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

Abstract

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.

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

“…17,18 In addition to paclitaxel, doxorubin, 5-FU and camptothecin have, meanwhile, been successfully encapsulated in cationic lipid complexes to realize vascular targeting therapy in preclinical animal models. 9,19,20 However, the clinical success of vascular targeting and antiangiogenic agents depends upon potential combination with conventional therapies. To date, antivascular drugs can not eradicate tumors completely, and remarkable antitumoral effects can be achieved in the clinical situation only by combining antivascular tumor therapy with conventional cytotoxic radio-or 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 mechanism, as shown by intravital microscopy 10 or DCE-MRI, 11 respectively.Although antiangiogenic inhibitors and vascular targeting agents can regress primary tumor growth and inhibit tumor metastasis in experimental tumor models, antivascular tumor therapy as monotherapy has failed to provide convincing results in clinical trials. To date, antiangiogenic drugs and vascular targeting agents cannot eradicate tumors completely, and remarkable antitumoral effects can be achieved only by…”

“…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.…”

Liposomal formulations of poorly soluble camptothecin: drug retention and biodistribution

“…Previously, several studies have been performed on incorporation of CPT in liposomes, however the experimental designs used were different and none besides the one from Saetern and colleagues has reported a thorough study of many different liposome compositions. Despite of this the results from the mentioned studies could be summarized to relieve the following effect of different types of lipids: Inclusion of cationic lipids has shown to increase the incorporation of CPT (Eichhorn et al, 2007, Saetern et al, 2004b, Sugarman et al, 1996, the same has been shown with anionic lipids even though not to the same extent (Burke et al, 1993, Saetern et al, 2004b, Sugarman et al, 1996. Inclusion of fatty acids with increased degree of saturation as well as cholesterol has in most studies shown to decrease incorporation (Daoud et al, 1995, Saetern et al, 2004b, Sugarman et al, 1996 but in some cases the opposite effect has been observed when fatty acids with increased degree of saturation has been included in liposome formulations (Burke et al, 1993).…”

“…Several patents (Burke, 1996, Perez-Soler et al, 1998 are available and numerous studies (Sugarman et al, 1996, Proulx et al, 2001, Burke et al, 1992, Saetern et al, 2004b, Watanabe et al, 2008, Eichhorn et al, 2007, Clements et al, 1996, Daoud et al, 1995 reported on liposomal formulations of camptothecins, whereof the majority of studies is on liposomal CPT-formulations investigated water soluble CPT-derivatives such as topotecan (Yang et al, 2012, Tardi et al, 2000, Liu et al, 2002, Subramanian et al, 1995, Zucker et al, 2012, Drummond et al, 2010, Dadashzadeh et al, 2008, irinotecan (Chou et al, 2003, Sadzuka, 2000, Sadzuka et al, 1998, Sadzuka et al, 1999, Sadzuka et al, 1997, Drummond et al, 2006, Zhang et al, 2012, Hattori et al, 2009), lurtotecan (MacKenzie et al, 2004, Loos et al, 2000, Desjardins et al, 2001, Colbern et al, 1998, SN-38 {Zhang, 2004Atyabi, 2009Sadzuka, 2005Lei, 2004#1330}, 9-nitro-CPT (Chen et al, 2008, Chen et al, 2006, Gilbert et al, 2002, Koshkina et al, 1999 and DB-67 (Bom et al, 2001. The focus on the present study is in contrast on poorly water soluble and lipophilic parent CPT-compound.…”