Abstract:
:Targeting of anti-tumor drugs to the urinary bladder for the treatment of bladder carcinoma may be useful, since these agents generally have a low degree of urinary excretion and are highly toxic elsewhere in the body. The anti-tumor drug doxorubicin was coupled to the low-molecular weight protein lysozyme via the acid-sensitive cis-aconityl linker. All free amino groups of the lysozyme were used for drug attachment to achieve intact excretion of the doxorubicin-aconityl-lysozyme conjugate into the bladder. In the bladder, the cytotoxic drug should be regenerated through acidification of the urine. First, the doxorubicin-aconityl-lysozyme conjugate was tested in rats for its target specificity and general toxicity. Wistar rats were injected intravenously with 2 mg/kg free doxorubicin or 10 mg/kg lysozyme-conjugated doxorubicin. Total urinary excretion of doxorubicin was about 10 times higher if the drug was coupled to lysozyme (39 +/- 3% versus 4.4 +/- 0.4%). Free doxorubicin had no detectable toxic effects on heart, liver and lung but caused severe renal damage (proteinuria, N-acetylglucosaminidase excretion and glomerulosclerosis). None of the rats injected with doxorubicin-lysozyme conjugate showed such renal toxicity. Second, we tested whether doxorubicin could be released from the conjugate in the bladder through acidification of the urine and if the released doxorubicin could still exert a cytotoxic effect. Doxorubicin-aconityl-lysozyme (2 mg/kg conjugated doxorubicin, i.v.) was administered in rats with acidified urine (pH 6.1 +/- 0.1) and in rats with a high urinary pH (8.2 +/- 0.4). Ten times more doxorubicin was released from the conjugate in the group with acidified urine (15 +/- 7% versus 1.7 +/- 0.1%). In agreement with this, cytotoxicity was also higher in the low pH group (IC50 of 255 +/- 47 nM versus 684 +/- 84 nM doxorubicin). In conclusion, a specific delivery of doxorubicin to the urinary bladder combined with a reduced toxicity of doxorubicin in the kidneys can be achieved by coupling this anti-tumor drug to the low-molecular weight protein lysozyme via an acid-labile linker. A release of cytotoxic doxorubicin in the urinary bladder can be achieved by acidification of the urine. This technology, after further optimization, may provide an interesting tool for the treatment of bladder carcinoma.
journal_name
J Drug Targetjournal_title
Journal of drug targetingauthors
Haas M,Moolenaar F,Elsinga A,Van der Wouden EA,de Jong PE,Meijer DK,de Zeeuw Ddoi
10.1080/10611860290007568keywords:
subject
Has Abstractpub_date
2002-02-01 00:00:00pages
81-9issue
1eissn
1061-186Xissn
1029-2330journal_volume
10pub_type
杂志文章abstract::In this study, folate receptor (FR) targeted liposome microbubbles loaded with oridonin (ORI) (F-LMB-ORI), liposome loaded with ORI (L-ORI) and liposome microbubbles loaded with ORI (LMB-ORI) were prepared. In vitro release properties, cellular uptake and cytotoxicity in HepG-2 cells as well as in vivo antitumor effec...
journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
pub_type: 杂志文章,评审
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
pub_type: 杂志文章,评审
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
pub_type: 杂志文章,评审
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journal_title:Journal of drug targeting
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doi:10.3109/1061186X.2013.878944
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journal_title:Journal of drug targeting
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doi:10.1080/10611860601148908
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journal_title:Journal of drug targeting
pub_type: 杂志文章
doi:10.3109/10611861003599479
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abstract::Drug efflux by the membrane transporter P-glycoprotein (P-gp) plays a key role in multidrug resistance (MDR). In order to bypass P-gp, thus overcoming MDR, a hybrid peptide comprising a cell penetrating peptide (Tat) and a drug binding motif (DBM) has been developed to noncovalently bind and deliver doxorubicin (Dox) ...
journal_title:Journal of drug targeting
pub_type: 杂志文章
doi:10.3109/10611860903548347
更新日期:2010-07-01 00:00:00
abstract::Notch pathway was found to be activated in most glioblastomas (GBMs), underlining the importance of Notch in formation and recurrence of GBM. In this study, a Notch inhibitory peptide, dominant negative MAML (dnMAML), was conjugated to elastin-like polypeptide (ELP) for tumor targeted delivery. ELP is a thermally resp...
journal_title:Journal of drug targeting
pub_type: 杂志文章
doi:10.1080/1061186X.2017.1289537
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abstract::A biophysical model was developed, using Ascaris suum as a model gastrointestinal nematode, to provide quantitative perspectives into the microenvironmental pH within the water-filled, porous, negatively charged cuticle matrix of gastrointestinal nematodes. The central features of the model include (a) the constant ra...
journal_title:Journal of drug targeting
pub_type: 杂志文章
doi:10.3109/10611869409015888
更新日期:1994-01-01 00:00:00
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journal_title:Journal of drug targeting
pub_type: 杂志文章,评审
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更新日期:2017-09-01 00:00:00
abstract::The aim of this study was to evaluate the pharmacokinetics (PK), tissue distribution, and the specific drug targeting of cefpiramide sodium-loaded liposomes (CPMS-Lips) compared with cefpiramide sodium solution (CPMS-Sol) in mice. CPMS-Lips were prepared by reverse phase evaporation method. In the PK and biodistributi...
journal_title:Journal of drug targeting
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doi:10.3109/10611861003667607
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abstract::Nanostructured lipid carrier (NLC) is second generation smarter drug carrier system having solid matrix at room temperature. This carrier system is made up of physiological, biodegradable and biocompatible lipid materials and surfactants and is accepted by regulatory authorities for application in different drug deliv...
journal_title:Journal of drug targeting
pub_type: 杂志文章,评审
doi:10.3109/1061186X.2012.716845
更新日期:2012-12-01 00:00:00
abstract::The human papillomavirus type-16 (HPV-16) E7 protein is considered a major viral oncoprotein involved in cervical cancer (CxCa) and a potential candidate for the development of a vaccine against this neoplasia. Here, two lactic acid bacteria (the model one Lactococcus lactis and a probiotic one Lactobacillus plantarum...
journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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abstract::Microparticles-adsorbed insulin and zinc insulin (PenfilN) were molded to self-dissolving micropiles (SDMPs) with chondroitin sulfate as the base for the percutaneous administration of insulin. Porous silicon dioxide (Sylysia 320, 440 and 730) and porous calcium silicate (FloriteRE) were used as microparticles. As a r...
journal_title:Journal of drug targeting
pub_type: 杂志文章
doi:10.1080/10611860701349794
更新日期:2007-06-01 00:00:00
abstract::Resveratrol is a promising neuroprotective agent against neurodegenerative disorders such as Alzheimer's disease. Resveratrol-loaded transferosomes and nanoemulsions were developed and labelled with gold nanoparticles (GNPs). The water maze test was utilised to identify the effect on spatial memory recovery. The treat...
journal_title:Journal of drug targeting
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更新日期:2019-12-01 00:00:00
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journal_title:Journal of drug targeting
pub_type: 杂志文章,评审
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abstract::Drug delivery is an important consideration in disease treatment. There are many opportunities for novel methods and technologies to hold promising roles in overcoming traditional obstacles. Delivery systems functionalised to boast synergistic antimicrobial effects, specific targeting, and enhanced bioavailability all...
journal_title:Journal of drug targeting
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abstract::Liposomes have been prepared from dipalmitoylphosphatidylcholine (DPPC), cholesterol (Chol) and dimethyldioctadecylammonium bromide (DDAB). The cationic vesicles adsorb to biofilms of the skin-associated bacteria Staphylococcus epidermidis, which have a negative charge. Encapsulation of the antibacterial drug vancomyc...
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