Dataset Information

Pharmacokinetic and biodistribution studies of N-(2-hydroxypropyl)methacrylamide copolymer-dexamethasone conjugates in adjuvant-induced arthritis rat model.

ABSTRACT: N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer has been found to be arthrotropic (joint-targeting) in the adjuvant-induced arthritis (AA) rat model using magnetic resonance imaging (MRI). In this manuscript, we report the quantitative pharmacokinetics and biodistribution (PK/BD) of (125)I-labeled HPMA copolymer-dexamethasone conjugate (P-Dex) in AA rats. Structural parameters of the prodrug such as the molecular weight (MW) and Dex content were found to have strong impact on the PK/BD profiles of P-Dex. The increase of MW (14,000, 24,000, and 42,000 g/mol) and Dex content (0, 151, and 313 micromol/g) enhances the arthrotropism of P-Dex. For the conjugate with highest MW and Dex content (P-H-M(W)/Dex), the percentage of injected doses per gram (ID/g) of ankle synovial tissue at day seventh postadministration is 1% g(-1), which confirms P-Dex as an arthrotropic macromolecular prodrug. For liver and spleen, the ID/g values are 0.51 and 3.64% g(-1), respectively. As an antigen-presenting organ, the sequestration of the prodrug by spleen may be explained by its abnormal enlargement associated with the systemic inflammatory disease model. Gradual reduction of spleen weight due to the inflammation resolution effect of P-Dex may also contribute to the high ID/g values. Increase of Dex content and reduction of MW would increase P-Dex distribution to kidney. The highest ID/g value for kidney at day seventh postadministration (0.91% g(-1)) was found with P-L-M(w) (MW = 14,000 g/mol, Dex content =288 micromol/g), which may suggest kidney tubuli reabsorption of the conjugates. The P-Dex's distribution to heart and lung is minimum.

SUBMITTER: Quan LD

PROVIDER: S-EPMC2914173 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacokinetic and biodistribution studies of N-(2-hydroxypropyl)methacrylamide copolymer-dexamethasone conjugates in adjuvant-induced arthritis rat model.

Quan Ling-Dong LD Yuan Fang F Liu Xin-Ming XM Huang Jian-Geng JG Alnouti Yazen Y Wang Dong D

Molecular pharmaceutics 20100801 4

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer has been found to be arthrotropic (joint-targeting) in the adjuvant-induced arthritis (AA) rat model using magnetic resonance imaging (MRI). In this manuscript, we report the quantitative pharmacokinetics and biodistribution (PK/BD) of (125)I-labeled HPMA copolymer-dexamethasone conjugate (P-Dex) in AA rats. Structural parameters of the prodrug such as the molecular weight (MW) and Dex content were found to have strong impact on the PK/BD profil ...[more]

PMID: 20557133

Similar Datasets

Project description:Degradable diblock and multiblock (tetrablock and hexablock) N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gemcitabine (GEM) and -paclitaxel (PTX) conjugates were synthesized by reversible addition-fragmentation chain-transter (RAFT) copolymerization followed by click reaction for preclinical investigation. The aim was to validate the hypothesis that long-circulating conjugates are needed to generate a sustained concentration gradient between vasculature and a solid tumor and result in significant anticancer effect. To evaluate the impact of molecular weight of the conjugates on treatment efficacy, diblock, tetrablock, and hexablock GEM and PTX conjugates were administered intravenously to nude mice bearing A2780 human ovarian xenografts. For GEM conjugates, triple doses with dosage 5 mg/kg were given on days 0, 7, and 14 (q7dx3), whereas a single dose regime with 20 mg/kg was applied on day 0 for PTX conjugates treatment. The most effective conjugates for each monotherapy were the diblock ones, 2P-GEM and 2P-PTX (Mw ≈ 100 kDa). Increasing the Mw to 200 or 300 kDa resulted in decrease of activity most probably due to changes in the conformation of the macromolecule because of interaction of hydrophobic residues at side chain termini and formation of "unimer micelles". In addition to monotherapy, a sequential combination treatment of diblock PTX conjugate followed by GEM conjugate (2P-PTX/2P-GEM) was also performed, which showed the best tumor growth inhibition due to synergistic effect: complete remission was achieved after the first treatment cycle. However, because of low dose applied, tumor recurrence was observed 2 weeks after cease of treatment. To assess optimal route of administration, intraperitoneal (i.p.) application of 2P-GEM, 2P-PTX, and their combination was examined. The fact that the highest anticancer efficiency was achieved with diblock conjugates that can be synthesized in one scalable step bodes well for the translation into clinics.

Project description:The design, synthesis, and physicochemical characterization of conjugates are arduous and tedious processes. Several synthetic pathways for polymeric conjugation have been reported; however, conjugation through monomers with suitable reaction conditions can be a simple and robust approach. In the present study, three different conjugates of hydrophilic N-2-hydroxypropyl methacrylamide (HPMA) and hydrophobic polycaprolactone (PCL) were synthesized. The followed synthetic pathway not only was simple and robust but also reduced the overall synthetic steps as well as harsh reaction conditions significantly. In a nutshell, three conjugates, i.e., N-2-hydroxypropyl methacrylamide and polycaprolactone (HP-PCL), n-butanol-polycaprolactone-N-2-hydroxypropyl methacrylamide (nBu-PCL-HP), and isoamyl alcohol-polycaprolactone-N-2-hydroxypropyl methacrylamide (ISAL-PCL-HP), were synthesized through this simple synthetic strategy following the monomer conjugation approach along with exhaustive spectroscopic and rheological characterization. The conjugates HP-PCL, nBu-PCL-HP, and ISAL-PCL-HP were characterized by Fourier transform infrared (FT-IR) and NMR (13C and 1H) spectroscopies. The size and ζ potential of conjugates were determined through the dynamic light scattering (DLS) method. The nBu-PCL-HP conjugate displayed a hexagonal-like shape, as evidenced by scanning electron microscopy (SEM) with an obtained size of 237.9 ± 0.21 nm. X-ray diffraction (XRD) analysis proved the crystalline nature of nBu-PCL-HP conjugates. The results of smartly synthesized conjugates intrigued us to study their flow properties in detail. Rheological evaluation resulted in their non-Newtonian type of flow with the best-fit behavior for all of the conjugates followed as per the Herschel-Bulkley and power-law models applied herein. Conclusively, the synthesized HPMA and PCL conjugates may have applications in the preparation of blends, fibers, etc. in the future. The study portrayed that the explored synthetic scheme using monomers and initiators could be a suitable approach for the synthesis of HPMA and PCL conjugates.

Project description:CC chemokines and their receptors play a fundamental role in trafficking and activation of leukocytes at sites of inflammation, contributing to joint damage in rheumatoid arthritis. Met-RANTES, an amino-terminal-modified methionylated form of RANTES (CCL5), antagonizes the binding of the chemokines RANTES and macrophage inflammatory protein 1alpha (MIP-1alpha; CCL3) to their receptors CCR1 and CCR5, respectively. The aim of this study was to investigate whether Met-RANTES could ameliorate adjuvant-induced arthritis (AIA) in the rat.Using immunohistochemistry, enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, Western blot analysis, adoptive transfer, and chemotaxis, we defined joint inflammation, bony destruction, neutrophil and macrophage migration, Met-RANTES binding affinity to rat receptors, proinflammatory cytokine and bone marker levels, CCR1 and CCR5 expression and activation, and macrophage homing into joints with AIA.Administration of Met-RANTES as a preventative reduced the severity of joint inflammation. Administration of Met-RANTES to ankles with AIA showed decreases in inflammation, radiographic soft tissue swelling, and bone erosion. Met-RANTES significantly reduced the number of neutrophils and macrophages at the peak of arthritis compared with saline-injected controls. Competitive chemotaxis in peripheral blood mononuclear cells demonstrated that Met-RANTES inhibited MIP-1alpha and MIP-1beta at 50% inhibition concentrations of 5 nM and 2 nM, respectively. Furthermore, levels of tumor necrosis factor alpha, interleukin-1beta, macrophage colony-stimulating factor, and RANKL were decreased in joints with AIA in the Met-RANTES group compared with the control group. Interestingly, the expression and activation of CCR1 and CCR5 in the joint were down-regulated in the Met-RANTES group compared with the control group. Functionally, Met-RANTES administration decreased adoptively transferred peritoneal macrophage homing into the joint.The data suggest that the targeting of Th1-associated chemokine receptors reduce joint inflammation, bone destruction, and cell recruitment into joints with AIA.

Dataset Information

Pharmacokinetic and biodistribution studies of N-(2-hydroxypropyl)methacrylamide copolymer-dexamethasone conjugates in adjuvant-induced arthritis rat model.

Publications

Pharmacokinetic and biodistribution studies of N-(2-hydroxypropyl)methacrylamide copolymer-dexamethasone conjugates in adjuvant-induced arthritis rat model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets