcium phosphate scaf- folds that mimic the natural bone struc- ture and chemical composition. Calcium phosphate scaffolds provide not only initial structural integrity for bone cells, but also direct their prolifer- ation and differentiation, and they can assist in the ultimate assembly of new tissue. Therefore, ceramic nanoscaffolds are usually 3-D and porous, although in some cases they are 2-D coatings or films. They mimic the in vivo environ- ment of cells more completely than do nanoparticles. It is easy to understand that there is an urgent need for developing nano- materials scaffolds that are biomimetic. That is because so many natural tis- sue architectures are hierarchical with micron as well as nanostructured fea- tures. For example, in the connective tissue, nanoscale structural proteins, such as collagen fibers and elastin-fibers entangle into a nonwoven micron- structural mesh that provide mechani- cal strength and for the tissue. Similarly, at the nanoscale, bone (b) is composed of periodically assembled collagen fibers and calcium phosphate Fig. 3 (a) Nanotubular titania produced by anodizing titanium orthopedic implants. (b) , both . The Release profiles of coprecipitated penicillin/streptomycin (on nanotubular titania by development of ceramic scaffolds for immersing in simulated body fluid (SBF)) in phosphate-buffered (PBS) for up to biomedical applications that mimic 3 weeks. (Adopted from Ref. 30.). natural tissue structure is increasingly high anionic-exchange capacity, high methotrexate conjugated to LDH has related to nanotechnology. These tech- swelling properties and pH-mediated a much greater in vitro anticancer niques have been playing an extremely . These are the properties effect compared with clinically used important role in the design, fabrica- that make them promising for drug and doxorubicin. They believe this is prob- tion and modification of sophisticated gene delivery.26, 27 LDHs can be readily ably because of enhanced cellular drug drug-delivery scaffolds. synthesized though aqueous coprecipi- uptake via clathrin-mediated endocyto- The structural advantages of ceramic tation by adding a strong base solution sis and controlled release inside cells. nanoscaffolds include high poros- into the solution containing metallic Recent in vitro and in vivo studies ity, high volume-to-area ratios, high cations. The sizes of LDHs can be eas- further indicated that LDHs in the size surface area, high structural stability ily controlled by pH, temperature and range of 100–200 nm might have the and long degradation times. These reaction time. highest delivery efficiency of drugs, and properties make them potent systems In particular, researchers have dem- reduced effects compared to for the storage and controlled release onstrated that the anticancer drug LDHs of other sizes.26 of drugs, especially drugs for in-situ

28 American Ceramic Society Bulletin, Vol. 89, No. 2 anti- and anti-inflammatory purposes. Therefore, most drug-eluted Table 2. Representative ceramic nanoscaffolds for drugdelivery applications ceramic nanoscaffolds serve multiple Ceramics Material and structural features Applications functions, such as drug delivery, direct- Titania Nanotubular surfaces Improving drug loading efficiency and prolonged drug ing cell growth or tissue generation, release of antibiotics for orthopedic implant applica- and mechanical support. Indeed, the tions;30, 31 growth factor delivery32 mechanical support provided by ceram- Calcium phosphate (CaP) Calcium phosphate Controllable delivery of growth factor and promotion of ic scaffolds far exceeds that provided by cement (CPC) nano- new bone growth33 polymeric scaffolds. porous scaffolds Table 2 summarizes the ceramic Silica/CaP nanophase Prolonged continuous release of drugs up to 70 days34 nanoscaffolds that are under active composites research for drug delivery purposes. Silica Silica nanospheres Improving loading capacity and delivery amount of the Researchers, for example are looking incorporated with drug44 at nanotubular titania and calcium scaffolds phosphate-based nanoscaffolds for drug orthopedic implants that used this sys- Electrospun scaffolds and growth factor delivery. In particu- tem showed an increase in drug-loading Many researchers are also looking at lar, nanotubular titania structures with efficiency and prolonged drug release, electrospun nanostructured scaffolds as a tube width of tens of nanometers and and the drug delivery system showed drug-delivery materials. Although elec- a tube length of a few hundred nano- reduced Staphylococcus Epidermis coloni- trospun nanostructured ceramics are meters increase bone growth more than zation and initial .31 rare compared with polymers for drug the forms of titanium that are currently Besides antibiotics, another research delivery and their potential for drug in use. A form of nanotubular titania project to improve bone implant effi- delivery has yet to be fully explored, can release antibiotics and growth fac- cacy has shown that growth factors the advantages of electrospinning are tors after implantation (Fig. 3(a)). like the peptide sequence clear: The method allows for the con- Nanotubular titania structures can be of a segment of bone morphoge- venient fabrication of ceramic nano- readily fabricated by direct anodization netic protein-2 (the knuckle epitope, structures with controllable morphology of existing titanium orthopedic implants CKIPKASSVPTELSAISTLYL) can be and size. in an electrochemical cell that uses the successfully incorporated into the nano- The principle of electrospinning is to titanium as an anode and platinum as a tubular titania structures to promote charge solutions containing polymers, cathode in the presence of fluorine-based osteoblast adhesion.32 ceramics or metallic precursors with a 28, 29 electrolytes. In fact, anodization Special cements are also being incor- high voltage. The charged solution is theoretically can be applied to any metal porated into nanoscaffolds. For exam- drawn by electric field from a nozzle that is stable to oxidation to fabricate ple, one group has been fabricating onto collector to form desirable nanoscale tubular or porous surfaces. self-setting calcium phosphate cements structures. The structures can be fab- Researchers recently demonstrated into injectable high-strength nanoscaf- ricated to mimic various architectures an example of using nanotubular titania folds by incorporating and of biological systems, such as fibrous as a drug delivery platform when they various porogens, such as absorbable proteins assembled in a native extracel- showed they could load penicillin-based fibers and mannitol. These components lular matrix or collagen fibrils in bone antibiotics by coprecipitating the drug strengthen the scaffolds and provide (Fig. 4). and calcium phosphate crystals on the sequentially formed pores that promote For example, investigators have elec- nanostructures.30 This delivery system new bone growth.33 trospun a mixture of calcium phosphate showed a time-delayed release of anti- Controlled release is also an impor- precursors with polyvinyl chloride and biotics for up to three weeks. It accom- tant property here. The CPC nanoscaf- then sintered the material into highly plishes this with a small initial burst, folds can deliver growth factors and pro- interconnected nanofibrous networks. in contrast to a 150-minute complete teins in a time-delayed manner by sim- They believe this electrospun scaffold release of drugs after being physically ply altering the CPC-to-chitosan ratio in will work well for treating bone defects adsorbed on nanotubular titania (Fig. the fabrication process.33 Another recent and drug delivery.37 3(b)).30 This system also demonstrated study on scaffolds comprised of BONIT good cytocompatibility properties, as matrix, a biphasic nanophase composite Challenges tested by osteoblasts, or bone form- of silica and calcium phosphates (HA/ As mentioned above, targeted drug ing cells. This means the material has tricalcium phosphate), showed the mate- delivery and precise control of drug a strong potential for supporting bone rial can deliver a continuous release of release kinetics (continuous or on-off growth. gentamicin, an aminoglycoside antibi- release) are two challenging topics In another study, researchers modified otic extensively used for orthopedics, faced by all drug delivery researchers. nanotubular titania by attaching amine from the scaffolds for 70 days without an Nanophase ceramics seem to offer solu- or methyl groups. An examination of initial burst release.34 tions to traditional drug delivery prob-

American Ceramic Society Bulletin, Vol. 89, No. 2 29 Nanophase ceramics for improved drug delivery

in actual clinical trials. (a) Because of slow biodegradation or non- degradation, all ceramic drug platforms also face the potentially large challenge of removal from the body after delivering drugs. The challenge becomes much more serious for nano- phase ceramics, because their size allows them to easily penetrate cell Authors: Thomas J. Webster, left, is an membranes and biologi- associate professor of and cal barriers, including, orthopedics at Brown University. Lei Yang (b) perhaps, the blood–brain is a graduate student at the school. Brian barrier. Once in the W. Sheldon (not pictured) is a professor cells, these materials of engineering at Brown. may be difficult to get out. The truth is that the causes for cytotoxicity are mate- little knowledge exists in rial specific and not fully understood. understanding removal Again, because these preliminary find- mechanisms of ceramic ings are mostly based on in-vitro cell nanocarriers. In part, models, a systematic approach to test there has been a lack of the toxicity of nanoceramics, especially studies on the metabo- in-vivo toxicity, is highly desirable. lism and elimination routes of nanoparticles. Extraordinary opportunities Another concern is the ahead vast variations in nano- In summary, nanophase ceram- Fig. 4. (a) and of rat tendon materials’ physical and ics have exceptional opportunities showing collagen fibrils and collagen-bound proteogly- chemical properties that to assist targeted drug delivery efforts cans, the image size is 2×2 μm (Adopted from Ref. 35.); (b) cause such studies to be due to their unique ability to modu- Electrospun poly-L-lactide (PLLA)/collagen/hydroxyapatite inconsistent and incom- nanofibers mimicking bone structures (Adopted from Ref. 36.). late drug release kinetics, incorporate prehensive. multifunctional molecules and target lems because of their unique material Even more important, the toxicity of specific focus sites. Although the chal- properties centered on greater surface nanophase ceramics is still unclear and, lenges that nanophase ceramics face areas. Unfortunately, targeting efficient like other nanomaterials, becoming an are serious and the toxicity of nano- and controllable drug release is still not increasing concern to the scientific and materials is an increasing concern, the a reality for clinical use. medical community. Although some extraordinary properties of nanophase In fact, efforts to aim them at desir- studies exist,38 gaps in knowledge con- ceramics and the continual advances able sites and employ multiphase-drug cerning the interaction of nanoparticles in understanding their and release or quantity-controlled drug within the body are still significant. elimination routes from the body offer release are still in the early stage of Already, it seems that in some cases more promising avenues to diagnose, application. In nearly all the current the advantages nanoceramics have for understand and treat numerous diseases studies, researchers have primarily used improving drug-delivery may through drug delivery. n in vitro models to assess the efficacy of unfortunately be their downfall. For nanophase ceramic drug delivery sys- example, some ceramic nanoparticles References tems (such as targeting efficiency, drug (such as iron oxide and ) 1 Webster TJ. Nanophase ceramics as improved bone tissue engi- revealed cytotoxic effects when their neering materials. American Ceramic Society Bulletin 2003;82:23- release kinetics and biocompatibility). 28. 38 There is a great difference between concentration is above only 10 μg/mL. 2 Goldberg M, Langer R and Jia X. Nanostructured materials for Although the generation of reactive applications in drug delivery and . J Biomater Sci in-vivo and in-vitro systems. Clearly, Polymer Edn 2007; 18: 241-68. further verification of their properties oxygen species and the internalization 3 Quan CY, Chang C, Wei H, Chen CS, Xu XD, Cheng SX, et of nanoparticles are two common nano- al. Dual targeting of a thermosensitive nanogel conjugated with and overall more assessment of nano- transferrin and RGD-containing peptide for effective cell uptake phase ceramic systems are still needed material-induced cytotoxicity pathways, and drug release. Nanotechnology 2009; 20: 335101.

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Mo-Sci licenses SRNL’s porous, drug-delivering microballoons

The Department of The microspheres typically have a announced that a licensing agreement 50 µm diameter, but can range from has been reached between Savannah 2 µm to 100 µm. The shells are about River National Lab and specialty glass 10,000 Å. The June 2008 issue of the provider Mo-Sci Corp. The Missouri- Bulletin has a lot of good information based Mo-Sci will use SRNL’s unique about how they are made and the wide porous-walled range of potential hollow glass uses. microspheres as a “This isn’t like making Microspheres, transport mecha- hollow glass . We per se, aren’t new, nism for targeted manufacture the PW-HG but there are three (Credit: SRNL/ Bulletin .) drug delivery, things particularly SRNL microsphere filled with palladium. hydrogen storage spheres to exact specifica- important about The top of the microsphere has been removed to display contents. and other uses. tions, and the customer the PW-HG “Mo-Sci had microspheres. The gaseous materials can pass into and the background loads the microspheres first is that they be confined within the microspheres. in glass manu- with the materials, like have a network Several mechanisms are available facturing and medical drugs,” says Ted of interconnected to attain a controlled release of the processing porous pores engineered microsphere’s contents. wall hollow glass Day, president of Mo-Sci. into the thin Another feature is that these micro- microspheres,” shells. Moreover, spheres can be coated and/or lined says Ted Day, the SRNL with nanomaterials and structures president of Mo-Sci. “We’ve been researchers figured out how to custom- to, for example, improve absorbency. doing this for research purposes for ize the properties and dimensions of Proteins or fluorescent indicators can about 5 years.” these pores. Thus, solid, and be attached to guide and monitor the

American Ceramic Society Bulletin, Vol. 89, No. 2 31 Mo-Sci licenses SRNL’s porous, drug delivering microballoons spheres for drug-delivery purposes or to have been successfully demonstrated to Clinic, and likely understands the ins have them act, for example, as a supe- store and release the gas. and outs of getting PW-HG micro- rior MRI contrast agent. Mo-Sci’s involvement is a good sign. sphere applications to market. A third feature is that, at a macro The company was founded in 1985 An article (“Porous-wall hollow glass level, large volumes of the PW-HG by Missouri University of Science & microspheres as novel potential nano- spheres can be made to flow like a fluid Technology professor Del Day found carriers for biomedical applications”) They even look like water when poured much success in using a different type jointly written by Wick, other SRNL from container to container. Moreover, of glass microspheres to deliver tiny researchers and investigators at the they are recyclable. amounts of strong radiation in cancer Medical College of Georgia will soon “This isn’t like making hollow glass treatment. Mo-Sci’s spheres have been be published in the print version of beads. We manufacture the PW-HG particularly successful in the treatment : Nanotechnology, Biology spheres to exact specifications, and the of cancerous liver tumors, where the and Medicine and is now available customer loads the microspheres with spheres can be targeted fairly precisely online. the materials, like medical drugs,” says to deliver radiation. They have the The article provides more detail Day. secondary benefit of blocking the blood about the uses of the PHWG micro- SRNL originally developed the supply to tumors. spheres for the delivery of anti-cancer unique microspheres as a solid-state Mo-Sci has worked with medical drugs. storage method for hydrogen. They institutions, such as the Cleveland Visit: www.mo-sci.com. n

Nanodiamond-Gd complex: ‘Contrast agent on steroids’ Dean Ho’s nanodiamond team at enhance the relaxivity properties of Northwestern University always seems the Gd(III)–nanodiamond complex,” to be coming up with something new. says Ho. “This might explain why these This time, Ho and a team led by NU complexes are so bright and such good cancer researcher Thomas J. Meade say contrast agents.” they have figured out a way to couple “The nanodiamonds are utterly gadolinium with nanodiamonds to unique among nanoparticles,” Meade make a MRI contrast agent that deliv- says. “A nanodiamond is like a ers greatly improved images. ship – it gives us a nontoxic platform “The results are a leap and not a upon which to put different types of small one,” says Meade in a NU news drugs and imaging agents.” release, “It is a game-changing event for The team also studied the toxicity sensitivity. This is an imaging agent on of the Gd(III)–nanodiamond complex steroids. The complex is far more sensi- using fibroblasts and HeLa cells as bio- tive than anything else I’ve seen.” Researchers have figured out a way to logical testbeds, and it found that that In the past, Ho has shown, at least couple gadolinium with nanodiamonds to the material didn’t negatively affect the with in-vitro studies, that nanodia- make a MRI contrast agent that delivers hybrid complex on cellular viability. monds seem to have excellent biocom- greatly improved images. Now the focus is on moving from in- patibility and can be used for drug, vitro to in-vivo. The researchers hope protein and DNA delivery. However, nanodiamond complex that demon- to be moving into preclinical applica- researchers in that area are looking for strated a greater than ten-fold increase tion of the new contrast agent in vari- a system to deliver drugs that has a sec- in “relaxivity.” Relaxivity refers to abil- ous animal models. ond function: tracking. (The ideal drug- ity of magnetic compounds to increase They also think they can fine delivery system adds one more function the relaxation rates of the surrounding tune and improve the agent by nail- that allows the material to be targeted water proton spins. Relaxivity is used to ing down how the structure of the to a particular tissue or site.) improve the contrast of the image. Gd(III)–nanodiamond complex governs In a paper study published online “Nanodiamonds have been shown increased relaxivity. by the journal Nano Letters, the team to be effective in attracting water Visit: www.n-base.org/research/nano- says it has developed a Gd(III)– molecules to their surface, which can .html. n

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