Bisphosphonate Prodrugs Research Articles

Analysis of the Effector Functions of Vδ2 γδ T Cells and NK Cells against Cholangiocarcinoma Cells.

Cholangiocarcinoma (CCA) is a rare disease characterized by malignant cells derived from the epithelial cells of the biliary duct system. Despite extensive treatments, the prognosis for CCA remains poor, emphasizing the critical need for the development of novel treatments. Considerable attention has been directed towards innate immune effector cells, which can recognize tumor cells independently of the major histocompatibility complex, laying the foundation for the development of off-the-shelf drugs. In this study, we cultured innate immune cells obtained from the peripheral blood of healthy adults and conducted a comparative analysis of the effector functions against CCA cell lines by Vδ2 γδ T cells and NK cells. This analysis was performed using standard short- and long-term cytotoxicity assays, as well as ELISA for IFN-γ. Vδ2 γδ T cells demonstrated cytotoxicity and IFN-γ production in response to CCA cells in a TCR-dependent manner, particularly in the presence of tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate, a bisphosphonate prodrug. In contrast, direct killing and antibody-dependent cellular cytotoxicity were relatively slow and weak. Conversely, NK cells displayed potent, direct cytotoxicity against CCA cells. In summary, both Vδ2 γδ T cells and NK cells show promise as innate immune effector cells for adoptive transfer therapy in the context of CCA.

Development of Innate-Immune-Cell-Based Immunotherapy for Adult T-Cell Leukemia-Lymphoma.

γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia-lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL.

CAR-Modified Vγ9Vδ2 T Cells Propagated Using a Novel Bisphosphonate Prodrug for Allogeneic Adoptive Immunotherapy.

The benefits of CAR-T therapy could be expanded to the treatment of solid tumors through the use of derived autologous αβ T cell, but clinical trials of CAR-T therapy for patients with solid tumors have so far been disappointing. CAR-T therapy also faces hurdles due to the time and cost intensive preparation of CAR-T cell products derived from patients as such CAR-T cells are often poor in quality and low in quantity. These inadequacies may be mitigated through the use of third-party donor derived CAR-T cell products which have a potent anti-tumor function but a constrained GVHD property. Vγ9Vδ2 TCR have been shown to exhibit potent antitumor activity but not alloreactivity. Therefore, in this study, CAR-T cells were prepared from Vγ9Vδ2 T (CAR-γδ T) cells which were expanded by using a novel prodrug PTA. CAR-γδ T cells suppressed tumor growth in an antigen specific manner but only during a limited time window. Provision of GITR co-stimulation enhanced anti-tumor function of CAR-γδ T cells. Our present results indicate that, while further optimization of CAR-γδ T cells is necessary, the present results demonstrate that Vγ9Vδ2 T cells are potential source of 'off-the-shelf' CAR-T cell products for successful allogeneic adoptive immunotherapy.

New Progress in Improving the Delivery Methods of Bisphosphonates in the Treatment of Bone Tumors

Bone tumors are tumors that occur in the bone or its accessory tissues, including primary tumors and metastatic tumors. The main mechanism of bisphosphonate is to inhibit the resorption of destructive bone, inhibit the activity of osteoclasts and reduce the concentration of blood calcium. Therefore, bisphosphonates can be used for malignant hypercalcaemia, pain caused by osteolytic bone metastasis, prevention of osteolytic bone metastasis, multiple myeloma osteopathy, improving radiosensitivity and so on. However, the traditional administration of bisphosphonates can cause a series of adverse reactions. To overcome this disadvantage, it is necessary to develop novel methods to improve the delivery of bisphosphonates. In this paper, the latest research progress of new and improved bisphosphonate drug delivery methods in the treatment of bone tumors is reviewed. At present, the main design idea is to connect bisphosphonate nanoparticles, liposomes, microspheres, microcapsules, couplings, prodrugs and bone tissue engineering to targeted anti-tumors systems, and positive progress has been made in in vitro and animal experiments. However, its safety and effectiveness in human body still need to be verified by more studies.

Effect of 4,5-diazafluorene derivative on γδ T cell-mediated cytotoxicity against renal cell carcinoma

AimsThis study aimed to investigate the effect of previously synthesized 4,5-diazafluorene derivative (14c) on γδ T cell-mediated cytotoxicity against renal cell carcinoma (RCC). Materials and methodsA real-time cell analyzer monitored cell proliferation, and Cell Counting Kit-8 determined cell viability. A reverse transcription-polymerase chain reaction analyzed gene expression, and protein expression was determined by cellular immunofluorescence analysis and Western blot. Key findingsThe compound 14c induced the expression of immunomodulatory molecules, such as natural killer group 2, member D ligands (NKG2DLs), fibroblast-associated (Fas) death receptor, and tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAILRs) in RCC. In addition, 14c induced DNA damage responses in RCC. Blocking DNA damage by KU-55933 reduced the effect of γδ T cells on 14c-treated RCC, suggesting that DNA damage responses were involved in the augmentation of γδ T cell-mediated cytotoxicity. Treating 786-O cells with a nitrogen-containing bisphosphonate prodrug further enhanced the anti-tumor effect of γδ T cell plus 14c combination treatment. SignificanceThe present evidence indicates that 14c induced DNA damage responses in RCC and augmented γδ T cell-mediated cytotoxicity primarily through NKG2D/NKG2DLs pathways, suggesting potential cancer immunotherapy for harnessing γδ T cells and small compounds that induce DNA damage responses.

Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug.

Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in a major histocombatibility complex (MHC) ‐unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis‐pivaloyloxymethyl 2‐(thiazole‐2‐ylamino)ethylidene‐1,1‐bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vγ2Vδ2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating αβ T cells resulted in some mice with circulating human αβ T cells rather than Vγ2Vδ2 cells. Vγ2Vδ2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor‐α and interferon‐γ in response to PTA‐treated tumor cells. Thus, PTA expands Vγ2Vδ2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed up the development of allogeneic Vγ2Vδ2 T cell therapies derived from HLA‐matched normal donors for patients with poor autologous Vγ2Vδ2 T cell responses.

Design, Synthesis, and Pharmacokinetics of a Bone-Targeting Dual-Action Prodrug for the Treatment of Osteoporosis.

A dual-action bone-targeting prodrug has been designed, synthesized, and evaluated for in vitro and in vivo metabolic stability, in vivo tissue distribution, and rates of release of the active constituents after binding to bones through the use of differentially double-labeled derivatives. The conjugate (general structure 7) embodies the merger of a very potent and proven anabolic selective agonist of the prostaglandin EP4 receptor, compound 5, and alendronic acid, a potent inhibitor of bone resorption, optimally linked through a differentially hydrolyzable linker unit, N-4-carboxymethylphenyl-methyloxycarbonyl-leucinyl-argininyl-para-aminophenylmethylalcohol (Leu-Arg-PABA). Optimized conjugate 16 was designed so that esterase activity will liberate 5 and cathepsin K cleavage of the Leu-Arg-PABA element will liberate alendronic acid. Studies with doubly radiolabeled 16 provide a proof-of-concept for the use of a cathepsin K cleavable peptide-linked conjugate for targeting of bisphosphonate prodrugs to bone and slow release liberation of the active constituents in vivo. Such conjugates are potential therapies for the treatment of bone disorders such as osteoporosis.

Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug

Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV. Using a similar approach, we synthesized bisphosphonate prodrugs and found that they efficiently limit tumor cell growth. Pivoxil bisphosphonate esters enter cells where esterases convert them to their active acids. The bisphosphonate esters stimulated γδ T cells to secrete TNF-α in response to a variety of tumor cells more efficiently than their corresponding acids. The most active compound, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1- bisphosphonate (7), specifically expanded γδ T cells and stimulated them to secrete interferon-γ and kill tumor cells. In preclinical studies, combination therapy with compound 7 and γδ T cells prolonged survival of mice inoculated with either human bladder cancer or fibrosarcoma cells. Therefore, bisphosphonate prodrugs could enhance the effectiveness of adoptive cancer immunotherapy with γδ T cells.

Cover Picture: Targeting Cancer Cells with a Bisphosphonate Prodrug (ChemMedChem 24/2016)

Cover Picture: Targeting Cancer Cells with a Bisphosphonate Prodrug (ChemMedChem 24/2016)

Targeting Cancer Cells with a Bisphosphonate Prodrug.

Nitrogen-containing bisphosphonates have antitumor activity in certain breast cancer and myeloma patients. However, these drugs have limited oral absorption, tumor cell entry and activity, and cause bone side effects. The potencies of phosphorylated antiviral drugs have been increased by administering them as prodrugs, in which the negative charges on the phosphate moieties are masked to make them lipophilic. We synthesized heterocyclic bisphosphonate (BP) prodrugs in which the phosphonate moieties are derivatized with pivaloyloxymethyl (pivoxil) groups and that lack the hydroxy "bone hook" on the geminal carbon. When the lipophilic BP prodrugs enter tumor cells, they are converted into their active forms by intracellular esterases. The most active BP prodrug, tetrakispivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (7), was found to potently inhibit the in vitro growth of a variety of tumor cell lines, especially hematopoietic cells, at nanomolar concentrations. Consistent with this fact, compound 7 inhibited the prenylation of the RAP1A small GTPase signaling protein at concentrations as low as 1-10 nm. In preclinical studies, 7 slowed the growth of human bladder cancer cells in an immunodeficient mouse model. Thus, 7 is significantly more active than zoledronic acid, the most active FDA-approved BP, and a potential anticancer therapeutic.

Bisphosphonate prodrugs: Synthesis and biological evaluation in HuH7 hepatocarcinoma cells

We investigated the biological effects of new synthesized bisphosphonates (BPs) on HuH7 hepatocarcinoma cells. BPs containing p-bromophenyl (R1 = p-Br, Ph, 2) in their side chain were the more potent to inhibit HuH7 cell viability. In addition, phenyl diesterified analogues (R2 = R3 = Ph, 2a) were more potent than methyl (R2 = R3 = Me, 2b) or non-esterified BPs (2) inducing more necrosis suggesting that they better entered into cells. Phosphodiesterase inhibitor (IBMX) reversed the effect of the esterified BPs and not that of non-esterified ones suggesting role of cell phosphodiesterases to release active BPs. BP analogues inhibited HuH7 cell migration but esterified ones had no effect on invasion due to the hiding of phosphonic groups. All together, these results indicated the therapeutic interest of these new BP prodrugs.

Development of Novel Bisphosphonate Prodrugs of Doxorubicin for Targeting Bone Metastases That Are Cleaved pH Dependently or by Cathepsin B: Synthesis, Cleavage Properties, and Binding Properties to Hydroxyapatite As Well As Bone Matrix

Bone metastases are a frequent cause of morbidity in cancer patients. The present palliative therapeutic options are chemotherapy, hormone therapy, and the administration of bisphosphonates. The affinity between bisphosphonates and the apatite structure of bone metastases is strong. Thus, we designed two low-molecular-weight and water-soluble prodrugs which incorporate a bisphosphonate group as a bone targeting ligand, doxorubicin as the anticancer agent, and either an acid-sensitive bond (1) or a cathepsin B cleavable bond (3) for ensuring an effective release of doxorubicin at the site of action. Cleavage studies of both prodrugs showed a fast release of doxorubicin but sufficient stability over several hours in human plasma. Effective binding of prodrug 1 and 3 was demonstrated with hydroxyapatite and with native bone. In orientating toxicity studies in nude mice, the MTD of 1 was 3-fold higher compared to conventional doxorubicin, whereas 3 showed essentially the same MTD as doxorubicin.

Silica xerogels and hydroxyapatite nanocrystals for the local delivery of platinum–bisphosphonate complexes in the treatment of bone tumors: A mini-review

The present review focuses on the “drug targeting and delivery” approach of the selective transportation of cisplatin to bone tumors and bone metastases. This aim is realized by binding cisplatin to (bis)phosphonate ligands or their derivatives. Geminal bisphosphonates are in clinical use in the treatment of several bone-related diseases because of their high affinity for calcium ions and hence for bones. Platinum–bisphosphonate complexes may be easily loaded onto calcium-containing inorganic matrices, such as calcium-doped sol–gel derived silica xerogels and hydroxyapatite nanocrystals, for local administration at the site of the bone malignancy. The composites may be used as bone-filler materials that, in addition to their action as bone substitutes, can also act as controlled platinum-drug releasing agents. The release kinetics of the drug can be tailored for specific therapeutic applications modulating the physico-chemical features of the inorganic matrices. Moreover, apatite nanocrystals loaded with platinum–bisphosphonate prodrugs can be used as injectable material for nanomedical applications (e.g. intracellular drug delivery).

Abstract 1760: Development of bisphosphonate prodrugs of doxorubicin for targeting bone metastases that are cleaved pH dependently or by cathepsin B

Abstract Bone metastases occur in up to 80 % of patients with advanced breast or prostate cancer and significantly affect the quality of life. Most frequently, bone metastases cause bone fractures, severe pain and hypercalcaemia. Current options for treating of bone metastases are surgery, radiotherapy, chemotherapy, hormone therapy, and the administration of bisphosphonates. These treatments are primarily palliative and can improve the quality of life in some cases, however without increasing the survival time of the patients. Bisphosphonates are presently the most active inhibitors of bone degradation, and they can reduce bone pain, bone destruction and tumor growth. Their therapeutic effects are due to the high affinity between bisphosphonates and the apatite structure of bone and bone metastases. In order to improve the outcome of treating bone metastases, new therapeutic approaches are urgently required. As bone-seeking agents, bisphosphonates show an uptake in the bone of 20-60% of the applied dose, and in general the uptake in bone metastases is 10-20-fold higher than in healthy bone tissue. In addition, bone metastases are characterized by an acidic pH and the over-expression of several proteases including cathepsins, matrix metalloproteases, plasmin and uPA. Surprisingly, no prodrug approaches have been reported to date that exploit the bone targeting effect of low-molecular weight bisphosphonates with a concomitant release of a bound drug in bone metastases. To this purpose, we developed water-soluble bisphosphonate prodrugs of doxorubicin for targeting bone metastases by conjugating a thiol-bearing aliphatic bisphosphonate with the 6-maleimidocaproyl hydrazone derivative of doxorubicin (1) that is cleaved pH dependently, or by attaching a maleimide derivative of the dipeptide Val-Ala-PABC (PABC = p-benzyloxycarbonyl) to the aliphatic bisphosphonate (2). Incubation studies with cathepsin B and 2 at 37 °C showed a cleavage of doxorubicin after two hours with a half time of ∼ 45 min and 1 released doxorubicin quantitatively at pH 5.0 after 2 h. The plasma stabilities (human and mouse) of both prodrugs were in the range of 3-6 h at 37 °C. Binding studies of 1 and 2 with a major component of bone, i.e. hydroxyapatite, demonstrated binding of 80-90 % of both prodrugs after 4 h at 37 °C. Finally, in an orientating toxicity study in nude mice the maximum tolerated dose (MTD) of 1 was three-fold higher compared to conventional doxorubicin whereas 2 showed essentially the same MTD as doxorubicin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1760. doi:1538-7445.AM2012-1760

Chemotherapeutic bone-targeted bisphosphonate prodrugs with hydrolytic mode of activation

Osseous tissues are considered to be limited as therapeutic target sites due to their biological properties. We have designed and synthesized two kinds of hydrolytically activated chemotherapeutic prodrugs containing bisphosphonate, a bone-targeting moiety. The first can be conjugated to drug molecules with an available hydroxy group; the drug is attached to the bisphosphonate component through an ester-labile linkage. The second is for use with drug molecules with amine functional group. In this case, a self-immolative linker is used to attach the drug to the bisphosphonate component through a carbonate-labile linkage. The concept was demonstrated using the drugs camptothecin, which has a hydroxy functional group, and tryptophan, which is a model molecule for a drug with amine functionality. Both prodrugs showed significant binding capability to hydroxyapatite, the major component of bone, and were hydrolytically activated under physiological conditions.

Bisphosphonate Prodrugs: Synthesis of New Aromatic and Aliphatic 1‐Hydroxy‐1,1‐bisphosphonate Partial Esters.

ChemInformVolume 36, Issue 46 Organoelement Compounds Bisphosphonate Prodrugs: Synthesis of New Aromatic and Aliphatic 1-Hydroxy-1,1-bisphosphonate Partial Esters. Maelle Monteil, Maelle Monteil Lab. Chim. Struct. Spectrosc. Biomol., CNRS, Univ. Paris-Nord, F-93017 Bobigny, Fr.Search for more papers by this authorErwann Guenin, Erwann Guenin Lab. Chim. Struct. Spectrosc. Biomol., CNRS, Univ. Paris-Nord, F-93017 Bobigny, Fr.Search for more papers by this authorEvelyne Migianu, Evelyne Migianu Lab. Chim. Struct. Spectrosc. Biomol., CNRS, Univ. Paris-Nord, F-93017 Bobigny, Fr.Search for more papers by this authorDidier Lutomski, Didier Lutomski Lab. Chim. Struct. Spectrosc. Biomol., CNRS, Univ. Paris-Nord, F-93017 Bobigny, Fr.Search for more papers by this authorMarc Lecouvey, Marc Lecouvey Lab. Chim. Struct. Spectrosc. Biomol., CNRS, Univ. Paris-Nord, F-93017 Bobigny, Fr.Search for more papers by this author Maelle Monteil, Maelle Monteil Lab. Chim. Struct. Spectrosc. Biomol., CNRS, Univ. Paris-Nord, F-93017 Bobigny, Fr.Search for more papers by this authorErwann Guenin, Erwann Guenin Lab. Chim. Struct. Spectrosc. Biomol., CNRS, Univ. Paris-Nord, F-93017 Bobigny, Fr.Search for more papers by this authorEvelyne Migianu, Evelyne Migianu Lab. Chim. Struct. Spectrosc. Biomol., CNRS, Univ. Paris-Nord, F-93017 Bobigny, Fr.Search for more papers by this authorDidier Lutomski, Didier Lutomski Lab. Chim. Struct. Spectrosc. Biomol., CNRS, Univ. Paris-Nord, F-93017 Bobigny, Fr.Search for more papers by this authorMarc Lecouvey, Marc Lecouvey Lab. Chim. Struct. Spectrosc. Biomol., CNRS, Univ. Paris-Nord, F-93017 Bobigny, Fr.Search for more papers by this author First published: 18 October 2005 https://doi.org/10.1002/chin.200546166Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume36, Issue46November 15, 2005 RelatedInformation

Bisphosphonate prodrugs: synthesis of new aromatic and aliphatic 1-hydroxy-1,1-bisphosphonate partial esters

Methods for the preparation of various 1-hydroxy-1,1-bisphosphonate partial esters were developed. They were obtained from (alkyl or phenyl) bis(trimethylsilyl) phosphite and aromatic or aliphatic acid chlorides, followed by methanolysis.

Dose-dependent pharmacokinetics and disposition of bisphosphonic prodrug of diclofenac based on osteotropic drug delivery system (ODDS).

Rat pharmacokinetics and in vivo disposition of a novel bisphosphonic prodrug of diclofenac (DIC-BP), synthesized with the aim of osteotropic delivery of diclofenac, were determined at whole body, organ and cellular levels in a dose range 0.32-10mg/kg. With an increase in injected dose, total body clearance was decreased while the distribution volume at steady state (V(dss)) was reduced and plasma half-life was prolonged. Over 50% of a dose of DIC-BP was selectively transported into osseous tissues after intravenous injection into rats at doses up to 1mg/kg. As dose increased, the skeletal distribution decreased with hepatic and splenic accumulations increasing. The intrahepatic distribution at 10mg/kg revealed that liver macrophages play a significant role in hepatic uptake of DIC-BP. This is consistent with general arguments that bisphosphonates themselves cannot distribute in soft tissues, but are taken up by the reticuloendothelial system as foreign substances when they form large complexes or aggregate with endogenous metals in plasma. Therefore, to optimize the osteotropic delivery of diclofenac via a bisphosphonic prodrug, the dosage regimen should be such that plasma concentration of DIC-BP is maintained at a level lower than that required for precipitate formation of complexes, similar to the usage of other bisphosphonates.

Bisphosphonate Prodrugs. Selective Synthesis of (1‐Hydroxyethylidene)‐1,1‐bisphosphonate Partial Esters.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Relationship between physicochemical and osteotropic properties of bisphosphonic derivatives: rational design for osteotropic drug delivery system (ODDS).

The objective of this investigation is to develop a rational design of Osteotropic Drug Delivery System (ODDS), which we have proposed as a novel method for drug delivery to the skeleton via bisphosphonic prodrug, based on the relationship between physicochemical and pharmacokinetic properties of bisphosphonates. The theoretical octanol/water partition coefficients (clog P) of 13 bisphosphonates were calculated by computer software, CLOGP ver. 3.05 (Daylight C.I.S., Inc. Irvine, CA) and related to pharmacokinetic or osteotropic parameters after intravenous injection into rats. On the other hand, to optimize ODDS of diclofenac (DIC-BP), the effects of doses or infusion rates on the in vivo disposition were investigated in relation to solubility product value (Ksp) of DIC-BP-calcium complex. Clog P had good correlations with total plasma clearance, apparent distribution volume and the fraction dose delivered to the whole skeleton after bolus injection into rats (r = -0.868 approximately -0.914). The targetability of bisphosphonates to the skeleton was linearly decreased with an increase in clog P value and the more hydrophilic bisphosphonates were suitable for ODDS in bolus administration. On the other hand, DIC-BP, a relatively lipophilic bisphosphonate, was effectively and selectively delivered to the skeleton only when administered as a slow infusion to keep plasma concentration lower than that calculated from Ksp value where DIC-BP could precipitate with calcium in the plasma circulation. Our results suggest the possibility of a rational design of ODDS via bisphosphonic prodrugs, after consideration of compound lipophilicity and precipitability of bisphosphonate-calcium complex.