Pharmacokinetic and pharmacodynamic evaluation of a novel in situ forming poly(ethylene glycol)-based hydrogel for the controlled delivery of the camptothecins

Lalloo, Anita; Chao, Piyun; Hu, Peidi; Stein, Stanley J.; Sinko, Patrick J.

doi:10.1016/j.jconrel.2006.03.002

Cited by 68 publications

(42 citation statements)

References 33 publications

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“…Relatively flat plasma drug levels were measured following oral administration of the polymer conjugates. These steady plasma drug concentrations may provide not only a safety benefit by reducing the magnitude of peak plasma drug levels [40], but may also result in sustained drug exposure of tumor [41]. High absorption rates for oral free drug in the SI were compensated by the prolonged absorption times for released drug in the cecum and colon.…”

Section: Discussionmentioning

confidence: 99%

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Gao

Lü

Kopečková

et al. 2007

Journal of Controlled Release

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A water soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer -9-aminocamptothecin (9-AC) conjugate was designed for oral colon-specific drug delivery for the treatment of colon cancer. Comparative studies between the polymer conjugate and free drug have been performed to assess their biodistribution and pharmacokinetics in mice. After oral administration of equal doses of the polymer conjugate or free 9-AC, the drug concentrations in major organs at fixed time points were determined using an HPLC-fluorescence assay. Only 2±1% of 9-AC released from the polymer conjugate was detected in small intestine (SI), and the mean peak concentration of free 9-AC was 45-fold higher than that from released drug. Colon-specific release of 9-AC produced high local concentrations. The mean peak concentration of released 9-AC in cecal contents, feces, cecal tissue, and colon tissue were, respectively, 3.2-fold, 3.5-fold, 2.2-fold and 1.6-fold higher than that using free 9-AC. In plasma, the high and sharp drug concentration profile from free drug was in contrast to the relatively low and flat pharmacokinetic profile obtained from drug released from the HPMA copolymer. There was no significant difference between released and free drug for the area under the concentration-time curve (AUC) and bioavailability values. As a consequence of the colonspecific release of unmodified 9-AC from the polymer conjugate, antitumor efficacy can be anticipated to be enhanced due to prolonged colon tumor exposure to higher and more localized drug concentrations.

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Section: Discussionmentioning

confidence: 99%

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Gao

Lü

Kopečková

et al. 2007

Journal of Controlled Release

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“…The concentration of drug in rat blood was also higher in the GbE niosome group than in the GbE group, which may be because the niosomes had a prolonged retention time in vivo, resulting in a stable blood concentration. Several reports have shown that the bioavailability of drugs can be improved 46,47 due to altered pharmacokinetic behavior and in vivo distribution, and higher accumulation in the brain would be useful when using GbE as pharmacotherapy for diseases affecting the brain.…”

Section: In Vivo Distribution Of Gbe Niosomes In the Ratmentioning

confidence: 99%

Development of a novel niosomal system for oral delivery of Ginkgo biloba extract

Jin¹,

Wen²,

Garg³

et al. 2013

IJN

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Background:The aim of this study was to develop an optimal niosomal system to deliver Ginkgo biloba extract (GbE) with improved oral bioavailability and to replace the conventional GbE tablets. Methods: In this study, the film dispersion-homogenization method was used to prepare GbE niosomes. The resulting GbE niosome suspension was freeze-dried or spray-dried to improve the stability of the niosomes. GbE-loaded niosomes were formulated and characterized in terms of their morphology, particle size, zeta potential, entrapment efficiency, and angle of repose, and differential scanning calorimetry analysis was performed. In vitro release and in vivo distribution studies were also carried out. Results: The particle size of the optimal delivery system prepared with Tween 80, Span 80, and cholesterol was about 141 nm. There was a significant difference (P , 0.05) in drug entrapment efficiency between the spray-drying method (about 77.5%) and the freeze-drying method (about 50.1%). The stability study revealed no significant change in drug entrapment efficiency for the GbE niosomes at 4°C and 25°C after 3 months. The in vitro release study suggested that GbE niosomes can prolong the release of flavonoid glycosides in phosphate-buffered solution (pH 6.8) for up to 48 hours. The in vivo distribution study showed that the flavonoid glycoside content in the heart, lung, kidney, brain, and blood of rats treated with the GbE niosome carrier system was greater than in the rats treated with the oral GbE tablet (P , 0.01). No flavonoid glycosides were detected in the brain tissue of rats given the oral GbE tablets, but they were detected in the brain tissue of rats given the GbE niosomes. Conclusion: Niosomes are a promising oral system for delivery of GbE to the brain.

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“…17,[42][43][44] Our work employing doxycycline in a hydrogel is an attempt to identify a drug and a delivery method that might have a beneficial impact on the chronic effect of conjunctivalization of the cornea after ocular SM exposure. Blindness from conjuctivalization is attributed to limbal stem cell deficiency.…”

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confidence: 99%

Doxycycline Hydrogels as a Potential Therapy for Ocular Vesicant Injury

Gordon

Desantis

Deshmukh

et al. 2010

Journal of Ocular Pharmacology and Therapeutics

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Purpose: The goals of this study were (1) to compare the injury at the basement membrane zone (BMZ) of rabbit corneal organ cultures exposed to half mustard (2 chloroethyl ethyl sulfide, CEES) and nitrogen mustard with that of in vivo rabbit eyes exposed to sulfur mustard (SM); (2) to test the efficacy of 4 tetracycline derivatives in attenuating vesicant-induced BMZ disruption in the 24-h period postexposure; and (3) to use the most effective tetracycline derivative to compare the improvement of injury when the drug is delivered as drops or hydrogels to eyes exposed in vivo to SM. Methods: Histological analysis of hematoxylin and eosin-stained sections was performed; the ultrastructure of the corneal BMZ was evaluated by transmission electron microscopy; matrix metalloproteinase-9 was assessed by immunofluorescence; doxycycline as drops or a hydrogel was applied daily for 28 days to eyes exposed in vivo to SM. Corneal edema was assessed by pachymetry and the extent of neovascularization was graded by length of longest vessel in each quadrant. Results: Injury to the BMZ was highly similar with all vesicants, but varied in degree of severity. The effectiveness of the 4 drugs in retaining BMZ integrity did not correlate with their ability to attenuate matrix metalloproteinase-9 expression at the epithelial-stromal border. Doxycycline was most effective on organ cultures; therefore, it was applied as drops or a hydrogel to rabbit corneas exposed in vivo to SM. Eyes were examined at 1, 3, 7, and 28 days after exposure. At 7 and 28 days after SM exposure, eyes treated with doxycycline were greatly improved over those that received no therapy. Corneal thickness decreased somewhat faster using doxycycline drops, whereas the hydrogel formulation decreased the incidence of neovascularization. Conclusions: Corneal cultures exposed to 2-chloroethyl ethyl sulfide and nitrogen mustard were effective models to simulate in vivo SM exposures. Doxycycline as drops and hydrogels ameliorated vesicant injury. With in vivo exposed animals, the drops reduced edema faster than the hydrogels, but use of the hydrogels significantly reduced neovascularization. The data provide proof of principle that a hydrogel formulation of doxycycline as a daily therapy for ocular vesicant injury should be further investigated.

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Pharmacokinetic and pharmacodynamic evaluation of a novel in situ forming poly(ethylene glycol)-based hydrogel for the controlled delivery of the camptothecins

Cited by 68 publications

References 33 publications

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Development of a novel niosomal system for oral delivery of Ginkgo biloba extract

Doxycycline Hydrogels as a Potential Therapy for Ocular Vesicant Injury

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