EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx®, Doxil®) at a 6-week interval in patients with metastatic breast cancer

Hamilton, Anne; Biganzoli, Laura; Coleman, Robert E.; Mauriac, L.; Hennebert, Philippe; Awada, Ahmad; Nooij, MA; Beex, L.V.A.M.; Piccart, Martine; Hoorebeeck, Irène Van; Bruning, P.F.; Valeriola, Dominique de

doi:10.1093/annonc/mdf157

Cited by 93 publications

(40 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pegylated lipid systems carrying smallmolecule drugs have been used clinically (35)(36)(37)(38), and such systems have been adapted for use in RNAi therapy (10,14,26,27). We investigated a pegylated lipid system for this purpose because pegylation reduces the rate of plasma clearance by the liver.…”

Section: Discussionmentioning

confidence: 99%

Tumor Regression in Mice by Delivery of Bcl-2 Small Interfering RNA with Pegylated Cationic Liposomes

et al. 2008

View full text Add to dashboard Cite

The pharmacokinetics and antitumor activity of pegylated small interfering RNA (siRNA)/cationic liposome complexes were studied after systemic administration to mice. We designed pegylated-lipid carriers for achieving increased plasma concentrations of RNA and hence improved accumulation of RNA in tumors by the enhanced permeability and retention effect. We compared the pharmacokinetics of siRNA complexed with liposomes incorporating pegylated lipids with longer (C-17 or C-18), shorter (C-12 to C-16), or unsaturated (C-18:1) acyl chains. When longer acyl chains were used, the plasma concentrations of siRNA obtained were dramatically higher than when shorter or unsaturated chains were used. This may be explained by the higher gelto-liquid-crystalline phase-transition temperature (Tc) of lipids with longer acyl chains, which may form more rigid liposomes with reduced uptake by the liver. We tested a siRNA that is sequence specific for the antiapoptotic bcl-2 mRNA complexed with a pegylated liposome incorporating a C-18 lipid (PEG-LIC) by i.v. administration in a mouse model of human prostate cancer. Three-fold higher accumulation of RNA in the tumors was achieved when PEG-LIC rather than nonpegylated liposomes was used, and sequence-specific antitumor activity was observed. Our siRNA/PEG-LIC complex showed no side effects on repeated administration and the strength of its antitumor activity may be attributed to its high uptake by the tumors. Pegylation of liposomes improved the plasma retention, uptake by s.c. tumors, and antitumor activity of the encapsulated siRNA. PEG-LIC is a promising candidate for siRNA cancer therapy. [Cancer Res 2008;68(21):8843-51]

show abstract

Section: Discussionmentioning

confidence: 99%

Tumor Regression in Mice by Delivery of Bcl-2 Small Interfering RNA with Pegylated Cationic Liposomes

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Table 3. Pharmacokinetic properties in human of marketed preparation of doxorubicin (free or encapsulated in conventional or PEGylated liposomes) [8,[68][69][70].…”

Section: Clinical Application Of Pegylated Liposomesmentioning

confidence: 99%

PEGylation of Proteins and Liposomes: a Powerful and Flexible Strategy to Improve the Drug Delivery

Milla¹,

Dosio²,

Cattel

2012

CDM

347

276

View full text Add to dashboard Cite

Abstract:PEGylation is one of the most successful strategies to improve the delivery of therapeutic molecules such as proteins, macromolecular carriers, small drugs, oligonucleotides, and other biomolecules. PEGylation increase the size and molecular weight of conjugated biomolecules and improves their pharmacokinetics and pharmacodinamics by increasing water solubility, protecting from enzymatic degradation, reducing renal clearance and limiting immunogenic and antigenic reactions. PEGylated molecules show increased half-life, decreased plasma clearance, and different biodistribution, in comparison with non-PEGylated counterparts. These features appear to be very useful for therapeutic proteins, since the high stability and very low immunogenicity of PEGylated proteins result in sustained clinical response with minimal dose and less frequent administration. PEGylation of liposomes improves not only the stability and circulation time, but also the 'passive' targeting ability on tumoral tissues, through a process known as the enhanced permeation retention effect, able to improve the therapeutic effects and reduce the toxicity of encapsulated drug.The molecular weight, shape, reactivity, specificity, and type of bond of PEG moiety are crucial in determining the effect on PEGylated molecules and, at present, researchers have the chance to select among tens of PEG derivatives and PEG conjugation technologies, in order to design the best PEGylation strategy for each particular application.The aim of the present review will be to elucidate the principles of PEGylation chemistry and to describe the already marketed PEGylated proteins and liposomes by focusing our attention to some enlightening examples of how this technology could dramatically influence the clinical application of therapeutic biomolecules.

show abstract

“…However, due to this alteration of the pharmacokinetic profile of free doxorubicin, the doselimiting toxicities of the long-circulating liposomal doxorubicin have been shifted towards mucocutaneous reactions such as palmar-plantar erythrodysesthesia (PPE) and mucositis/ stomatitis (Hamilton, et al 2002, Lotem, et al 2000, Uziely, et al 1995. The current hypothesis for the development of PPE is that the small size and long circulation time of Doxil ® allow for the liposome accumulation in the skin where the basal layers of the skin are damaged with prolonged exposure to doxorubicin as the liposomes slowly release this drug with known vesicant properties.…”

Section: Introductionmentioning

confidence: 99%

Tumor-specific antibody-mediated targeted delivery of Doxil® reduces the manifestation of auricular erythema side effect in mice

Elbayoumi

Torchilin

2008

International Journal of Pharmaceutics

View full text Add to dashboard Cite

A mucocutaneous reaction in mice associated with Doxil ® treatment was identified as Auricular Erythema (AE). Given that the immuno-targeting of Doxil ® to tumors was found to influence also its systemic biodistribution pattern, the attempt was made to exploit a specific targeting of Doxil ® to reduce the manifestation of this adverse reaction. This problem is of general significance, since cutaneous reactions often lead to alterations of Doxil ® dosing regimen in patients and might subsequently compromise the therapeutic outcome of cancer treatment. Tumor-bearing mice were used to study the biodistribution and skin-tissue accumulation effects of the tumor-targeted Doxil ® (the clinically used anti-cancer formulation) coupled with the anti-cancer monoclonal 2C5 antibody (mAb 2C5) as well as AE caused by Doxil ® application. The modification of Doxil ® with mAb 2C5 resulted in a significant decrease in the normal skin accumulation of doxorubicin compared to original Doxil ® and substantially reduced AE. The frequency of AE was decreased by 3-4-fold with the mAb 2C5-modified doxorubicin-loaded long-circulating liposomes. Thus, targeting of Doxil ® with the anticancer mAb 2C5 not only can increase the tumor-specific accumulation of the drug, but also diminishes the cutaneous side-effect of the original Doxil ® therapy.

show abstract

EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx®, Doxil®) at a 6-week interval in patients with metastatic breast cancer

Abstract: The recommended dose of Caelyx/Doxil using this schedule is 60 mg/m2 every 6 weeks. This is a safe and effective regimen that permits prolonged administration of anthracycline to patients with metastatic breast cancer.

Cited by 93 publications

References 15 publications

Tumor Regression in Mice by Delivery of Bcl-2 Small Interfering RNA with Pegylated Cationic Liposomes

Tumor Regression in Mice by Delivery of Bcl-2 Small Interfering RNA with Pegylated Cationic Liposomes

PEGylation of Proteins and Liposomes: a Powerful and Flexible Strategy to Improve the Drug Delivery

Tumor-specific antibody-mediated targeted delivery of Doxil® reduces the manifestation of auricular erythema side effect in mice

Contact Info

Product

Resources

About