Vascular and pharmacokinetic effects of EndoTAG-1 in patients with advanced cancer and liver metastasis

Fasol, Ulrike; Frost, Annette; Büchert, Martin; Arends, J.; Fiedler, Ulrike; Scharr, Dirk; Scheuenpflug, Juergen; Mross, Klaus

doi:10.1093/annonc/mdr300

Cited by 90 publications

(67 citation statements)

References 29 publications

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“…[17][18][19] Liposomal PTX formulations that are currently on the market (Lipusu ) all use unsaturated PC (1,2-dioleoyl-snglycero-3-phosphocholine or EggPC) without PEGylated lipid supplementation, probably owing to these limitations in the stability of PTX-loaded liposomes. [20][21][22] Saturated PCs, however, tend to produce liposomes that retain loaded drugs longer than unsaturated PCs, owing to the absence of oxidation-prone bonds and the higher phase-transition temperature of the resulting liposomes [23][24][25] and PEGylation of liposomes extends the circulation time of loaded drugs in the bloodstream and thus increase drug accumulation in tumors 26 by reducing interactions of liposomes with the reticuloendothelial system. Therefore, a formulation stabilizer enabling the PEGylated/saturated PC-based liposomes to retain PTX stably may provide an injectable PTX formulation with improved clinical performance.…”

Section: Introductionmentioning

confidence: 99%

Development of paclitaxel-loaded liposomal nanocarrier stabilized by triglyceride incorporation

Hong

Choi

Kim

et al. 2016

IJN

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Studies have highlighted the challenge of developing injectable liposomes as a paclitaxel (PTX) carrier, a challenge attributable to the limitations in liposomal stability caused by PTX loading. Poor stability of PTX-loaded liposomes is caused by PTX-triggered aggregation or fusion of liposomal membranes and is exacerbated in the presence of PEGylated lipid. In the present study, the effect of triglyceride incorporation on the stability of PTX-loaded/PEGylated liposomes was explored. Incorporation of a medium chain triglyceride Captex 300 into saturated phosphatidylcholine (PC)-based liposomes (1,2-dimyristoyl- sn -glycero-3-phosphocholine [DMPC]:cholesterol [CHOL]:N-(Carbonyl-methoxypolyethyleneglycol 2000)-1, 2-distearoyl- sn -glycero-3-phospho-ethanolamine [PE-PEG]), produced a fine, homogeneous, and membrane-filterable PTX-loaded liposomes fulfilling the requirement of an injectable lipid formulation. Triglyceride incorporation also greatly inhibited the time-dependent leakage of PTX from saturated PC-based liposomes, which appears to be mediated by the inhibition of liposome fusion. In contrast, triglyceride incorporation induced the destabilization and PTX leakage of unsaturated PC-based liposomes, indicating the opposite effect of triglyceride depending on the fluidity status of PC constituting the liposomal membrane. PTX release profile and the in vitro and in vivo anticancer efficacy of triglyceride-incorporated DMPC:CHOL:PE-PEG liposomes were similar to Taxol ® while the toxicity of liposomal PTX was significantly lower than that of Taxol. Taken together, triglyceride incorporation provided an injectable PTX formulation by functioning as a formulation stabilizer of PEGylated/saturated PC-based liposomes.

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Section: Introductionmentioning

confidence: 99%

Development of paclitaxel-loaded liposomal nanocarrier stabilized by triglyceride incorporation

Hong

Choi

Kim

et al. 2016

IJN

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“…The pharmacokinetic parameters were similar to the liposomal paclitaxel. 48 ET liposomes were well tolerated, as 50% of the patients had stable disease after the first treatment cycle. 48 Fibroblast growth factor receptors (FGFR) are reported to be overexpressed on the surface of tumor neovasculature, as well as in a variety of tumor cells.…”

Section: Targeting Of Endothelial Cells Using Positively Charged Lipomentioning

confidence: 99%

“…48 ET liposomes were well tolerated, as 50% of the patients had stable disease after the first treatment cycle. 48 Fibroblast growth factor receptors (FGFR) are reported to be overexpressed on the surface of tumor neovasculature, as well as in a variety of tumor cells. 49,50 Wang et al 51 used truncated basic fibroblast growth factor (bFGF)-conjugated cationic liposomes to improve the biodistribution and pharmacokinetics of paclitaxel in tumor-bearing mice.…”

Section: Targeting Of Endothelial Cells Using Positively Charged Lipomentioning

confidence: 99%

“…48 Patients with advanced cancer and liver metastasis were treated with ET after single or repeated doses (22 mg/m 2 , intravenously) the tumor vasculature or pharmacokinetic effects were evaluated. The pharmacokinetic profile, which was measured by dynamic contrast-enhanced magnetic resonance imaging and contract-enhanced ultrasound, showed slight accumulation of paclitaxel in tumor tissues after repeated doses.…”

Section: Targeting Of Endothelial Cells Using Positively Charged Lipomentioning

confidence: 99%

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Molecular targeting of liposomal nanoparticles to tumor microenvironment

Zhao¹,

Rodriguez²

2012

IJN

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Liposomes are biodegradable and can be used to deliver drugs at a much higher concentration in tumor tissues than in normal tissues. Both passive and active drug delivery by liposomal nanoparticles can significantly reduce the toxic side effects of anticancer drugs and enhance the therapeutic efficacy of the drugs delivered. Active liposomal targeting to tumors is achieved by recognizing specific tumor receptors through tumor-specific ligands or antibodies coupled onto the surface of the liposomes, or by stimulus-sensitive drug carriers such as acid-triggered release or enzyme-triggered drug release. Tumors are often composed of tumor cells and nontumor cells, which include endothelial cells, pericytes, fibroblasts, stromal, mesenchymal cells, innate, and adaptive immune cells. These nontumor cells thus form the tumor microenvironment, which could be targeted and modified so that it is unfavorable for tumor cells to grow. In this review, we briefly summarized articles that had taken advantage of liposomal nanoparticles as a carrier to deliver anticancer drugs to the tumor microenvironment, and how they overcame obstacles such as nonspecific uptake, interaction with components in blood, and toxicity. Special attention is devoted to the liposomal targeting of anticancer drugs to the endothelium of tumor neovasculature, tumor associated macrophages, fibroblasts, and pericytes within the tumor microenvironment.

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“…Interaction of positively charged liposomes with tumor blood vessels is known. 23 Selective destruction of blood vessels has been observed before by TNFα in combination with melphalan, 24 by multiple doses of doxorubicin-containing liposomes, 25 and by a combination of galactosamine and endotoxin. 26 Overexpression of some isoforms of VEGF also leads to hemorrhage.…”

mentioning

confidence: 97%

Hemorrhage in mouse tumors induced by dodecaborate cluster lipids intended for boron neutron capture therapy

Schaffran¹,

Jiang²,

Bergmann³

et al. 2014

IJN

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The potential of boron-containing lipids with three different structures, which were intended for use in boron neutron capture therapy, was investigated. All three types of boron lipids contained the anionic dodecaborate cluster as the headgroup. Their effects on two different tumor models in mice following intravenous injection were tested; for this, liposomes with boron lipid, distearoyl phosphatidylcholine, and cholesterol as helper lipids, and containing a polyethylene glycol lipid for steric protection, were administered intravenously into tumor-bearing mice (C3H mice for SCCVII squamous cell carcinoma and BALB/c mice for CT26/WT colon carcinoma). With the exception of one lipid (B-THF-14), the lipids were well tolerated, and no other animal was lost due to systemic toxicity. The lipid which led to death was not found to be much more toxic in cell culture than the other boron lipids. All of the lipids that were well tolerated showed hemorrhage in both tumor models within a few hours after administration. The hemorrhage could be seen by in vivo magnetic resonance and histology, and was found to occur within a few hours. The degree of hemorrhage depended on the amount of boron administered and on the tumor model. The observed unwanted effect of the lipids precludes their use in boron neutron capture therapy.

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Vascular and pharmacokinetic effects of EndoTAG-1 in patients with advanced cancer and liver metastasis

Cited by 90 publications

References 29 publications

Development of paclitaxel-loaded liposomal nanocarrier stabilized by triglyceride incorporation

Development of paclitaxel-loaded liposomal nanocarrier stabilized by triglyceride incorporation

Molecular targeting of liposomal nanoparticles to tumor microenvironment

Hemorrhage in mouse tumors induced by dodecaborate cluster lipids intended for boron neutron capture therapy

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