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AIMS Bioengineering, Volume (Issue): Page.
DOI:
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http://www.aimspress.com/journal/Bioengineering
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Review
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Nanoparticles for the treatment of osteoporosis
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P. Mora-Raimundo,a M.Manzano,ab and M.Vallet-Regí *ab
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a
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Complutense de Madrid, Instituto de Investigaci ́on Sanitaria Hospital 12 de Octubre i + 12, Plaza de
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Ramón y Cajal s/n, E-28040 Madrid, Spain. E-mail: [email protected]
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b
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Madrid, Spain. Fax: +34 913941786; Tel: +34 913941861
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Abstract: Osteoporosis is by far the most frequent metabolic disease affecting bone. Current clinical
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therapeutic treatments are not able to offer long-term solutions. Most of the clinically used anti-
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osteoporotic drugs are administered systemically, which might lead to side effects in non-skeletal
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tissues. Therefore, to solve these disadvantages, researchers have turned to nanotechnologies and
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nanomaterials to create innovative and alternative treatments. One of the innovative approaches to
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enhance osteoporosis therapy and prevent potential adverse effects is the development of bone-
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targeting drug delivery technologies. It minimizes the systemic toxicity and also improves the
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pharmacokinetic profile and therapeutic efficacy of chemical drugs. This paper reviews the current
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available bone targeting drug delivery systems, focusing on nanoparticles, proposed for osteoporosis
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treatment. Bone targeting delivery systems is still in its infancy, thus, challenges are ahead of us,
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including the stability and the toxicity issues. Newly developed biomaterials and technologies with
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potential for safer and more effective drug delivery, require multidisciplinary collaboration between
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scientists from many different areas, such as chemistry, biology, engineering, medicine, etc, in order
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to facilitate their clinical applications.
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Keywords: nanoparticles, osteoporosis, drug delivery system, anti-osteoporotic drugs, osteoclast,
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osteoblast, bone-targeting
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Departamento de Química Inorgánica y Bioinorgánica, Facultad de Farmacia. Universidad
Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN),
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1 Introduction
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1.1 Osteoporosis:
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Osteoporosis is a progressive skeletal disease characterized by reduced bone mass and
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microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and
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susceptibility to fracture. According to the definition given by the World Health Organization,
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osteoporosis is diagnosed when a patient has a bone mineral density of 2.5 standard deviations or more
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below the average value of bone mass for young healthy adults.[1] In adults, bone is remodeled by a
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coordinated process in which bone resorbing osteoclasts remove old bone, and bone-forming
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osteoblasts synthesize and mineralize new bone matrix.[2] Disturbances in this physiological process
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lead to a decreased bone mass, namely, osteoporosis. Unfortunately, the current treatments for
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osteoporosis have notable restrictions, including adequacy and long-term safety issues.[3] It does not
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exist yet a satisfactory solution to the problem of bone weakening due to osteoporosis.[4] The treatment
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options of osteoporosis are limited to anti-resorptive drugs, that slow down the excess of bone
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resorption (principal cause of primary osteoporosis); and anabolic agents, that effectively increase the
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bone mass that has previously disappeared as a consequence of resorption excess.[5] With increased
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aging population and life expectancy, bone diseases have become the most prevalent degenerative
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disorders and a major public health problem in many countries,[6,7] which has fuelled the interest in
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prevention and treatment. According to the International Osteoporosis Foundation, osteoporosis is
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estimated to affect one in three women and one in five men over the age of 50 years.[8] In fact, a bone
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will break every 3 seconds because of this disease. This problem has an enormous human and socio-
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economic impact. In the European Union, the economic burden of incidents and prior fragility fractures
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mainly due to osteoporosis was estimated at €29 billion in the five largest EU countries (France,
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Germany, Italy, Spain and UK) and €38,7 billion in the 27 EU countries.[9]
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1.2 Current treatments for osteoporosis:
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Therapeutic strategies to limit bone loss and prevent fracture are predominantly divided in two main
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groups (Figure 1),[9] anti-resorptive drugs, that target osteoclasts, and bone forming accelerators or
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anabolic drugs, designed for osteoblast stimulation.[10]
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suppressing osteoclast activity preserving bone mass and increasing bone strength.[4,11] On the other
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hand, anabolic drugs are able to induce bone formation and can reverse bone deterioration generated
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by the osteoporosis progression.[4,12]
Anti-resorptive drugs act mainly by
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Figure 1. Schematic diagram about the different approaches of osteoporosis treatment.
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1.2.1 Anti-resorptive drugs:
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In the last few years osteoporosis therapeutics have been monopolized by bisphosphonates (BP)
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capable of averting further bone degradation in well-established osteoporosis.[13] BP disrupts
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osteoclast activity by inhibiting farnesyl pyrophosphate synthase, critical enzyme for membrane
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protein prenylation and osteoclast detachment from bone.[14] Ultimately, they induce osteoclast
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apoptosis, thus reducing bone resorption.[15] Even though they are capable of reducing the fracture
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risk and bone turn over, the effect of these drugs in increasing or recovering bone mass is really small,
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at <2% per year.[16] Furthermore, BP are not easily absorbed by intestine, presenting variable
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bioavailability, being necessary to ingest the drug 2 hours before breakfast and avoid the administration
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of a second drug or for 30 minutes in order to minimize the interactions with cations like calcium,
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iron, etc.[13] It is necessary to orally administrate high doses, what causes several side effects like
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esophagitis[3], due to the local action on the mucosa, or jaw necrosis due to an excessive inhibition of
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bone resorption.[17] Taking this into consideration, it is relevant to know about long-term treatment
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with bisphosphonates. Clinical studies have examined the effects of using bisphosphonates in
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treatments of 3, 5 or 10 years. They showed a persistent antifracture and bone mineral density
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increasing effects beyond 3 years of treatment.[18] On the other hand, more serious adverse effects, or
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discontinuation due to adverse effects were reported between patients with 10 years treatment versus
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those with just 5 years treatment.[19]
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Another anti-resorptive drug is raloxifene (RLX). RLX is a second generation non-steroidal
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benzothiophene, selective estrogen receptor modulator (SERM). It acts as estrogen agonist in bone.
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RLX reduces bone loss by inhibiting the activity of cytokines which increase bone resorption.
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Although RLX is rapidly absorbed by the intestine, it will suffer an extensive pre-systemic glucuronide
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conjugation. Consequently, the absolute bioavailability achieved is very low.
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Osteoclast differentiation is triggered when Receptor Activator of Nuclear Factor κB ligand (RANKL)
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binds to its receptor, RANK, present on the surface of osteoclasts and osteoclast precursors.[20] This
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interaction will promote osteoclast differentiation through preosteoclast fusion and osteoclast survival.
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Consequently, it generates multinucleated mature bone-resorbing osteoclasts, which increment the
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bone resorption rate.[2,10,20] According to this concept, a monoclonal humanized anti-RANKL
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antibody has been developed and currently used as osteoporosis therapy.[10]
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1.2.2 Anabolic drugs:
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Recombinant human parathyroid hormone (rPTH)[21] and estrogens[22] are anabolic agents for bone
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formation that have demonstrated their efficacy in osteoporosis.[5,22,23] rPTH by daily administration
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has proven to be more efficient than BP therapy by increasing bone mass. This drug is used for its
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capability of stimulating bone formation[24] and for its ability to suppress apoptosis of osteoblasts.[25]
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However, the increased hypercalcemic and tumor risk associated with prolonged hormone
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administration, and need for daily injections, limits the long-term treatment to 24 months.[26]
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Another way explored to promote bone formation is the administration of growth factors like bone
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morphogenetic proteins (BMPs). They stimulate bone formation and increase bone strength and
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density.[5,27] However, supraphysiological doses are necessary to achieve therapeutic effects, what
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can lead to undesirable effects such as uncontrolled bone formation, inflammation or even
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tumorigenesis.[28] Furthermore, the short half-life of BMPs limited their systemic administration.[29]
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More recently, gene silencing through the delivery of small interfering RNA (siRNA) has been used
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as treatment for bone disease such as osteoporosis. Due to the several advantages that this therapy
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presents, its study has increased notably.[30] In this type of therapy, siRNA targeted those genes that
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had been identified to down regulate bone formation without modulating bone resorption. However,
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high doses of siRNA are necessary to sufficiently stimulate bone formation, what drives to a high risk
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for adverse effects in non-skeletal tissues.[31]
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Taking these aspects into consideration, one of the most important and persistent problems of
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osteoporosis treatment is the several side effects of the different current drugs. It is clear that the
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development of specific delivery systems for each developed drug is necessary.
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2. Drug delivery and bone release by nanotechnology
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Drugs delivered systemically are absorbed into the blood stream and distributed through the body.
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They are rapidly clear from the body and poorly penetrate into bone tissue. Bone compared to other
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organs like brain, liver, or kidney is less vascularized which is the principal reason why drugs penetrate
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less in bone than in other tissues.[32] Thus, they are generally administered in a high dose or/and
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frequently, what can result in systemic toxicity. It would be safer and more effective if the drug could
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be delivered specifically to bone tissue through a controllable drug delivery system.[33] Drug delivery
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systems (DDS) are designed for improving the therapeutic effect of drugs, minimizing their potential
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toxic side effects. In the last few years the use of nanoparticles as DDS applied to bone diseases has
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gained growing attention (Figure 2). The drug carrier would transport the drug to bone tissue, there
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releasing the therapeutic agent, which either promotes bone growth or reduces bone resorption. In this
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sense DDS optimize the drug doses, protect drug from biodegradation and reduce the drug exposure
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to non-target cells.[23,34] For example, during the treatment with estrogen, the distribution of the drug
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to other tissues different from bone can produce several effects such as intrauterine hemorrhage,
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increasing uterus weight or even endometrial and breast cancer.[35,36] Recent research developed an
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estradiol-prodrug, consisting of estradiol conjugated with asn Asp-oligopeptide carrier. They found
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that it was selective to bone, and even produced a long-term action on bone, avoiding the side effects
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of estradiol. The use of this selective bone delivery system would also extend medication intervals,
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resulting in a better quality of life for patients.[37]
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A targeted drug delivery system is a system that releases the drug in a preselected site. The bone
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targeting moieties and the carriers are the most important elements in a drug delivery system targeting
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bone diseases.[36]
Osteoporosis + nanoparticles
Nanoparticles + bone targeting
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20
Years
2016
2014
2012
2010
50
0
Years
Figure 2. Number of publications with the terms “osteoporosis + nanoparticles” in Web of Science;
(right) Number of publications with the terms “Nanoparticles + bone targeting” in Web of Science
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2008
2006
2004
2002
10
100
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
2010
2012
2014
2016
# Publications
30
0
139
150
2000
# Publications
40
2.1 Bone-Targeting moieties:
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In order to guide nanoparticles to bone, it is important to find moieties with strong affinity to it. It is
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known that bones are made of a mineralized matrix, being hydroxyapatite (HA) its principal
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component.[38] Since HA crystals are present in a high concentration in bone, it would represent a
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promising target for selective delivery.[39] Moieties with high affinity to HA should be taken into
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consideration.
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2.1.1 Tetracycline and bisphosphonate:
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Tetracycline and bisphosphonate have strong affinity with the calcium present on HA, so they can be
used as bone-targeting moieties.[35] Tetracycline was the first to be used because of its strong
affinity with calcium. It is used as antibiotic but, due to the high affinity to bone it caused children's
teeth to stain yellow, so its usage was discontinued in pediatric medicine. Despite this fact, its use as
antibiotic in adults and as bone targeting moiety has persisted.[40] Consequently, smaller molecules
with similar bind capacities as tetracycline were designed, as tetracycline analogues.[41] . Neale et al.
tried to reduce potential side effects caused by tetracycline's biological activity by minimalizing
tetracycline structure. The modifications were still able to bind HA but did not retain the biological
activity.[42] Despite these efforts, its complicated chemical structure and its poor stability during
chemical modifications, pledged its use.[36] Unlike tetracycline, bisphosphonates have attracted the
attention as bone-targeting moieties in recent years. They are widely used to treat the osteolysis
diseases due to their high affinity to HA, their capacity to bind at sites with osteoclastic activity and
their ability to inhibit bone resorption. These facts permit to use the same molecule for targeting and
for treating the disease.[14]
2.1.2 Oligopeptides:
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Furthermore, some studies found moieties capable of discriminating between bone-resorption surface
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and bone-formation surface. It has been reported that eight repeating sequences of aspartate (Asp8)
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preferentially bind to bone-resorption surface, and (AspSerSer)6 showed favorable binding to bone-
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formation surface.[31] Thanks to this, it is possible to use one moiety or another depending on the type
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of drug used. If it is an antiresorptive agent, it should be used Asp8 which guides to bone resorption
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surface, or if it is an anabolic agent, it should be used instead (AspSerSer)6 that should be guide instead
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to bone formation surface.[43]
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2.2 Nanocarriers in osteoporosis therapy:
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In the last few years, nanoparticles have been found to be promising carriers for efficient therapeutic
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delivery in bone disease therapy. For bone regeneration in osteoporosis patients, the development of
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nanoparticles is ideal since bone itself is a nanocomposite. In addition to this dimensional similarity,
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they can offer drug protection from biodegradation, transport efficiency, and even improve its
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pharmacokinetic, pharmacodynamics, biodistribution and targeting.[36] Thanks to their capability to
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be chemically modified they can enhance therapeutic loading, increase tissue specificity, decreasing
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doses without sacrificing treatment efficacy.[44]
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Table 1. Summary of bone targeting drug delivery system with therapeutic activity
Therapy
Bone targeting moiety
Carrier
Reference
Thermolysis
ALN
Fe3O4 NPs
[45]
ALN
ALN
Gold NPs
[17]
RANKL siRNA
AspSerSer6
[46]
ALN
ALN
Cationic
Liposomes
HA NPs
RIS
RIS
ZnHA NPs
[13]
RANK siRNA
*
MBG´s
[10]
RLX
*
Chitosan NPs
[23]
Ethinylestradiol
*
Liposomes
[48]
[47]
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*The targeting moiety is not specified; ALN: Alendronate RANKL: Receptor Activator for Nuclear Factor κB ligand
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siRNA: small interfering RNA RIS: Risedronate RLX: Raloxifene; Asp: Aspartate Ser: Serine; HA: Hydroxyapatite NPs:
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nanoparticles MBG: Mesoporous bioactive glass nanospheres
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2.2.1 Organic nanoparticles for osteoporosis treatment:
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2.2.1.1 Liposomes:
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Liposomes were the first nano-delivery system that succeeded in becoming a clinical application.[49]
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Generally, liposomes are made by the self-assembly of lipid molecules with a hydrophilic head group
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and hydrophobic tail. The addition of cholesterol reduces the membrane permeability, and then it
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improves the mechanical characteristics of the liposome.[48,50] This structure permits to have an
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aqueous core enclosed within a phospholipid bilayer that permits to load drugs with different solubility.
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Hydrophobic agents would be in the bilayer membrane, while hydrophilic agents would be in the
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aqueous core.[51] One of the biggest handicaps of liposomes is the rapid uptake by reticuloendothelial
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system (RES), which is traduced in a low circulation half-life. Incorporating polyethynel glycol-lipid
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(PEG-lipid) conjugated with the bilayer will decrease the uptake by RES so the time in blood stream
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will increase.[52]
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During the last years a new generation of liposomes was created for the specific delivery of genes to
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treat bone diseases. Lu et al. prepared ethinylestradiol liposome (EEL) and investigated its action
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against postmenopausal osteoporosis using the ovarectomized rat model. They concluded that EEL,
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compared to free ethinylestradiol, were more effective in stimulating the amount of calcium deposition
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in bone, and also increasing the osteoblast activity and the active bone formation.[48] Zhang et al.
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linked (AspSerSer)6 with a cationic liposome which encapsulates an osteogenic siRNA. This siRNA
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targets a negative regulator of osteogenic lineage activity (Plekhol).[53] Cationic liposomes are made
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of cationic lipids which have one or more amines present in the polar head. These liposomes bind and
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condense DNA spontaneously to form complexes with high affinity to cell membranes and capable of
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delivering the plasmids into the cells.[54,55] This permits the delivery of therapeutic cargos
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(e.g.,siRNAs) to the target osteogenic-linage cells, as an alternative to the modulation of bone-
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resorption.[31]. Compared to the cationic liposomes, neutral liposomes have lower toxicity, longer
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circulation half-life, and less interaction with proteins.[53] Neutrally charged lipoplexes can be
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implemented to the cationic liposome system in order to solve these problems. Similar to this, Hengst
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et al. designed liposomes and used cholesteryl-trisoxyethylenebisphosphonic acid (CHOL-TOE-BP),
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a new tailor-made bisphosphonate derivate, as bone targeting moiety. These liposomes were designed
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for the treatment of bone related diseases such as osteoporosis.[56]
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2.2.1.2 PLGA-nanoparticles
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Compared to liposomes, rigid nanoparticles are promising as delivery system because of their high
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capacity of cargo and their nano-size. Synthetic biodegradable polymers as poly-lactide (PLA) and the
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copolymer poly(lactide-co-glycolide) (PLGA) have been extensively used for the synthesis of
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nanoparticles,[57] due to their excellent host biocompatibility, non-toxicity, and tuneable degradation
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rates.[58] It is possible to achieve different drug release profiles by modifying the molecular weight,
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the copolymer ratio, the particle size, the porosity, and the manufacturing conditions.[34] Another
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advantage of PLGA is that it can be functionalized and modified allowing the attachment of biological
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molecules.[59] Furthermore, it has been FDA-approved for a number of biomedical applications.
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PLGA properties such as swelling, the molecular interaction potential with the cargo[34], the
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controllable degradation period (about 16 months)[35] make it the perfect candidate for the design of
controlled delivery systems. Jiang et al. have developed PLGA-based nanoparticles with a short
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sequence of poly-aspartic acids that have shown to interact exclusively with hard tissues. Fluorescein
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isothiocyanate (FITC) was tagged to the nanoparticles in order to study their distribution and binding
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capacity. The in vitro and ex vivo studies showed the exclusive binding affinity of FITC-poly-Asp
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nanoparticles to bone tissue.[59] The accumulation of the nanoparticles in bone niches permits a higher
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local drug concentration, reducing side effects and lengthening the therapeutic window. Similar to this,
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Fu et al. developed bone-targeting nanoparticles using PLGA-PEG copolymers and Aspn-based bone
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targeting moieties (1-3). Asp3-nanoparticles showed the best binding capacity to apatite.[60]
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Moreover, Cong et al. designed PLGA-PEG nanoparticles and functionalized with alendronate (ALN),
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which is a type of bisphosphonate, as bone targeting moiety.[61]
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2.2.1.3 Chitosan NP´s
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Chitosan is one of the most used polymers in drug delivery due to its properties like biocompatibility,
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non-toxicity and biodegradability with ecological safety.[23] Chitosan is a copolymer of β-(1-4) linked
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2-acetamido-2-deoxy-β-D-glucopyranose and 2-amino-2-deoxy-β-D-glycopyranose, is obtained by
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deacetylation of chitin which is widely distributed in nature. The presence of amino groups permits it
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to be protonated at low pH that makes it soluble in water. On the other hand, when the pH increases
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over 6 the chitosan amines become deprotonated so the polymer becomes insoluble.[62] Saini et al.
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prepared nanoparticles by an ionic gelation process of chitosan and tripolyphosphate (Figure 2).[23]
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The interactions between the positive amino groups of chitosan and the negative charged
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tripolyphosphate caused the formation of the nanoparticles.[63] After that the drug raloxifene was
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loaded in the nanoparticles in order to achieve a new formulation for the intranasal delivery of
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raloxifene for osteoporosis therapy. Mucoadhesive nature of the polymer helped the nanoparticle in
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adhering to the nasal mucosa what permits the direct delivery of the drug to systemic circulation.
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Finally it was concluded that raloxifene loaded chitosan nanoparticles could be a novel drug delivery
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system for osteoporosis treatment. [23]
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2.2.2 Inorganic nanoparticles for osteoporosis treatment:
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2.2.2.1 Bioactive-silica nanoparticles:
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Some studies have suggested a beneficial effect of dietary silica on skeletal development in rats.[64]
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Clinical studies revealed positive associations between dietary silica intake and bone mineral density
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(BMD) in human cohorts.[65] Silica is famous for being nontoxic in vivo below the concentration of
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50000 ppm without adverse effects in rats.[2] However the mechanisms by which silica affects skeletal
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development are unknown. Some studies postulated that silica nanoparticles would be bioactive and
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beneficial to the skeleton.[2] Beck et al. examined the effect of 50nm silica-based nanoparticles on the
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differentiation of osteoclast and osteoblast. The authors of the study finally revealed that the
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nanoparticles were biologically active; they suppress osteoclast differentiation and stimulate osteoblast
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differentiation and mineralization in vitro. However, the exact mechanisms are not completely
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understood. The nuclear factor kappaB (NF-κB) is a transcription factor necessary for osteoclast
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differentiation,[66] and a potent inhibitor of osteoblast differentiation and activity.[67] Therefore,
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antagonists of NF-κB will promote osteoblast differentiation and will suppress osteoclast
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formation.[68] It is true that these nanoparticles suppress NF-κB signaling after 24h, what could be a
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partial explanation of how nanoparticles may regulate osteoclast and osteoblast differentiation.[2]
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Furthermore, in vivo nanoparticles have the capacity to increase BMD in mice, suggesting their
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possible application in osteoporosis treatment.[2] Recently, Ha et al. investigated the cellular
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mechanism by which silica-based nanoparticles stimulate differentiation and mineralization of
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osteoblasts. They revealed that nanoparticles are internalized by caveolae-mediated endocytosis,
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stimulate ERK1/2 signaling pathway, which is necessary for the processing of LC3β-I to LC3β-II,
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stimulating the autophagosome assembly. Although it is not completely understood, this process is
272
stimulatory to osteoblast differentiation and mineralization.[69] This conclusion is supported by a
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recent study which found that the inhibition of the autophagosome formation blocked bone
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mineralization.[70]
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Mesoporous silica nanoparticles (MSNs) have been also reported as a drug delivery system.[71,72] In
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2001, the mesoporous material MCM-41 was proposed for the first time as DDS.[73] Sun et al.
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fabricated MSNs anchored by zolendronate for targeting bone sites, which can be used as DDS of
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antiosteoporotic drugs.[74] Gene silencing through delivering small interfering RNA (siRNA) has a
279
lot of advantages due to the intrinsic nature of RNA interference (RNAi). SiRNA interferes reducing
280
the expression of a specific gene. This technique has gained great potential as bone disease therapy
281
enhancing bone tissue formation.[30] Among different silica-based nanoparticles, MSNs have great
282
potential to deliver molecules like siRNA. Generally, siRNAs have very short half-life, poor capacity
283
of penetration through the cell membranes, and are immediately degraded by RNase.[10]
284
Consequently, more research is necessary in order to find a nanocarrier which can solve these
285
problems. Because of their unique properties like, large surface area, surface functionality, tunable
286
pore size, loading capacity, and biocompatibility, MSN study as potential delivery systems for genetic
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molecules have increased.[75,76] Mesoporous bioactive glass nanospheres (MBG) are a type of
288
calcium-added MSNs. They have potential applications for hard tissue repairs and regeneration. Kim
289
et al. demonstrated a novel therapeutic application in which MBGs suppress osteoclastic functions by
290
delivering RANK siRNA. [10]
291
2.2.2.2 Metal nanoparticles:
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Thermotherapy has been attractive for the treatment of osteoporosis. It is capable of generating cell
293
death by disrupting cell membranes and denaturing intracellular proteins.[77] It has been used in order
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to control osteoporosis by destroying osteoclasts through thermolysis. Iron (II, III) oxide (Fe3O4)
295
nanoparticles are chemically stable, nontoxic, and cost efficient. They have a high magnetic field that
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can be used to increase local temperature, and in this way trigger osteoclast regulation.[78] Lee et al.
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synthesized nanoparticles of Fe3O4 by co-precipitation and then coated them with dextran (Dex), in
298
order to increase nanoparticle dispersion in aqueous solvents.[45] After that, to acquire the capacity to
299
bind bone surface, they grafted ALN onto magnetic nanoparticles. ALN has two principal groups, an
300
amino group, responsible for the inhibition of osteoclast activity, and a bisphosphonate group which
301
has high affinity to bone hydroxyapatite. The amino group is responsible for the main side effects
302
observed, namely nausea, abdominal discomfort or vomiting. Thus, they inactivated that group by
303
grafting it with the nanoparticles. Consequently, the ALN/Dex/Fe3O4 nanoparticles have affinity to
304
bone, can be phagocyted by osteoclasts, and then by radiofrequency induce thermolysis and cause
305
osteoclast death. [45]
306
Other metal nanoparticles, like gold nanoparticles, have been studied for osteoporosis applications.
307
Recent studies reported that gold nanoparticles can promote osteoblast differentiation and inhibit
308
osteoclast differentiation.[17,79] Choi et al. reported that chitosan-conjugated-gold nanoparticles at
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nontoxic concentrations (1 ppm) stimulate osteogenic differentiation of human adipose-derived
310
mesenchymal stem cells (hADMSCs). According to their results, mechanical stimulation by uptake of
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chitosan-conjugated AuNPs in hADMSCs enhances its differentiation into osteoblasts through the
312
activation of the Wnt/β-catenin signaling pathway. Consequently, the accumulation of β-catenin
313
promotes the differentiation of hADMSCs to osteoblast[79]. Lee et al. showed that 30nm gold
314
nanoparticles conjugated with ALN have a synergistic effect of inhibiting osteoclast
315
differentiation.[17] As we mentioned previously RANKL is a determinant factor for osteoclasts
316
differentiation, and reactive oxygen species (ROS) play an important role in this respect.[80] Gold
317
nanoparticles reduce the production of ROS by RANKL and also increase the expression of glutathione
318
peroxidase-1[81], both actions suppress osteoclast formation.[82]
319
2.2.2.3 Hydroxyapatite nanoparticles:
320
HA is a bio-mineral, one of the principal constituents of human bones matrix and teeth. HA is
321
biocompatible, biodegradable, and has excellent osteoconductive properties.[83] Early studies
322
demonstrated
323
regeneration.[84,85] In this regard, nanocarrier itself helps bone tissue to grow, and increases bone
324
mass deposition. Hwang et al.[47] designed HA-based nanoparticles which can deliver drugs and bone
325
mineral to bone tissue. In order to functionalize nanoparticles surface, they were coated by a layer-by-
326
layer method with three layers of poly (allylamine) (PAA) and alginate (ALG) (Figure 3). Then, at the
327
outmost layer, ALN was conjugated, which confers the capacity to bind bone tissue. ALN was used as
328
a targeting moiety and also as anti-resoprtive drug. The HA acts like a core for the nanoparticles, and
329
when they arrive to bone matrix they increase bone density by inducing osteoconduction.[47]
that
nano-sized
HA
promotes
osteoblast
bioactivity,
enhancing
bone
Polyallylamine
Alendronate
Layer
by
Layer
Sodium alginate
HA NPs
LbL-HA-NPs
ALN-LbL-HA NPs
330
331
Figure 3. Schematic design of ALN-LbL-HA NPs
332
Some studies reported that HA-based nanoparticles loaded with risendronate (RIS), which is a
333
bisphosphonate, increase bone density and improve stiffness and strength of bone. Compared to the
334
administration of RIS alone, HA-based nanoparticles loaded with RIS were much efficient, even with
335
lower concentrations of RIS, which reduced side effects.[83] Khajuria et al. chose zinc-hydroxyapatite
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(ZnHA) to design their nanoparticles.[13] They decided to dop the HA with zinc. Since several studies
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demonstrated that zinc-HA enhanced HA bioactivity. Zinc shares properties with calcium, so it can
338
replace calcium in HA and therefore in bone. Zinc enhances bone growth and bone mineralization by
339
stimulating osteogenesis of osteoblasts, represses osteoclast function,[68] and improves bone protein
340
synthesis.[86] However, it is important to know that concentrations over 225 mg of zinc generate
341
cytotoxic effects.[87] These ZnHA-based nanoparticles were loaded with RIS in order to achieve bone
342
targeting. The results demonstrated that ZnHA/RIS nanoparticles present a therapeutic advantage over
343
pure RIS or HA/RIS nanoparticles. [13]
344
Table 2. Summary of advantages and disadvantages of different types of nanoparticles
Type of nanoparticle
Advantages
Disadvantages
Liposomes
Load drugs with different solubilities
*Neutral liposomes: Longer
circulation half life, lower toxicity
Rapid uptake by
reticuloendothelialsystem
Toxicity
PLGA-nanoparticles
High capacity of cargo
Biocompatibility
Different drug release profiles
More in vivo
tests such as bone targeting
andwhole body biodistribution are
needed
Mesoporous Silica
Nanoparticles
Surface funstionality
Loading capacity
Biocompatibility
Bone-bioactivity related to ionic
release
The limited accessibility and high
cost of organic template lead to its
restricted use in practical
applications
There are not many studies done in
vivo, and this can be challenging for
MSN in clinical applications
Metal- nanoparticles
Hyperthermia treatment, inducing
thermolysis by radiofrequency.
Drug delivery, and can be used as
magnetic resonance imaging (MRI)
contrast agents
They can spontaneously aggregate
and cause vessel embolism after
intravenous application
Hydroxyapatite nanoparticles
HA promotes osteoblast bioactivity ,
nanocarrier itself helps bone tissue to
grow
Its brittleness that makes it a hardly
processed material.
345
346
3. Conclusion
347
Osteoporosis is a disease that has become a worldwide challenge, involving clinical, social and
348
economic issues. Health systems and industry should be aware of this problem mainly because of the
349
increase in life expectancy. This has a consequence of an ageing population more susceptible to suffer
350
osteoporosis. Being osteoporosis a disease that affects a increasing proportion of the population, its
351
treatment will have a great economic interest for the pharmaceutical industry. Current pharmacological
352
therapy presents some limitations related to bioavailability issues and toxicity. The emergence of
353
nanotechnology has provided new strategies for improving the properties of these therapies. Among
354
different nanocarries bone-targeted nanoparticles represents a great potential for clinical applications
355
in delivering drugs to bone niches. They are able to increase local drug concentration, reduce off-target
356
side effects, and would lengthen the therapeutic window. However, only limited work has been
357
reported so far on the release pattern and mechanism(s) involved, especially for the newly developed
358
carriers. Consequently, more research is awaiting driven by the optimization of the carriers, focusing
359
on drug release, stability and safety. Although more research is needed for clinical applications, there
360
is an opportunity for prospective treatment options by enhancing nanotechnology.
361
Acknowledgements
362
The authors thank funding from the the European Research Council (Advanced Grant VERDI; ERC-
363
2015-AdG Proposal no. 694160).
364
References
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
1. Kanis JA, Kanis JA. Assessment of fracture risk and its application to screening for
postmenopausal osteoporosis: Synopsis of a WHO report. Osteoporos Int. 1994;4: 368–381.
doi:10.1007/BF01622200
2. Beck GR, Ha SW, Camalier CE, Yamaguchi M, Li Y, Lee JK, et al. Bioactive silica-based
nanoparticles stimulate bone-forming osteoblasts, suppress bone-resorbing osteoclasts, and
enhance bone mineral density in vivo. Nanomedicine Nanotechnology, Biol Med. Elsevier B.V.;
2012;8: 793–803. doi:10.1016/j.nano.2011.11.003
3. Khajuria DK, Razdan R, Mahapatra DR. Drugs for the management of osteoporosis: A review.
Rev Bras Reumatol. 2011;51: 365–382.
4. Arcos D, Boccaccini AR, Bohner M, Díez-Pérez A, Epple M, Gómez-Barrena E, et al. The
relevance of biomaterials to the prevention and treatment of osteoporosis. Acta Biomater. Acta
Materialia Inc.; 2014;10: 1793–1805. doi:10.1016/j.actbio.2014.01.004
5. Wei D, Jung J, Yang H, Stout DA, Yang L. Nanotechnology Treatment Options for Osteoporosis
and Its Corresponding Consequences. Curr Osteoporos Rep. Current Osteoporosis Reports; 2016;
1–9. doi:10.1007/s11914-016-0324-1
6. Riggs BL, Melton LJ. The worldwide problem of osteoporosis: Insights afforded by epidemiology.
Bone. 1995;17. doi:10.1016/8756-3282(95)00258-4
7. Mackey PA, Whitaker MD. Osteoporosis: A Therapeutic Update. J Nurse Pract. Elsevier, Inc;
2015;11: 1011–1017. doi:10.1016/j.nurpra.2015.08.010
8. Hernlund E, Svedbom A, Ivergård M, Compston J, Cooper C, Stenmark J, et al. Osteoporosis in
the European Union: Medical management, epidemiology and economic burden: A report prepared
in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation
of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos. 2013;8. doi:10.1007/s11657013-0136-1
9. Kanis JA, McCloskey E V., Johansson H, Cooper C, Rizzoli R, Reginster JY. European guidance
for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int.
2013;24: 23–57. doi:10.1007/s00198-012-2074-y
10. Kim T, Singh RK, Sil M, Kim J, Kim H. Acta Biomaterialia Inhibition of osteoclastogenesis
through siRNA delivery with tunable mesoporous bioactive nanocarriers. Acta Biomater. Acta
Materialia Inc.; 2016;29: 352–364. doi:10.1016/j.actbio.2015.09.035
11. Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, et al. Parathyroid
hormone and teriparatide for the treatment of osteoporosis: A review of the evidence and suggested
guidelines for its use. Endocr Rev. 2005;26: 688–703. doi:10.1210/er.2004-0006
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
12. Weitzmann MN, Ha SW, Vikulina T, Roser-Page S, Lee JK, Beck GR. Bioactive silica
nanoparticles reverse age-associated bone loss in mice. Nanomedicine Nanotechnology, Biol Med.
Elsevier B.V.; 2015;11: 959–967. doi:10.1016/j.nano.2015.01.013
13. Khajuria DK, Disha C, Vasireddi R, Razdan R, Mahapatra DR. Risedronate/zinc-hydroxyapatite
based nanomedicine for osteoporosis. Mater Sci Eng C. Elsevier B.V.; 2016;63: 78–87.
doi:10.1016/j.msec.2016.02.062
14. Giger E V., Castagner B, Leroux JC. Biomedical applications of bisphosphonates. J Control
Release. Elsevier B.V.; 2013;167: 175–188. doi:10.1016/j.jconrel.2013.01.032
15. Iñiguez-Ariza NM, Clarke BL. Bone biology, signaling pathways, and therapeutic targets for
osteoporosis. Maturitas. 2015;82: 245–255. doi:10.1016/j.maturitas.2015.07.003
16. Kanakaris NK, Petsatodis G, Tagil M, Giannoudis P V. Is there a role for bone morphogenetic
proteins in osteoporotic fractures? Injury. Elsevier Ltd; 2009;40 Suppl 3: S21–S26.
doi:10.1016/S0020-1383(09)70007-5
17. Lee D, Heo DN, Kim H, Ko W, Lee SJ, Heo M, et al. Inhibition of Osteoclast Differentiation and
Bone Resorption by Bisphosphonate- conjugated Gold Nanoparticles. Nat Publ Gr. Nature
Publishing Group; 2016; 1–11. doi:10.1038/srep27336
18. Eriksen EF, Díez-Pérez A, Boonen S. Update on long-term treatment with bisphosphonates for
postmenopausal osteoporosis: A systematic review. Bone. Elsevier B.V.; 2014;58: 126–135.
doi:10.1016/j.bone.2013.09.023
19. Black DM, Schwartz A V, Ensrud KE, Cauley J a, Levis S, Quandt S a, et al. Effects of continuing
or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term
Extension
(FLEX):
a
randomized
trial.
JAMA.
2006;296:
2927–2938.
doi:10.1097/01.ogx.0000259157.48200.87
20. Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, et al. RANK is
essential for osteoclast and lymph node development. Genes Dev. 1999;13: 2412–2424.
doi:10.1101/gad.13.18.2412
21. Trejo CG, Lozano D, Manzano M, Doadrio JC, Salinas AJ, Dapía S, et al. The osteoinductive
properties of mesoporous silicate coated with osteostatin in a rabbit femur cavity defect model.
Biomaterials. Elsevier Ltd; 2010;31: 8564–8573. doi:10.1016/j.biomaterials.2010.07.103
22. Barry M, Pearce H, Cross L, Tatullo M, Gaharwar AK. Advances in Nanotechnology for the
Treatment of Osteoporosis. Curr Osteoporos Rep. Current Osteoporosis Reports; 2016;14: 87–94.
doi:10.1007/s11914-016-0306-3
23. Saini D, Fazil M, Ali MM, Baboota S, Ali J. Formulation, development and optimization of
raloxifene-loaded chitosan nanoparticles for treatment of osteoporosis. Drug Deliv. 2014;7544: 1–
14. doi:10.3109/10717544.2014.900153
24. Ponnapakkam T, Katikaneni R, Sakon J, Stratford R, Gensure RC. Treating osteoporosis by
targeting parathyroid hormone to bone. Drug Discov Today. Elsevier Ltd; 2014;19: 204–208.
doi:10.1016/j.drudis.2013.07.015
25. Narayanan D, Anitha A, Jayakumar R, Chennazhi KP. In vitro and in vivo evaluation of
osteoporosis therapeutic peptide PTH 1-34 loaded PEGylated chitosan nanoparticles. Mol Pharm.
2013;10: 4159–4167. doi:10.1021/mp400184v
26. Lindsay R, Krege JH, Marin F, Jin L, Stepan JJ. Teriparatide for osteoporosis: importance of the
full course. Osteoporos Int. 2016; 1–16. doi:10.1007/s00198-016-3534-6
27. Ong KL, Villarraga ML, Lau E, Carreon LY, Kurtz SM, Glassman SD. Off-label use of bone
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
morphogenetic proteins in the United States using administrative data. Spine (Phila Pa 1976).
2010;35: 1794–1800. doi:10.1097/BRS.0b013e3181ecf6e4
28. Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone
morphogenetic protein-2 trials in spinal surgery: Emerging safety concerns and lessons learned.
Spine J. Elsevier Inc; 2011;11: 471–491. doi:10.1016/j.spinee.2011.04.023
29. Canalis E. Update in new anabolic therapies for osteoporosis. J Clin Endocrinol Metab. 2010;95:
1496–1504. doi:10.1210/jc.2009-2677
30. Tokatlian T, Segura T. siRNA applications in nanomedicine. Wiley Interdiscip Rev
Nanomedicine Nanobiotechnology. 2010;2: 305–315. doi:10.1002/wnan.81
31. Guo B, Wu H, Tang T, Zhang B-T, Zheng L, He Y, et al. A delivery system targeting bone
formation surfaces to facilitate RNAi-based anabolic therapy. Nat Med. Nature Publishing Group;
2012;18: 309–316. doi:10.1038/nm.2617
32. Lin JH. Bisphosphonates: A review of their pharmacokinetic properties. Bone. 1996;18: 75–85.
doi:10.1016/8756-3282(95)00445-9
33. Aoki K, Alles N, Soysa N, Ohya K. Peptide-based delivery to bone. Adv Drug Deliv Rev. Elsevier
B.V.; 2012;64: 1220–1238. doi:10.1016/j.addr.2012.05.017
34. Cenni E, Granchi D, Avnet S, Fotia C, Salerno M, Micieli D, et al. Biocompatibility of poly(d,llactide-co-glycolide) nanoparticles conjugated with alendronate. Biomaterials. 2008;29: 1400–
1411. doi:10.1016/j.biomaterials.2007.12.022
35. Choi SW, Kim JH. Design of surface-modified poly(d,l-lactide-co-glycolide) nanoparticles for
targeted
drug
delivery
to
bone.
J
Control
Release.
2007;122:
24–30.
doi:10.1016/j.jconrel.2007.06.003
36. Xinluan W, Yuxiao L, Helena NH, Zhijun Y, Ling Q. Systemic Drug Delivery Systems for Bone
Tissue
Regeneration
–
A
Mini
Review.
2015;
1575–1583.
doi:10.2174/1381612821666150115152841
37. Yokogawa K, Miya K, Sekido T, Higashi Y, Nomura M, Fujisawa R, et al. Selective delivery of
estradiol to bone by aspartic acid oligopeptide and its effects on ovariectomized mice.
Endocrinology. 2001;142: 1228–1233. doi:10.1210/en.142.3.1228
38. Pignatello R. PLGA-Alendronate Conjugate as a New Biomaterial to Produce Osteotropic Drug
Nanocarriers.IntechopenCom. Available: http://www.intechopen.com/source/pdfs/23623/InTechPlga_alendronate_conjugate_as_a_new_biomaterial_to_produce_osteotropic_drug_nanocarriers.
39. Heller DA, Levi Y, Pelet JM, Doloff JC, Wallas J, Pratt GW, et al. Modular “click-in-emulsion”
bone-targeted nanogels. Adv Mater. 2013;25: 1449–1454. doi:10.1002/adma.201202881
40. Willson TM, Henke BR, Momtahen TM, Garrison DT, Moore LB, Geddie NG, et al. Bone
targeted drugs 2. Synthesis of estrogens with hydroxyapatite affinity. Bioorganic Med Chem Lett.
1996;6: 1047–1050. doi:10.1016/0960-894X(96)00165-5
41. Yarbrough DK, Hagerman E, Eckert R, He J, Choi H, Cao N, et al. Specific binding and
mineralization of calcified surfaces by small peptides. Calcif Tissue Int. 2010;86: 58–66.
doi:10.1007/s00223-009-9312-0
42. Carrow JK, Gaharwar AK. Bioinspired polymeric nanocomposites for regenerative medicine.
Macromol Chem Phys. 2015;216: 248–264. doi:10.1002/macp.201400427
43. Lee M-S, Su C-M, Yeh J-C, Wu P-R, Tsai T-Y, Lou S-L. Synthesis of composite magnetic
nanoparticles Fe3O4 with alendronate for osteoporosis treatment. Int J Nanomedicine. 2016;11:
4583–4594. doi:10.2147/IJN.S112415
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
44. Kedmi R, Ben-Arie N, Peer D. The systemic toxicity of positively charged lipid nanoparticles and
the role of Toll-like receptor 4 in immune activation. Biomaterials. Elsevier Ltd; 2010;31: 6867–
6875. doi:10.1016/j.biomaterials.2010.05.027
45. Hwang S-J, Lee J-S, Ryu T-K, Kang R-H, Jeong K-Y, Jun D-R, et al. Alendronate-modified
hydroxyapatite nanoparticles for bone-specific dual delivery of drug and bone mineral. Macromol
Res. 2016;24: 623–628. doi:10.1007/s13233-016-4094-5
46. Lu T, Ma Y, Hu H, Chen Y, Zhao W, Chen T. Ethinylestradiol liposome preparation and its effects
on
ovariectomized
rats’
osteoporosis.
Drug
Deliv.
2011;18:
468–477.
doi:10.3109/10717544.2011.589085
47. Allen TM, Cullis PR. Liposomal drug delivery systems: From concept to clinical applications.
Adv Drug Deliv Rev. Elsevier B.V.; 2013;65: 36–48. doi:10.1016/j.addr.2012.09.037
48. Kundu SK, Sharma AR, Lee SS, Sharma G, Doss CGP, Yagihara S, et al. Recent trends of polymer
mediated liposomal gene delivery system. Biomed Res Int. 2014;2014. doi:10.1155/2014/934605
49. Madni A, Sarfraz M, Rehman M, Ahmad M, Akhtar N, Ahmad S. Liposomal Drug Delivery: A
Versatile Platform for Challenging Clinical Applications. 2014;17: 401–426.
doi:10.18433/J3CP55
50. Fang C, Shi B, Pei YY, Hong MH, Wu J, Chen HZ. In vivo tumor targeting of tumor necrosis
factor-α-loaded stealth nanoparticles: Effect of MePEG molecular weight and particle size. Eur J
Pharm Sci. 2006;27: 27–36. doi:10.1016/j.ejps.2005.08.002
51. Zhang J, Li X, Huang L. Non-viral nanocarriers for siRNA delivery in breast cancer. J Control
Release. Elsevier B.V.; 2014;190: 440–450. doi:10.1016/j.jconrel.2014.05.037
52. Hughes J, Yadava P, Mesaros R. Liposomes. 2010;605: 445–459. doi:10.1007/978-1-60327-3602
53. Ropert C. Liposomes as a gene delivery system. Brazilian J Med Biol Res. 1999;32: 163–169.
doi:10.1590/S0100-879X1999000200004
54. Hengst V, Oussoren C, Kissel T, Storm G. Bone targeting potential of bisphosphonate-targeted
liposomes. Preparation, characterization and hydroxyapatite binding in vitro. Int J Pharm.
2007;331: 224–227. doi:10.1016/j.ijpharm.2006.11.024
55. Vert M, Schwach G, Engel R, Coudane J. Something new in the field of PLA / GA bioresorbable
polymers? J Control Release. 1998;53: 85–92.
56. Mooney DT, Mazzoni CL, Breuer C, McNamara K, Hern D, Vacanti JP, et al. Stabilized
polyglycolic acid fibre based tubes for tissue engineering. Biomaterials. 1996;17: 115–124.
Available: http://www.vanderbilt.edu/viibre/members/documents/10033-Mooney-B-1996.pdf
57. Jiang T, Yu X, Carbone EJ, Nelson C, Kan HM, Lo KWH. Poly aspartic acid peptide-linked
PLGA based nanoscale particles: Potential for bone-targeting drug delivery applications. Int J
Pharm. Elsevier B.V.; 2014;475: 547–557. doi:10.1016/j.ijpharm.2014.08.067
58. Fu YC, Fu TF, Wang HJ, Lin CW, Lee GH, Wu SC, et al. Aspartic acid-based modified PLGAPEG nanoparticles for bone targeting: In vitro and in vivo evaluation. Acta Biomater. Acta
Materialia Inc.; 2014;10: 4583–4596. doi:10.1016/j.actbio.2014.07.015
59. Y. C, C. Q, M. L, J. L, G. H, G. T, et al. Alendronate-decorated biodegradable polymeric micelles
for potential bone-targeted delivery of vancomycin. J Biomater Sci Polym Ed. 2015;26: 629–643.
doi:10.1080/09205063.2015.1053170
60. Yi H, Wu LQ, Bentley WE, Ghodssi R, Rubloff GW, Culver JN, et al. Biofabrication with
chitosan. Biomacromolecules. 2005;6: 2881–2894. doi:10.1021/bm050410l
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
61. Aktaş Y, Andrieux K, Alonso MJ, Calvo P, Gürsoy RN, Couvreur P, et al. Preparation and in vitro
evaluation of chitosan nanoparticles containing a caspase inhibitor. Int J Pharm. 2005;298: 378–
383. doi:10.1016/j.ijpharm.2005.03.027
62. Schwarz K, Milne D. Growth-promoting effects of Silicon in rats. Nature. 1972;239: 333–334.
doi:10.1038/239333a0
63. Jugdaohsingh R. Silicon and bone health. J Nutr Health Aging. 2007;11: 99–110. Available:
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2658806/%5Cnhttp://www.pubmedcentral.nih.gov
/articlerender.fcgi?artid=2658806&tool=pmcentrez&rendertype=abstract
64. Boyce BF, Yao Z, Xing L. Functions of nuclear factor κb in bone. Ann N Y Acad Sci. 2010;1192:
367–375. doi:10.1111/j.1749-6632.2009.05315.x
65. Nanes MS. Tumor necrosis factor-α: Molecular and cellular mechanisms in skeletal pathology.
Gene. 2003;321: 1–15. doi:10.1016/S0378-1119(03)00841-2
66. Yamaguchi M, Neale Weitzmann M. The intact strontium ranelate complex stimulates
osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-κB activation. Mol Cell
Biochem. 2012;359: 399–407. doi:10.1007/s11010-011-1034-8
67. Ha SW, Neale Weitzmann M, Beck GR. Bioactive silica nanoparticles promote osteoblast
differentiation through stimulation of autophagy and direct association with LC3 and p62. ACS
Nano. 2014;8: 5898–5910. doi:10.1021/nn5009879
68. Liu F, Fang F, Yuan H, Yang D, Chen Y, Williams L, et al. Suppression of autophagy by FIP200
deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation. J
Bone Miner Res. 2013;28: 2414–2430. doi:10.1002/jbmr.1971
69. Baeza A, Manzano M, Colilla M, Vallet-Regí M. Recent advances in mesoporous silica
nanoparticles for antitumor therapy: our contribution. Biomater Sci. Royal Society of Chemistry;
2016;4: 803–813. doi:10.1039/C6BM00039H
70. Vallet-Regí M, Balas F, Arcos D. Mesoporous materials for drug delivery. Angew Chemie - Int
Ed. 2007;46: 7548–7558. doi:10.1002/anie.200604488
71. Vallet-Regi M, Rámila A, Del Real RP, Pérez-Pariente J. A new property of MCM-41: Drug
delivery system. Chem Mater. 2001;13: 308–311. doi:10.1021/cm0011559
72. Sun W, Han Y, Li Z, Ge K, Zhang J. Bone-Targeted Mesoporous Silica Nanocarrier Anchored by
Zoledronate
for
Cancer
Bone
Metastasis.
Langmuir.
2016;32:
9237–9244.
doi:10.1021/acs.langmuir.6b02228
73. Baeza A, Colilla M, Vallet-Regí M. Advances in mesoporous silica nanoparticles for targeted
stimuli-responsive drug delivery. Expert Opin Drug Deliv. 2015;12: 319–37.
doi:10.1517/17425247.2014.953051
74. Paris JL, Torre PD La, Manzano M, Cabañas MV, Flores AI, Vallet-Regí M. Decidua-derived
mesenchymal stem cells as carriers of mesoporous silica nanoparticles. in vitro and in vivo
evaluation on mammary tumors. Acta Biomater. Acta Materialia Inc.; 2016;33: 275–282.
doi:10.1016/j.actbio.2016.01.017
75. Jordan A, Scholz R, Maier-Hauff K, van Landeghem FKH, Waldoefner N, Teichgraeber U, et al.
The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. J Neurooncol.
2006;78: 7–14. doi:10.1007/s11060-005-9059-z
76. Figuerola A, Di Corato R, Manna L, Pellegrino T. From iron oxide nanoparticles towards
advanced iron-based inorganic materials designed for biomedical applications. Pharmacol Res.
Elsevier Ltd; 2010;62: 126–143. doi:10.1016/j.phrs.2009.12.012
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
77. Choi SY, Song MS, Ryu PD, Lam AT, Joo SW, Lee SY. Gold nanoparticles promote osteogenic
differentiation in human adipose-derived mesenchymal stem cells through the Wnt/beta-catenin
signaling pathway. Int J Nanomedicine. 2015;10: 4383–4392. doi:10.2147/IJN.S78775
78. Lee NK, Choi YG, Baik JY, Han SY, Jeong D, Bae YS, et al. HEMATOPOIESIS A crucial role
for reactive oxygen species in RANKL-induced osteoclast differentiation. 2005;106: 852–859.
doi:10.1182/blood-2004-09-3662.Supported
79. Sul O-J, Kim J-C, Kyung T-W, Kim H-J, Kim Y-Y, Kim S-H, et al. Gold nanoparticles inhibited
the receptor activator of nuclear factor-κb ligand (RANKL)-induced osteoclast formation by acting
as an antioxidant. Biosci Biotechnol Biochem. 2010;74: 2209–2213. doi:10.1271/bbb.100375
80. Lean JM, Jagger CJ, Kirstein B, Fuller K, Chambers TJ. Hydrogen peroxide is essential for
estrogen-deficiency bone loss and osteoclast formation. Endocrinology. 2005;146: 728–735.
doi:10.1210/en.2004-1021
81. Sahana H, Khajuria DK, Razdan R, Mahapatra DR, Bhat MR, Suresh S, et al. Improvement in
bone properties by using risedronate adsorbed hydroxyapatite novel nanoparticle based
formulation in a rat model of osteoporosis. J Biomed Nanotechnol. 2013;9: 193–201.
doi:10.1166/jbn.2013.1482
82. Lin L, Chow KL, Leng Y. Study of hydroxyapatite osteoinductivity with an osteogenic
differentiation of mesenchymal stem cells. J Biomed Mater Res - Part A. 2009;89: 326–335.
doi:10.1002/jbm.a.31994
83. Webster TJ, Ergun C, Doremus RH, Siegel RW, Bizios R. Enhanced functions of osteoblasts on
nanophase ceramics. Biomaterials. 2000;21: 1803–1810. doi:10.1016/S0142-9612(00)00075-2
84. Yamaguchi M. Role of nutritional zinc in the prevention of osteoporosis. Mol Cell Biochem.
2010;338: 241–254. doi:10.1007/s11010-009-0358-0
85. Ito A, Otsuka M, Kawamura H, Ikeuchi M, Ohgushi H, Sogo Y, et al. Zinc-containing tricalcium
phosphate and related materials for promoting bone formation. Curr Appl Phys. 2005;5: 402–406.
doi:10.1016/j.cap.2004.10.006
600
601
602
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