Development of Polyethylene Glycol-Conjugated Alendronate, a Novel Nitrogen-Containing Bisphosphonate Derivative: Evaluation of Absorption, Safety, and Effects After Intrapulmonary Administration in Rats

Katsumi, Hidemasa; Takashima, Miki; Sano, Junichi; Nishiyama, Kazushi; Kitamura, Noriko; Sakane, Toshiyasu; Hibi, Toru; Yamamoto, Akira

doi:10.1002/jps.22620

Cited by 29 publications

(15 citation statements)

References 37 publications

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“…PEG‐ALE was synthesized with a yield of 15% by reacting alendronate with methoxy‐PEG‐succinimidyl carboxymethyl ester, MW 2000 (methoxy‐PEG‐NHS) ( Figures A and C) 26. The synthesis of the PEG‐IP5 started from the known protected myo ‐inositol 1 27 that was alkylated with methoxy‐PEG‐toluenesulfonyl ester in the presence of base, and then deprotected by hydrogenolysis to afford compound 3 (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

siRNA Transfection with Calcium Phosphate Nanoparticles Stabilized with PEGylated Chelators

Giger¹,

Castagner²,

Räikkönen³

et al. 2012

Adv Healthcare Materials

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Despite the enormous therapeutic potential of siRNAs, their delivery is still problematic due to unfavorable biodistribution profiles and poor intracellular bioavailability. Calcium phosphate co-precipitate has been used for nearly 40 years for in vitro transfection due to its non-toxic nature and simplicity of preparation. However, rapid particle growth has largely prevented the translation of this method for in vivo purposes. It has recently been shown that bisphosphonate derivatives can physically stabilize calcium phosphate nanoparticles while still allowing for efficient cell transfection with plasmid DNA. Herein, two novel PEGylated chelating agents (PEG-alendronate and PEG-inositolpentakisphosphate) with enhanced stabilizing properties are introduced, and it is demonstrated that the bisphosphonate-stabilized nanoparticles can efficiently deliver siRNA in vitro. The nanoparticles are mainly taken up by clathrin-dependent endocytosis, and acidification of the endosomal compartment is required to release the entrapped siRNA into the cytosol. Furthermore, particle uptake enhances the inhibition of the mevalonate pathway by the bisphosphonate in macrophages.

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Section: Resultsmentioning

confidence: 99%

siRNA Transfection with Calcium Phosphate Nanoparticles Stabilized with PEGylated Chelators

Giger¹,

Castagner²,

Räikkönen³

et al. 2012

Adv Healthcare Materials

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“…The correlation between GI AE with increased pH and inflammation has been confirmed in these models using gastro protective and anti-inflammatory agents, showing a decrease in the occurrence and magnitude of these AE [43][44][45][46][47][48]. Thus, in the last years, different oral formulations than tablets have been tested and proposed for osteoporosis treatment [49]. However, at present only few studies investigated these new formulations in human subjects.…”

Section: New Alendronate Formulationmentioning

confidence: 91%

The potential impact of new effervescent alendronate formulation on compliance and persistence in osteoporosis treatment

2014

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Osteoporotic fractures are a public health problem and their incidence and subsequent economic and social costs are expected to rise in the next future. Different drugs have been developed to reduce osteoporosis and the risk of osteoporotic fractures, and among them, antiresorptive agents, and in particular oral alendronate, are the most widely utilized. However, one of the most common problems with antiresorptive drugs is poor adherence to treatment, which is associated with a high fracture incidence and with an increase in hospitalization costs. One of the main reasons of poor adherence to these treatments is the occurrence of adverse events, mainly at gastrointestinal (GI) level, including dyspepsia, dysphagia, and esophageal ulcers. In light of these considerations the aim of this paper is to perform a literature review to show the pathophysiologic bases of GI alendronate-induced adverse events and how new bisphosphonate formulations like effervescent alendronate can improve compliance and persistence to treatment and decrease the fracture rate incidence in osteoporotic patients.

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“…To improve bioavailability and safety of Ale, it has been conjugates to PEG that is known to inhibit unwanted interactions with elements of biological systems [75]. Intrapulmonary administration of PEG--aledronate conjugates in osteoporotic rats was shown to effectively inhibit decrease of the growth plate to a level achieved with Ale.…”

Section: Translation Of Anti-osteoporotic Activity Of Low-molecular-wmentioning

confidence: 98%

Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

Ossipov

2015

Expert Opinion on Drug Delivery

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Calcium-binding properties of BPs can be successfully extended via different conjugation strategies not only for purposes of bone targeting, but also in supramolecular assembly affording either new nanocarriers or bulk nanocomposite scaffolds. Interaction between carrier-linked BPs and drug molecules should also be considered for the control of release of these molecules and their optimized delivery. Bone-targeting properties of BP-functionalized nanomaterials should correspond to bone adhesive properties of their bulk analogs.

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Development of Polyethylene Glycol-Conjugated Alendronate, a Novel Nitrogen-Containing Bisphosphonate Derivative: Evaluation of Absorption, Safety, and Effects After Intrapulmonary Administration in Rats

Cited by 29 publications

References 37 publications

siRNA Transfection with Calcium Phosphate Nanoparticles Stabilized with PEGylated Chelators

siRNA Transfection with Calcium Phosphate Nanoparticles Stabilized with PEGylated Chelators

The potential impact of new effervescent alendronate formulation on compliance and persistence in osteoporosis treatment

Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

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