Targeting Systemically Administered Proteins to Bone by Bisphosphonate Conjugation

Uludağ, Hasan; Yang, Jennifer

doi:10.1021/bp0200447

Cited by 64 publications

(69 citation statements)

References 28 publications

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“…19 For bone targeting purposes, conjugates with ϳ 11 aminoBP/BSA were capable of seeking bone tissue after systemic administration due to their inherent affinity to the bone mineral hydroxyapatite. 6 Accordingly, the reaction conditions utilizing the SPDP and thiolBP were able to yield the necessary extent of BP substitution on the target protein.…”

Section: Control Of Bp Conjugation To Bsamentioning

confidence: 99%

“…The feasibility of this approach has been shown by conjugating BPs to several proteins, including albumin, 5 lysozyme, 6 nonspecific IgG, 7 and fetuin, 8 which were all shown to exhibit increased hydroxyapatite binding upon BP conjugation. The fetuin-BP conjugates were recently shown to exhibit an increased mineral affinity in vivo when they were implanted subcutaneously by using coralline apatite Pro-Osteon™ implants that are used for spinal surgery.…”

Section: Contract Grant Sponsor: Canadian Health Institutes Of Researmentioning

confidence: 99%

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Imparting mineral affinity to proteins with thiol–labile disulfide linkages

Bansal

Wright

Zhang

et al. 2005

J Biomedical Materials Res

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Chemical conjugation of bisphosphonates (BPs) to proteins is an effective means to enhance binding of proteins to mineral-containing biomaterials. BPs linked to proteins with reversible (i.e., cleavable) linkages were considered desirable over the conjugates linked with stable linkages because cleavable linkages allow protein release in free form from the mineral-containing biomaterials. To explore the feasibility of creating cleavable BP-protein conjugates, an amine- and a thiol-containing BP were conjugated to the model protein Bovine Serum Albumin (BSA) with N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), which resulted in disulfide-linked BP-BSA conjugates. Although disulfide-linked conjugates were stable under aqueous conditions, the conjugates in solution were readily cleaved in the presence of physiological concentrations (approximately 0.3 mM) of the thiol compound, cysteine. The imparted mineral affinity as a result of BP conjugation, as assessed by hydroxyapatite (HA) binding in vitro, was lost upon cleavage of the disulfide-linked BP. The conjugates bound to HA were also cleavable with cysteine, but their cleavage rate was significantly reduced as compared to the conjugates in solution. In conclusion, disulfide-linked BP conjugates were shown to be readily cleavable by the amino acid cysteine and this resulted in the loss of imparted mineral affinity of the proteins. The proposed approach will be useful for modulating in vivo delivery of proteins implanted with mineral-containing biomaterials.

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Section: Control Of Bp Conjugation To Bsamentioning

confidence: 99%

Section: Contract Grant Sponsor: Canadian Health Institutes Of Researmentioning

confidence: 99%

Imparting mineral affinity to proteins with thiol–labile disulfide linkages

Bansal

Wright

Zhang

et al. 2005

J Biomedical Materials Res

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“…Entretanto, a afinidade aos ossos não foi comprovada 43 . Uludag e colaboradores 44 , utilizando albumina sérica bovina (ASB) como proteína modelo, demonstraram in vitro que a afinidade da proteína modificada é diretamente proporcional à extensão de conjugação (5 BFs por proteína). O conjugado aminoBF (BF-ASB) mostrou ter alta afinidade óssea in vivo após injeção intra-óssea (tí-bia) em ratos 30 .…”

Section: Proteínas Dirigidas Aos Ossosunclassified

Bifosfonatos (BFs) como transportadores osteotrópicos no planejamento de fármacos dirigidos

Castro¹,

Silva²,

Chin³

et al. 2004

Quím. Nova

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Recebido em 14/4/03; aceito em 21/10/03 BISPHOSPHONATES AS OSTEOTROPIC CARRIERS FOR DESIGNING SITE-DIRECTED DRUGS. Drug therapy involving bone tissue diseases is difficult, calling for the design of specific drugs. The present paper is a brief review of a new site-directed system termed ODDS (osteotropic drug delivery system), based on a latenciation process, using bisphosphonates as bone carriers. This is an important tool for the rational prodrug design for obtaining selective drugs.Keywords: bisphosphonates; prodrugs; ODDS. INTRODUÇÃOA liberação seletiva de fármacos no local de ação via pró-fármacos tem gerado interesse considerável para aumentar a potência e diminuir os efeitos adversos dos protótipos dos quais derivam. Embora muitas formas de pró-fármacos seletivos tenham sido desenvolvidas, o tecido ósseo ainda permanecia como um alvo limitado, devido às suas propriedades biológicas e à falta de um sistema circulatório semelhante ao de outros tecidos 1 . O tecido ósseo adulto é distinguido de outros tecidos pela presença de fosfato e cálcio mineral, como a hidroxiapatita [Ca 10 (PO 4 ) 6 (OH) 2 ], que incorpora em sua estrutura outros íons e sais, sendo o principal componente mineral constituinte do osso e o elemento essencial responsável pela função de apoio mecânico 2-4 . Devido à dinâmica do tecido ósseo, este é continuamente desgastado pela atividade osteoclástica e substituído pela atividade osteoblástica, ambas reguladas por fatores sistêmicos e locais [5][6] . Como qualquer outro tecido, os ossos são suscetíveis a doenças que influenciam a atividade osteoclástica, como o hiperparatiroidismo e câncer, sendo a hipercalcemia resultado de destruição direta e localizada do tecido ósseo por células neoplásicas 7 . Exemplos primá-rios são a artrite reumatóide (AR) e a lesão espinhal, nas quais se observa a perda gradual e rápida de massa óssea 8,9 . Recentemente, propôs-se um novo e promissor sistema de liberação de fármacos para atingir o tecido ósseo via pró-fármacos denominado "Osteotropic Drug Delivery System (ODDS)", que utiliza os bifosfonatos como transportadores 10 . Os bifosfonatos (BFs) são conhecidos por sua alta afinidade pela hidroxiapatita. Esta propriedade trópica óssea dos BFs possibilitou sua utilização no planejamento de formas latentes de liberação de fármacos nas estruturas ósseas ou na medula óssea 1 . Os pirofosfatos (P-O-P) são reguladores fisiológicos da calcificação e reabsorção óssea, naturalmente presentes no soro e na urina. A ação dos bifosfonatos deve-se à sua semelhança estrutural com este grupo de compostos 11-13 (Figura 1).O trabalho nesta área tem-se concentrado na liberação de radioisótopos, mas, atualmente, as pesquisas compreendem a liberação de outras moléculas, cuja atividade farmacológica é bem definida. Estas incluem agentes antineoplásicos, anabolizantes, antiinflamatórios e, recentemente, proteínas 4 .A descoberta de que os BFs podiam inibir a reabsorção óssea foi realizada em 1960, após tentativas para identificar agentes que fossem semelhantes ao pirofosfato e q...

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“…The initiator used was succinimide-derivatized 4,4'-azobis(4-cyanovaleric acid), whose decomposition kinetics was similar to parent azo-compound: t 1/2 : 231 and 247 minutes, respectively, at 70 0 C in DMF [26]. To synthesize the initiator, 3 g (10.7 mmol) of 4,4'-azobis(4-cyanovaleric acid) and 2.5 g (21 mmol) NHS were dissolved in 50 mL anhydrous DMF.…”

Section: Synthesis and Characterization Of Random (Rp) And Comb Polymmentioning

confidence: 99%

Hydrogels of Thermoreversible Comb‐Polymers Exhibit Increased Resistance for Dissolution

Jalil

Uludağ

2004

Materialwissenschaft Werkst

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The N-isopropylacrylamide (NiPAM) polymers exhibit thermoreversible properties in aqueous solutions. The resiliency of NiPAM hydrogels is believed to influence the outcome when the polymers are utilized in biomedical applications. To determine the influence of polymer architecture on hydrogel resiliency, polymers of Ni-PAM, methyl methacrylate (MMA) and acrylic acid were synthesized as random polymers and as comb polymers, where MMA was incorporated as side-chains. Random polymers exhibited a Lower Critical Solution Temperature (LCST) that decreased in proportion to MMA content in polymers. The LCST of comb polymers was not dependent on MMA content or the length of MMA side-chain (between 3.0 and 10.1 kD). Whereas low molecular weight ($100 kD) random polymers did not form intact gels, comb-polymers of equivalent molecular weight were capable of forming intact gels. Gel resiliency, as determined by propensity of hydrogels to dissolve upon cooling, was improved when the molecular weight of comb-polymers was increased but the length of the MMA sidebranch did not influence the gel resiliency. We conclude that hydrogel dissolution was dependent on polymer architecture as well as the polymer molecular weight.

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Targeting Systemically Administered Proteins to Bone by Bisphosphonate Conjugation

Cited by 64 publications

References 28 publications

Imparting mineral affinity to proteins with thiol–labile disulfide linkages

Imparting mineral affinity to proteins with thiol–labile disulfide linkages

Bifosfonatos (BFs) como transportadores osteotrópicos no planejamento de fármacos dirigidos

Hydrogels of Thermoreversible Comb‐Polymers Exhibit Increased Resistance for Dissolution

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