The Evaluation of Therapeutic Efficacy and Safety Profile of Simvastatin Prodrug Micelles in a Closed Fracture Mouse Model

Zhang, Yijia; Jia, Zhenshan; Yuan, Hongjiang; Dusad, Anand; Ren, Ke; Wei, Xin; Fehringer, Edward V.; Purdue, P. Edward; Daluiski, Aaron; Goldring, Steven R.; Wang, Dong

doi:10.1007/s11095-016-1932-2

Cited by 15 publications

(7 citation statements)

References 23 publications

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“…peri-implant osteolysis). 16, 18–20 We posited that the mechanism for this passive targeting is different from the Enhanced Permeability and Retention (EPR) Effect 21 and may be explained by an ELVIS mechanism (Extravasation through Leaky Vasculature and Inflammatory cell-mediated Sequestration) 22–24 , in which the systemically administered nanomedicine would extravasate through the leaky vasculature at the inflammatory lesion and be sequestered locally via inflammatory cell infiltrates and activated resident cell. Concurrently, for systemic inflammatory conditions, a fraction of the nanomedicine administered may also be sequestered by white blood cells (WBC) in the circulation and be actively transported to the inflammatory lesion.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model

Wei

Zhao

et al. 2017

Mol. Pharmaceutics

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N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers were previously found to represent a versatile delivery platform for the early detection and intervention of orthopedic implant loosening. In this manuscript, we evaluated the impact of different structural parameters of the HPMA copolymeric system (e.g. molecular weight (MW), drug content) to its pharmacokinetics and biodistribution (PK/BD) profile. Using 125I, Alexa Fluor® 488 and IRDye® 800 CW-labeled HPMA copolymer-dexamethasone (P-Dex) conjugates with different MW and dexamethasone (Dex) contents, we found the MW to be the predominant impact factor on the PK/BD profiles of P-Dex, with Dex content as a secondary impact factor. In gamma counter-based PK/BD studies, increased MW of P-Dex reduced elimination, leading to lower clearance, longer half-life, and higher systemic exposure (AUC and MRT). In the semi-quantitative live animal optical imaging evaluation, the distribution of P-Dex to the peri-implant inflammatory lesion increased when MW was increased. This result was further confirmed by FACS analyses of cells isolated from peri-implant regions after systemic administration of Alexa Fluor® 488-labeled P-Dex. Since the in vitro cell culture study suggested that the internalization of P-Dex by macrophages is generally independent of P-Dex’ MW and Dex content, the impact of the MW and Dex content on its PK/BD profile was most likely exerted at physiological and pathophysiological levels rather than at the cellular level. In both gamma counter-based PK/BD analyses and semi-quantitative optical imaging analyses, P-Dex with 6 wt% Dex content showed fast clearance. Dynamic light scattering analyses unexpectedly revealed significant molecular aggregation of P-Dex at this Dex content level. The underlining mechanisms of the aggregation and fast in vivo clearance of the P-Dex warrant further investigation.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model

Wei

Zhao

et al. 2017

Mol. Pharmaceutics

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“…Three weeks after the initiation of prednisone dosing, closed femur fractures were created on prednisone exposed mice and the healthy control based on a previous report. 16 Briefly, the mice were anesthetized with isoflurane 1%–1.5% inhalation with a 1.5 L oxygen flow rate. The region around the knee of the right leg was shaved with an electric shaver and scrubbed with Betadine ® to prepare for surgery.…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoid-induced delayed fracture healing and impaired bone biomechanical properties in mice

Liu¹,

Akhter²,

Gao³

et al. 2018

CIA

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BackgroundThe objective of the study was to investigate the effects of glucocorticoid (GC) on the fracture healing process in a closed femur fracture mice model.Materials and methodsForty 12-week-old female CD-1 mice were randomly allocated into four groups: healthy control and mice with prednisone exposure (oral gavage), 6 mg/kg/day (GC-L), 9 mg/kg/day (GC-M) and 12 mg/kg/day (GC-H). Three weeks after the initiation of prednisone dosing, closed femur fractures were created on prednisone-exposed mice and the healthy control. Prednisone administration was continued for 9 weeks post-fracture, and X-ray imaging was performed weekly to monitor the fracture healing process until the mice were euthanized. Necropsy was performed after 9 weeks and the fractured femurs were isolated and processed at necropsy for micro-CT and biomechanical property analysis. Another 20 mice (control and GC-H, 10 mice/group) were used for histology and micro-CT analysis at early time point (2-week post fracture) with continued prednisone exposure.ResultsThe results showed that oral administration of prednisone for 3 months in this strain of mice could inhibit endochondral ossification and delay the healing process, especially hard callus formation (woven bone) and bone remodeling during healing. It also could significantly decrease bone biomechanical properties.ConclusionLong-term GC administration leads to significantly delayed fracture healing and impaired bone biomechanical properties. This mouse model may be used to systematically study the cellular and molecular mechanisms underlying fracture healing with GC treatment background and may also be used to study the influence of different therapeutic interventions for bone fracture healing.

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“…In vivo, the micelles are supposed to target the bone defect site and release conjugated simvastatin due to hydrolysis of ester bond linkages. The authors showed a gradual release of simvastatin and concomitant promotion of bone healing in femoral fractures after 21 days [223,224]. Taken together, the introduction of enzymatically cleavable linker within the scaffolds are promising strategies for targeted drug delivery with several proteases and linker sequences being available.…”

Section: Proteolytic Enzymesmentioning

confidence: 98%

Adjuvant Drug-Assisted Bone Healing: Advances and Challenges in Drug Delivery Approaches

et al. 2020

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Bone defects of critical size after compound fractures, infections, or tumor resections are a challenge in treatment. Particularly, this applies to bone defects in patients with impaired bone healing due to frequently occurring metabolic diseases (above all diabetes mellitus and osteoporosis), chronic inflammation, and cancer. Adjuvant therapeutic agents such as recombinant growth factors, lipid mediators, antibiotics, antiphlogistics, and proangiogenics as well as other promising anti-resorptive and anabolic molecules contribute to improving bone healing in these disorders, especially when they are released in a targeted and controlled manner during crucial bone healing phases. In this regard, the development of smart biocompatible and biostable polymers such as implant coatings, scaffolds, or particle-based materials for drug release is crucial. Innovative chemical, physico- and biochemical approaches for controlled tailor-made degradation or the stimulus-responsive release of substances from these materials, and more, are advantageous. In this review, we discuss current developments, progress, but also pitfalls and setbacks of such approaches in supporting or controlling bone healing. The focus is on the critical evaluation of recent preclinical studies investigating different carrier systems, dual- or co-delivery systems as well as triggered- or targeted delivery systems for release of a panoply of drugs.

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The Evaluation of Therapeutic Efficacy and Safety Profile of Simvastatin Prodrug Micelles in a Closed Fracture Mouse Model

Cited by 15 publications

References 23 publications

Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model

Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model

Glucocorticoid-induced delayed fracture healing and impaired bone biomechanical properties in mice

Adjuvant Drug-Assisted Bone Healing: Advances and Challenges in Drug Delivery Approaches

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