Paclitaxel Encapsulated in Cationic Liposomes Increases Tumor Microvessel Leakiness and Improves Therapeutic Efficacy in Combination with Cisplatin

Strieth, Sebastian; Eichhorn, Martin; Werner, Alexander; Sauer, Birgitta; Teifel, Michael; Michaelis, Uwe; Berghaus, Alexander; Dellian, Marc

doi:10.1158/1078-0432.ccr-07-4738

Cited by 57 publications

(36 citation statements)

References 20 publications

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“…To further improve the therapeutic efficacy of the novel treatment regimens, the replacement of etoposide and paclitaxel with liposomal preparations could present an interesting future perspective. Although currently no commercial liposomal preparation for etoposide is available, a vascular-targeting cationic liposomal preparation for paclitaxel has recently been established and is under clinical testing (Strieth et al 2008, Eichhorn et al 2010. Altogether our experiments indicate that the tested liposomal variants could represent interesting treatment options for ACC patients and should be investigated in more detail to allow a safe and effective translation into clinical studies.…”

Section: Discussionmentioning

confidence: 79%

Liposomal polychemotherapy improves adrenocortical carcinoma treatment in a preclinical rodent model

Hantel¹,

Jung²,

Mussack³

et al. 2014

Endocrine-Related Cancer

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Owing to high relapse rates and early metastatic spread, prognosis in adrenocortical carcinoma (ACC) patients remains poor, highlighting the importance of developing new treatment alternatives for them. Recently, polychemotherapy regimens including etoposide, doxorubicin, and cisplatin together with mitotane (EDP-M) have been defined as the standard treatment for late-stage disease patients. Nevertheless, the administration of conventional cytostatic drugs is associated with severe and dose-limiting side effects. In an attempt to optimize existing clinical treatment regimens, in this study, we investigated the therapeutic efficacy of EDP-M in comparison with that of a paclitaxel-modified scheme (paclitaxel, doxorubicin, cisplatin plus mitotane (PDP-M)) in preclinical in vitro and in vivo models. In addition, based on an extraordinary uptake phenomenon of liposomes in ACC cells, we further evaluated liposomal variants of these protocols (etoposide, liposomal doxorubicin, liposomal cisplatin plus mitotane (LEDP-M) and nab-paclitaxel, liposomal doxorubicin, liposomal cisplatin plus mitotane (LPDP-M)). In vitro, PDP-M was more potent in the induction of apoptosis and inhibition of cell viability as well as cell proliferation than EDP-M. Following the administration of a single therapeutic cycle, we further demonstrated that LEDP-M and LPDP-M exerted significant antitumoral effects in vivo, which were not as evident upon EDP-M and PDP-M treatments. These results were confirmed in a long-term experiment, in which the highest and sustained antitumoral effects were observed for LEDP-M. In summary, liposomal cytostatic substances could represent a promising option that deserves testing in appropriate clinical protocols for the treatment of ACC patients.

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Section: Discussionmentioning

confidence: 79%

Liposomal polychemotherapy improves adrenocortical carcinoma treatment in a preclinical rodent model

Hantel¹,

Jung²,

Mussack³

et al. 2014

Endocrine-Related Cancer

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“…The proliferation of endothelial cell plays a key role in tumor angiogenesis. For this reason, many studies have focused on antiangiogenesis or target endothelial cell receptors, such as paclitaxel encapsulated in cationic liposomes (28)(29)(30)(31)(32)(33). Paclitaxel encapsulated in cationic liposomes significantly inhibits tumor growth by a significant reduction of functional tumor microcirculation and induction of endothelial cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Antiangiogenic Activity of Sterically Stabilized Liposomes Containing Paclitaxel (SSL-PTX): In Vitro and In Vivo

et al. 2010

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Abstract. The purpose of this present study was to evaluate the antiangiogenic activity of sterically stabilized liposomes containing paclitaxel (SSL-PTX). The SSL-PTX was prepared by the thin-film method. The release of paclitaxel from SSL-PTX was analyzed using a dialysis method. The effect of SSL-PTX on endothelial cell proliferation and migration was investigated in vitro. The antitumor and antiangiogenic activity of SSL-PTX was evaluated in MDA-MB-231 tumor xenograft growth in BALB/c nude mice. The release of paclitaxel from SSL-PTX was 22% within 24 h. Our in vitro results indicated that SSL-PTX could effectively inhibit the endothelial cell proliferation and migration at a concentrationdependent manner. We also observed that metronomic SSL-PTX induced marked tumor growth inhibition in MDA-MB-231 xenograft model via the antiangiogenic mechanism, unlike that in paclitaxel injection (Taxol) formulated in Cremophor EL (CrEL). Overall, our results suggested that metronomic chemotherapy with low-dose, CrEL-free SSL-PTX should be feasible and effective.

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“…In addition to the simultaneous targeting of 2 tumor compartments, a direct interaction between both treatment modalities could further explain an additive therapeutic effect: tumor vascular targeting by EndoTAG TM -1 has been shown to increase tumor microvessel permeability as quantified by DCE-MRI 11 or intravital microscopy. 28 Transvascular transport is known to be a prerequisite for good antitumoral effects of small molecular chemotherapeutic drugs. Therefore, modifying the blood-tumor barrier by increasing tumor vessel permeability might be an important mechanism for enhanced antitumoral efficiency in response to EndoTAG TM -1 combination therapy.…”

Section: Discussionmentioning

confidence: 99%

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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Paclitaxel Encapsulated in Cationic Liposomes Increases Tumor Microvessel Leakiness and Improves Therapeutic Efficacy in Combination with Cisplatin

Cited by 57 publications

References 20 publications

Liposomal polychemotherapy improves adrenocortical carcinoma treatment in a preclinical rodent model

Liposomal polychemotherapy improves adrenocortical carcinoma treatment in a preclinical rodent model

Antiangiogenic Activity of Sterically Stabilized Liposomes Containing Paclitaxel (SSL-PTX): In Vitro and In Vivo

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

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