Neovascular targeting chemotherapy: Encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature

Strieth, Sebastian; Eichhorn, Martin; Sauer, Birgitta; Schulze, B.; Teifel, Michael; Michaelis, Uwe; Dellian, Marc

doi:10.1002/ijc.20083

Cited by 91 publications

(96 citation statements)

References 31 publications

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“…In earlier studies EndoTAG TM -1 was shown to increase significantly the antitumoral efficacy of the drug in different experimental tumor models. 8,10,17 Subsequent experiments investigated the mode of action and provided convincing evidence of tumor vascular targeting by Endo-TAG TM -1: impairment of tumor microvascular perfusion in response to EndoTAG TM -1 therapy has been demonstrated by intravital microscopy and DCE-MRI, 10,11 respectively. Moreover, tumor endothelial cell apoptosis and intratumoral thrombosis induced by EndoTAG TM -1 therapy indeed supported vascular targeting as the underlying mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…10 Oregon Green 488 paclitaxel encapsulated in cationic lipid complexes was injected i.v. yielding an effective Oregon Green paclitaxel dose of 0.053 mg/kg b.w.…”

Section: Analysis Of Intratumoral Drug Distributionmentioning

confidence: 99%

“…To investigate antitumoral efficiency of combined therapy C57/Bl6 mice were treated by EndoTAG TM -1 (3 Â 5 mg/kg b.w./week; days 10,12,14,17,19,21) and i.p. injection of cisplatin (2 Â 2.5 mg/kg b.w./week; days 11, 13, 18, 20; Platinex V R , Bristol-Myers Squibb, New York, NY).…”

Section: Experimental Protocol and Treatment Schedulesmentioning

confidence: 99%

“…We have previously shown that vascular targeting therapy can be realized by paclitaxel or camptothecin encapsulated in cationic lipid complexes. 8,9 Treatment with these liposomal compounds significantly retarded primary tumor growth and delayed metastatic disease by an antivascular mechanism, as shown by intravital microscopy 10 or DCE-MRI, 11 respectively.…”

mentioning

confidence: 96%

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Vascular targeting by EndoTAG™‐1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer

Eichhorn

Ischenko²,

Luedemann³

et al. 2009

Intl Journal of Cancer

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Cationic lipid complexed paclitaxel (EndoTAG TM -1) is a novel vascular targeting agent for the treatment of cancer. Here, the aim was to investigate intratumoral drug distribution after EndoTAG TM -1 therapy and analyze the impact of EndoTAG TM -1 scheduling on antitumoral efficacy. The therapeutic effect of EndoTAG TM -1 in combination with conventional gemcitabine or cisplatin therapy was evaluated in L3.6pl orthotopic pancreatic cancer and a subcutaneous Lewis lung (LLC-1) carcinoma model. Oregon Green paclitaxel encapsulated in cationic liposomes in combination with intravital fluorescence microscopy clearly exhibited delivery of the drug by EndoTAG TM -1 to the tumor endothelium, whereas Oregon Green paclitaxel dissolved in cremophor displayed an interstitial distribution pattern. The therapeutic efficacy of EndoTAG TM -1 was critically dependent on the application schedule with best therapeutic results using a metronomic rather than a maximum tolerated dose application sequence. The combination of EndoTAG TM -1 therapy and cytotoxic chemotherapy significantly enhanced antitumoral efficacy in both tumor models. Interestingly, only EndoTAG TM -1 in combination with gemcitabine was able to inhibit the incidence of metastasis in pancreatic cancer. In conclusion, vascular targeting tumor therapy by EndoTAG TM -1 combined with standard small molecular chemotherapy results in markedly enhanced antitumoral efficacy. Therefore, this combination represents a promising novel strategy for clinical cancer therapy.Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, is fundamental in tumor growth, progression and metastasis. 1 The complex network of tumor blood microvessels guarantees an adequate supply of tumor cells with nutrients and oxygen and provides efficient drainage of metabolites.Therapeutic strategies that target and disrupt already formed vessel networks of growing tumors are therefore actively pursued. In contrast with the antiangiogenesis approach, the aim of vascular targeting is to destroy the established tumor vasculature thus causing a rapid and extensive decrease in tumor blood flow, followed by secondary tumor cell death. 2,3 Ligand-directed vascular targeting agents and small molecular tubulin-binding agents have been successfully developed to induce a vascular shutdown of tumor microvessels. 4 In addition to these compounds, drug delivery systems are of considerable interest in realizing such a new therapeutic concept: cationic lipid complexes have been described to target angiogenic endothelial cells in tumor preferentially. [5][6][7] This property potentially enables selective delivery of cytotoxic drugs to tumor endothelial cells and thus vascular targeting chemotherapy. We have previously shown that vascular targeting therapy can be realized by paclitaxel or camptothecin encapsulated in cationic lipid complexes. 8,9 Treatment with these liposomal compounds significantly retarded primary tumor growth and delayed metastatic disease by an antivascular...

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Section: Discussionmentioning

confidence: 99%

“…10 Oregon Green 488 paclitaxel encapsulated in cationic lipid complexes was injected i.v. yielding an effective Oregon Green paclitaxel dose of 0.053 mg/kg b.w.…”

Section: Analysis Of Intratumoral Drug Distributionmentioning

confidence: 99%

Section: Experimental Protocol and Treatment Schedulesmentioning

confidence: 99%

mentioning

confidence: 96%

See 2 more Smart Citations

Vascular targeting by EndoTAG™‐1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer

Eichhorn

Ischenko²,

Luedemann³

et al. 2009

Intl Journal of Cancer

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“…Recent studies provided support of the concept for vascular targeted tumor therapy by use of paclitaxel encapsulated into cationic lipid complexes (MBT-0206) in different animal tumor models. [14][15][16] The standard clinical criterion for assessing tumor response to conventional chemo-or radiation therapy is based on measurement of tumor size. However, in case of an antivascular tumor treatment by cationic lipid complexes, changes in vascular function are likely to precede the subsequent changes in tumor size.…”

Section: Introductionmentioning

confidence: 99%

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

Eichhorn

Becker²,

Strieth³

et al. 2006

Cancer Biology & Therapy

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Cationic lipid complexes have been shown to be bound and internalized selectively by angiogenic tumor endothelial cells after intravenous injection. Based on this phenomenon, the chemotherapeutic agent paclitaxel was encapsulated into these lipid complexes providing a vascular targeting agent (MBT-0206). As noninvasive imaging techniques are of critical importance for optimizing antivascular cancer treatment in the clinic, we have evaluated the antivascular effects of MBT-0206 in the A-MEL-3 solid tumor model using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI).Twenty-four hours after three intravenous applications of MBT-0206, tumors of treated animals demonstrated a significant decrease of intratumoral blood volume and an increase of vascular permeability in comparison to size-matched control tumors. In contrast, animals treated with conventional paclitaxel given as Taxol ® at equal drug dose did not show any significant differences in vascular parameters acquired by DCE-MRI in comparison to controls. Immunohistological analysis confirmed a significant reduction of microvessel density in MBT-0206 treated tumors. Moreover, a significant increase of intratumoral microvascular occlusion following MBT-0206 treatment was observed compared to controls and paclitaxel treated animals.In conclusion, antivascular tumor therapy with MBT-0206 significantly impairs functional tumor microcirculation. DCE-MRI is a promising tool to quantify the antivascular effects of MBT-0206 during treatment.

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Cytotoxicity of cationic liposomes coated by N‐trimethyl chitosan and their in vivo tumor angiogenesis targeting containing doxorubicin

Xia-zhen

Wen

Zhang

et al. 2012

J of Applied Polymer Sci

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Doxorubicin (DOX)-loaded cationic liposomes (DOXL) coated by N-trimethyl chitosan (TMCs) has been previously shown to enhance DOX uptake by human umbilical vein endothelial cells (HUVECs) in vitro and the tumor inhibition on solid tumor in vivo, and the effects were both enhanced with the degree of quaternization (DQ) increase of TMCs. The aim of the present work is to study the cytotoxicity of the blank cationic liposomes (CLs) coated by TMCs with various DQ on L-929 mouse fibroblasts, by MTT assay, using the relative proliferation rate as the indicator, and the toxicity extent was classified according to the evaluation criteria of United States Pharmacopoeia. Furthermore, the in vivo tumor angiogenesis targeting of DOXL coated by TMC60 was studied. It was found that with the increase of TMCs concentration and DQ, cytotoxicity was increased accordingly. However, the cell proliferation rates of TMCs-coated CLs with TMCs concentrations of 0.02% and 0.05%(w/w) were all above 80%, even the concentration of TMC20 was increased to 0.2%(w/w), the cell proliferation rate was still above 80%, showing noncytotoxicity. The mouse H 22 tumor model was established by transplanted tumor experiment. In vivo fluorescence in tumor tissue was investigated through the tail vein injection of fluorescein isothiocyanate conjugated dextran at the 7th day after the administration of different DOX preparations. Compared with DOX solution and uncoated DOXL, the mice given TMC60-coated DOXL showed tumor angiogenesis with good shape, uniform arrangement, and small vascular branches, and the vascular density was decreased, suggesting promising tumor angiogenesis targeting of TMC60-coated DOXL.

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Neovascular targeting chemotherapy: Encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature

Cited by 91 publications

References 31 publications

Vascular targeting by EndoTAG™‐1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer

Vascular targeting by EndoTAG™‐1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer

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

Cytotoxicity of cationic liposomes coated by N‐trimethyl chitosan and their in vivo tumor angiogenesis targeting containing doxorubicin

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