Osteotropic Drug Delivery System (ODDS) Based on Bisphosphonic Prodrug. I: Synthesis and in Vivo Characterization of Osteotropic Carboxyfluorescein

Abstract

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug was designed as a novel method for site-specific and controlled delivery of drugs to the bone. Due to the chemical adsorption of bisphosphonic promoiety to the mineral component, hydroxyapatite, a bisphosphonic prodrug is predominantly taken up into the bone. To verify the concept, bisphosphonic promoiety was chemically introduced into 6-carboxyfluorescein (CF) as a model compound and the disposition after intravenous injection was studied in rats. The bisphosphonic prodrug of CF, disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP) was highly taken up to the skeleton (62.1% of dose) and the remainder was excreted into the urine (35.9% of dose). Subsequently, regeneration of CF by hydrolysis of CF-BP in the bone was observed. The microscopic observation showed that CF-BP was buried into the bone with a calcification of the bone. According to the remodeling of the bone, bisphosphonic prodrug buried was supposed to be released in the vicinity of the osteoclast or resorption surface of the bone. Thus, it is suggested that ODDS has a potential to achieve osteoclast-specific or resorption surface-specific targeting of the drugs.

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

“…Constitui-se em sistema, com certeza, muito promissor de transporte de fármacos, digno de estudos que envolvam o direcionamento de compostos e, conseqüentemente, a seletividade destas (6) e eficazes (7)(8)(9)(10) para a prevenção da perda óssea substâncias nos ossos, aumentando, significativamente, a esperança de se encontrar derivados eficazes e menos tóxicos com aplicação terapêutica em doenças ósseas. …”

“…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][3][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] .…”

“…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.…”

Bisphosphonate Prodrugs

“…In the litterature, three types of BP prodrugs have been published: 1) promoieties which are either bound to the middle carbon side chain, or 2) to phosphorus atoms via an ester or amide bonds and 3) bisphosphonates themselves are promoieties for other drugs. The first approach is based on a targeted carrier system that is activated by dipeptide prodrugs [27][28][29][30], while in the second method low log P app values are made to increase by masking one or more of the ionizable groups [31][32][33][34][35][36][37][38][39][40][41][42][43][44]. The third system, called the Ostetropic Drug Delivery System (ODDS), makes possible the targeted delivery of drugs to the bone or bone marrow [45][46][47][48][49][50][51][52].…”

PLGA-Alendronate Conjugate as a New Biomaterial to Produce Osteotropic Drug Nanocarriers

“…Moreover, most of the drugs used for the adjuvant therapy of osteolytic metastases interfere with signalling that induce osteoclast differentiation and osteoclast-mediated bone resorption, but they are not effective on tumour growth in the bone and their use is obviously associated with heavy side effects. [11,12,18,19]. Bisphosphonates (BP) have been for instance conjugated to small drugs [20,21], and proteins [22] with the aim at optimizing the treatment of osteoporosis, osteoarthritis, and bone cancer, and to radiopharmaceuticals to obtain novel agents for bone scintigraphy [23].…”