Superior therapeutic efficacy of N-l-leucyl-doxorubicin versus doxorubicin in human melanoma xenografts correlates with higher tumour concentrations of free drug

Breistøl, Knut; Hendriks, H.R.; Fodstad, Øystein

doi:10.1016/s0959-8049(99)00074-x

Cited by 25 publications

(15 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, the MTD of DOX-PEG 2k -CA 4 micelles and free DOX in BLAB/c mice are approximately 15 mg/kg and 10 mg/kg, respectively. The MTD of free DOX reported here is also consistent with previous results (8–12 mg/kg) from several independent studies [9, 25, 26]. Whereas, the MTDs of Doxil®, a very stable nanoformulation of DOX, were reported to be only comparable or even lower than that of free DOX, respectively in dogs and mice [27, 28].…”

Section: Resultssupporting

confidence: 92%

PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma

Xiao

Luo

et al. 2011

Journal of Controlled Release

104

View full text Add to dashboard Cite

Doxorubicin (DOX) is one of most common anti-cancer chemotherapeutic drugs, but its clinical use is associated with dose-limiting cardiotoxicity. We have recently developed a series of PEG-oligocholic acid based telodendrimers, which can efficiently encapsulate hydrophobic drugs and self-assemble to form stable micelles in aqueous condition. In the present study, two representative telodendrimers (PEG5k-CA8 and PEG2k-CA4) have been applied to prepare DOX micellar formulations for the targeted delivery of DOX to lymphoma. PEG2k-CA4 micelles, compared to PEG5k-CA8 micelles, were found to have higher DOX loading capacity (14.8% vs. 8.2%, w/w), superior stability in physiological condition, and more sustained release profile. Both of these DOX-loaded micelles can be efficiently internalized and release the drug in Raji lymphoma cells. DOX-loaded micelles were found to exhibit similar in vitro cytotoxic activities against both T- and B- lymphoma cells as the free DOX. The maximum tolerated dose (MTD) of DOX-loaded PEG2k-CA4 micelles in mice was approximately 15 mg/kg, which was 1.5-fold higher of the MTD of free DOX. Pharmacokinetics and biodistribution studies demonstrated both DOX-loaded micelles were able to prolong the blood retention time, preferentially accumulate and penetrate in B-cell lymphomas via the enhanced permeability and retention (EPR) effect. Finally, DOX-PEG2k-CA4 micelles achieved enhanced anti-cancer efficacy and prolonged survival in Raji lymphoma bearing mice, compared to free DOX and PEGylated liposomal DOX (Doxil®) at the equivalent dose. In addition, the analysis of creatine kinase (CK) and lactate dehydrogenase (LDH) serum enzymes level indicated that DOX micellar formulations significantly reduced the cardiotoxicity associated with free DOX.

show abstract

Section: Resultssupporting

confidence: 92%

PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma

Xiao

Luo

et al. 2011

Journal of Controlled Release

104

View full text Add to dashboard Cite

show abstract

“…For example, the MTD of pegylated liposomal DOX (DOXIL) was lower but the potency was improved (Colbern et al, 1999;Gabizon, 2001;Gabizon et al, 2003). When the drug is inactive by polymer conjugation or given in a prodrug form, a large increase in the MTD has been reported, as in the case of N-(2-hydroxypropyl)methyacrylamide (HPMA) copolymer-DOX (4.5-fold) (Duncan et al, 1998), PEO-bpoly(L-aspartate) conjugated of DOX (NK911) (20-fold) (Yokoyama et al, 1990(Yokoyama et al, , 1991, N-L-leucyl-DOX (threefold) (Bennis et al, 1993;Breistol et al, 1998Breistol et al, , 1999, and glucuronide prodrug DOX (25-fold) (Houba et al, 2001). In addition, the changes in PK profile of the drug associated with a carrier can increase the MTD as shown by PEO-b-poly(β-benzyl-L-aspartate) (PBLA) micelle (2.3-fold) (Kwon et al, 1997;Kataoka et al, 2000) and SP1049 (1.4-fold) (Danson et al, 2004).…”

Section: Mtd Determination Of Dphsm-f127mentioning

confidence: 99%

l-Histidine-based pH-sensitive anticancer drug carrier micelle: Reconstitution and brief evaluation of its systemic toxicity

Lee

Kim

et al. 2008

International Journal of Pharmaceutics

View full text Add to dashboard Cite

Adoxorubicin (DOX)-carrier micellar system consisting of poly(histidine)(5K)-b-poly(ethylene glycol)(2K) and poly(L-lactic acid)(3K)-b-PEG(2K)-folate has been developed targeting the early endosomal pH and it have been convincingly proved that intracellular high dose strategy using such micelles is effective in overcoming multidrug resistance (MDR) of cancer cells. Due to the low DOX concentrations in the micelle solution obtained by dialysis and the lack of long-term stability of the micelles, stable and lyophilized micelle formulations were the subject of investigation reported here by using excipients of sucrose, PEG or Pluronic. The reconstituted micelle solutions were examined by particle size, pH sensitivity, and cytotoxicity for MDR cells and the results were compared with the non-lyophilized micelles. Among tested excipients, Pluronic F127 (33 wt%) added to the polymer/drug solution prior to dialysis resulted in a reconstituted product stable for a week and presented equivalent benefits as the fresh micelle formulation. The blank micelles did not present any apparent systemic toxicity in mice up to 2400 mg/kg i.v. injection (800 mg/(kg day) for 3 days). The brief toxicity of reconstituted DOX loaded micelles was examined by the maximum tolerated dose (MTD), which was approximately 7.5-fold higher than free DOX and guaranteeing further animal toxicity and efficacy study.

show abstract

“…presumed to be a candidate enzyme for the activation of the prodrug to free doxorubicin, leading to an increased therapeutic window [126]. Further clinical evaluation must demonstrate that N-L-Leucyl-doxorubicin is not a suitable substrate for ubiquitous aminopeptidases in humans and that pharmacokinetic distribution is as favorable as in nude mice.…”

Section: Cathepsinsmentioning

confidence: 99%

Anticancer Prodrugs for Application in Monotherapy Targeting Hypoxia, Tumor-Associated Enzymes, and Receptors

Groot¹,

Damen²,

Scheeren

2001

CMC

114

View full text Add to dashboard Cite

In order to improve current chemotherapeutic treatment and diminish severe side effects, several prodrug strategies have evolved to achieve site-specific delivery of cytotoxic anticancer agents. This review concentrates on recent developments of antitumor prodrug monotherapy with prodrugs that are designed for direct recognition of tumor-associated factors, such as hypoxia, tumor-associated enzymes and receptors. Firstly, oxygen deficiency in the core of solid tumors leads to enhanced activity of reducing enzymes, like for example nitroreductases, which can be used for site- specific conversion of prodrug to drug. Secondly, some enzymes are present in elevated levels in tumor tissue: beta-glucuronidase leaks from necrotic areas within tumors, while tumor cells for invasive and metastatic activities need several tumor-associated proteases, like plasmin. These enzymes form an attractive target for designing selective prodrugs. Finally, tumor-selective expression of receptors can be exploited for the delivery of antitumor agents. Low molecular weight binding motifs for these receptors can be coupled to cytotoxic drugs in order to obtain tumor-homing conjugates. At present, receptor-binding motifs for a number of receptors that are required for angiogenesis are used for prodrug monotherapy. There exists an increasing body of literature, which describes the complex interplay not only between tumor-associated enzymes, but also between these enzymes and tumor-associated receptors in the process of tumor invasion and metastasis, indicating the feasibility of targeting cytotoxic drugs to these key players in tumor growth. This paper reviews the development and evaluation of anticancer prodrugs, and their application in the various prodrug monotherapy approaches.

show abstract

Superior therapeutic efficacy of N-l-leucyl-doxorubicin versus doxorubicin in human melanoma xenografts correlates with higher tumour concentrations of free drug

Cited by 25 publications

References 25 publications

PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma

PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma

l-Histidine-based pH-sensitive anticancer drug carrier micelle: Reconstitution and brief evaluation of its systemic toxicity

Anticancer Prodrugs for Application in Monotherapy Targeting Hypoxia, Tumor-Associated Enzymes, and Receptors

Contact Info

Product

Resources

About