Despite several decades of progress, bone-specific delivery is still limited by the unique anatomical features of bone, which mainly consists of inorganic hydroxyapatite. A practical approach to this problem is to produce targeted drugs that have a high affinity for hydroxyapatite. Bisphosphonates are a class of synthetic compounds structurally related to pyrophosphate. Bisphosphonates rapidly localise on the bone surface after being administered either intravenously or orally, since the P-C-P portion of the bisphosphonate structure has high affinity for hydroxyapatite. Therefore, bisphosphonate modification might be a promising method for targeting drugs selectively to the bone. Bisphosphonate-conjugated drugs are hydrophilic and highly water-soluble due to the acidic nature of the bisphosphonate moiety at physiological pH, and therefore they hardly permeate through the biological membrane of soft tissues. These physicochemical changes also reduce the intrinsic susceptibility of the drug to metabolism, promoting urinary or biliary excretion as unchanged drug. All these physicochemical and pharmacokinetic alterations contribute to the exceptional skeletal disposition of bisphosphonate-conjugated drugs. Bisphosphonate conjugation is based on chemical modification of the targeting molecule, and therapeutically optimised bisphosphonate derivatives have to be custom-developed on a case-by-case basis. The bisphosphonate moiety is usually coupled with the targeting drug through a specific linkage. The high affinity of bisphosphonate conjugates for the bone is not simply dependent on the bisphosphonate moiety but on the resultant molecule as a whole, including the linker and the linked drug. Lipophilicity (represented as log P) appears to be an appropriate index for predicting the osteotropic properties of bisphosphonate derivatives. Several strategies using bisphosphonate-conjugated drugs have been investigated at a laboratory level with the aim of obtaining therapeutically optimised treatments for conditions such as osteoporosis, osteoarthritis and bone cancer. In each case, the intention is to achieve prolonged local exposure to high concentrations of the targeting drug, thereby improving therapeutic index by enhancing pharmacological efficacy and minimising systemic adverse effects. Although most examples of bone-specific drug delivery via bone-seeking agents still remain in preclinical studies, several phosphonate-coupled radiopharmaceuticals, such as samarium-153 complexed to tetraphosphonate, are expected to be an effective pain palliation therapies for metastatic bone cancer and are currently being developed in clinical trials. Furthermore, recent reports on bisphosphonate-modified proteins have illustrated the feasibility of bone-specific delivery of biologically active protein drugs, such as cytokines and growth factors.
An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed for 17 beta-estradiol (E2) to improve patient compliance in estrogen replacement therapy of postmenopausal osteoporosis. The biological disposition and the targeting efficiency of a bisphosphonic prodrug of E2, disodium [17 beta-(3'-hydroxy-1',3',5'-estratrienyloxy)carbonylpropyl carboxamidomethylene]bisphosphonate (E2-BP), was investigated in ovariectomized rats. After intravenous injection, E2-BP was rapidly taken up into the bone and subsequently cleared from the bone at a half-life of 13.5 d. The bone concentration of regenerated E2 was maintained throughout 28 d. In contrast, E2 injected intravenously showed extremely low bone distribution and rapid clearance from the bone, and E2 administered orally showed even lower bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for E2 in the bone and plasma after injection of E2-BP and E2, were 64.6 and 451, respectively. These results suggest that ODDS has a potential to improve not only the apparent potency but also the therapeutic index of E2. As compared with the conventional estrogenic products, E2-BP should improve patient compliance with lower adverse effects and less frequent medication in long-term estrogen replacement therapy.
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.
An osteotropic drug delivery system (ODDS) based on the bisphosphonic prodrug was designed for 17beta-estradiol (E2) in order to improve patient compliance in estrogen replacement therapy of postmenopausal osteoporosis. The bisphosphonic prodrug of E2, disodium [17beta-(3 '-hydroxy- 1',3',5'-estratrienyloxy) carbonylpropyl carboxamidomethylene] bisphosphonate (E2-BP) was synthesized and its effects on bone mineral density and uterine weight were investigated in ovariectomized (OVX) rats. E2-BP was injected intravenously once a week (4 injections/experiment), and E2 was administrated orally 5 times a week (20 administrations/experiment). Once a week treatment with 0.1 mg/kg E2-BP significantly restored bone mineral reduction by 61.8% without significantly increasing uterine weight. Similarly, once in 4 weeks treatment with 1.0 mg/kg E2-BP (1 injection/experiment) showed almost the same therapeutic effects. On the other hand, 5 times a week oral treatment with 1.0 mg/kg E2 significantly improved bone mineral density by 90.5%, but increased uterine weight up to 98.2% of that of the sham group. In vitro bone resorption analysis revealed that E2-BP exhibits antiresorptive activity not as a bisphosphonate but as a prodrug of E2. These results demonstrated that E2-BP has the potential to improve patient compliance in estrogen therapy by its minimal adverse effects and less frequent medication.
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