Paclitaxel encapsulated in cationic lipid complexes (MBT-0206) impairs functional tumor vascular properties as detected by dynamic contrast enhanced magnetic resonance imaging

Eichhorn, Martin; Becker, Sven; Strieth, Sebastian; Werner, Alexander; Sauer, Birgitta; Teifel, Michael; Ruhstorfer, H.; Michaelis, Uwe; Griebel, Jürgen; Brix, Gunnar; Jauch, Karl‐Walter; Dellian, Marc

doi:10.4161/cbt.5.1.2346

Cited by 26 publications

(14 citation statements)

References 32 publications

(42 reference statements)

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“…24 For DCE-MRI measurements, animals were placed in an animal holder. During MRI experiments animals were anaesthetized with 1% isoflurane (Abott, Cham, Switzerland) administered with a face mask.…”

Section: Dce-mri Imagingmentioning

confidence: 99%

Cationic lipid complexed camptothecin (EndoTAG®-2) improves antitumoral efficacy by tumor vascular targeting

Eichhorn

Luedemann²,

Strieth³

et al. 2007

Cancer Biology & Therapy

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Neo-vascular targeting by cationic colloidal carriers enables to realize an innovative approach for tumor therapy. EndoTag-2 is a novel vascular targeting agent, comprising the mammalian topoisomerase I inhibitor camptothecin in its carboxylate form complexed to cationic lipid (cationic lipid complexed camptothecin). Here we studied tumor vascular targeting properties, antitumoral effects and mode of action of EndoTag-2. Tumor vascular targeting properties of fluorescently labelled EndoTag-2 were investigated by in vivo microscopy using A-MEL-3 tumors grown in the dorsal skinfold chamber preparation and by fluorescence histology of s.c. LLC-1 carcinomas. Therapeutic effects have been investigated in the s.c. LLC-1 carcinoma model and the L3.6pl human pancreatic cancer model implanted orthotopically in athymic nude mice. Antivascular effects have been studied by histological investigation of tumor microvessel density and non invasive investigation of tumor blood flow by dynamic contrast enhanced MRI imaging (DCE-MRI). EndoTag-2 selectively targeted tumor microvessels as confirmed by quantitative fluorescence microscopy. Compared to controls EndoTag-2 revealed remarkable antitumoral efficiency in s.c. LLC-1 carcinomas implanted in C57/Bl6 mice. Growth and metastasis of orthotopic L3.6pl human pancreatic tumors was significantly inhibited by EndoTag-2 treatment. Quantitative analysis of tumor microvessel density revealed significant reduction of microvessel density in lewis lung carcinomas up to 50%. DCE-MRI confirmed significant reduction of intratumoral vascular volume as well as tumor perfusion upon EndoTag-2 treatment. In conclusion this study shows that cationic lipid complexed camptothecin (EndoTag-2) is a markedly active antitumor agent based on an innovative vascular targeting approach.

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Section: Dce-mri Imagingmentioning

confidence: 99%

Cationic lipid complexed camptothecin (EndoTAG®-2) improves antitumoral efficacy by tumor vascular targeting

Eichhorn

Luedemann²,

Strieth³

et al. 2007

Cancer Biology & Therapy

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“…Many types of transporters have been reported in recent years including peptides (1)(2)(3)(4)(5), peptoids (6), polyamines (7,8), oligocarbamates (9), dendrimers (10,11), polysaccharides (12), steroids (13), cationic lipids (14,15), guanidinoglycosides (16), and even nanotubes (17). These transporters operate through a variety of mechanisms and some through multiple mechanisms depending on cell type, cargo, and other variables (5,(18)(19)(20)(21)(22).…”

mentioning

confidence: 99%

Real-time analysis of uptake and bioactivatable cleavage of luciferin-transporter conjugates in transgenic reporter mice

Wender

Goun²,

Jones³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Many therapeutic leads fail to advance clinically because of bioavailability, selectivity, and formulation problems. Molecular transporters can be used to address these problems. Molecular transporter conjugates of otherwise poorly soluble or poorly bioavailable drugs or probes exhibit excellent solubility in water and biological fluids and at the same time an enhanced ability to enter tissues and cells and with modification to do so selectively. For many conjugates, however, it is necessary to release the drug/probe cargo from the transporter after uptake to achieve activity. Here, we describe an imaging method that provides quantification of transporter conjugate uptake and cargo release in real-time in animal models. This method uses transgenic (luciferase) reporter mice and whole-body imaging, allowing noninvasive quantification of transporter conjugate uptake and probe (luciferin) release in real time. This process effectively emulates drug-conjugate delivery, drug release, and drug turnover by an intracellular target, providing a facile method to evaluate comparative uptake of new transporters and efficacy and selectivity of linker release as required for fundamental studies and therapeutic applications.drug delivery ͉ imaging ͉ transgenic animals M olecular transporters § are agents which, when covalently linked to or complexed with a cargo, enable or enhance its entry into cells or tissues. Many types of transporters have been reported in recent years including peptides (1-5), peptoids (6), polyamines (7,8), oligocarbamates (9), dendrimers (10, 11), polysaccharides (12), steroids (13), cationic lipids (14, 15), guanidinoglycosides (16), and even nanotubes (17). These transporters operate through a variety of mechanisms and some through multiple mechanisms depending on cell type, cargo, and other variables (5,(18)(19)(20)(21)(22). Among the classes of transporters, oligoguanidine based transporters are particularly promising, providing excellent water solubility and at the same time the remarkable ability to rapidly cross the nonpolar membrane of a cell. These transporters have been used for the delivery of small molecules, peptides, proteins, nucleic acids, liposomes, and imaging agents (23-29) and have been modified to provide selective delivery of drugs into target cells and tissue (30,31). Significantly, an octaarginine transporter has been shown to facilitate uptake into tissue (32), including human skin (23). A conjugate of octaarginine and Cyclosporin A enabling uptake of the latter selectively into the skin and thereby effectively eliminating its systemic toxicity has been advanced into Phase II clinical trials (23).There are two overarching and interrelated challenges confronting the further advancement of this field: the development of methods to quantify the uptake of new or existing transporters in real-time in animal models and the identification and evaluation of linkers that would allow for controllable release (if required) of a free drug/probe from the transporter conjugate only after cel...

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“…This novel therapeutic strategy was first realized by the synthesis of EndoTAG™-1 (formerly known as Lipopac/MBT-0206), comprised of paclitaxel encapsulated in cationic liposomes. EndoTAG™-1 has been shown to induce endothelial cell apoptosis and severe impairment of functional tumor microvasculature (105), by triggering intravascular thrombosis within treated tumors (89). Moreover, treatment with EndoTAG™-1 significantly retarded tumor growth and delayed the incidence of metastatic disease in subcutaneously growing experimental tumors (80).…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

Targeting Anticancer Drugs to Tumor Vasculature Using Cationic Liposomes

2010

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Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG), and the impact of the molar percent of the cationic lipid included in cationic liposomes on liposomal targeting efficacy. In addition, the discussion herein includes the therapeutic benefit of a dual targeting approach, using PEG-coated cationic liposomes in vascular targeting (of tumor endothelial cells), and tumor targeting (of tumor cells) of anticancer drugs. Cationic liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development.

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Paclitaxel encapsulated in cationic lipid complexes (MBT-0206) impairs functional tumor vascular properties as detected by dynamic contrast enhanced magnetic resonance imaging

Cited by 26 publications

References 32 publications

Cationic lipid complexed camptothecin (EndoTAG®-2) improves antitumoral efficacy by tumor vascular targeting

Cationic lipid complexed camptothecin (EndoTAG®-2) improves antitumoral efficacy by tumor vascular targeting

Real-time analysis of uptake and bioactivatable cleavage of luciferin-transporter conjugates in transgenic reporter mice

Targeting Anticancer Drugs to Tumor Vasculature Using Cationic Liposomes

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