Liposomal doxorubicin for active targeting: surface modification of the nanocarrier evaluated in vitro and in vivo: challenges and prospects.
Due to the inability of classical chemotherapeutic agents to exclusively target tumor cells, these treatments are associated with severe toxicity profiles. Thus, long-circulating liposomes have been developed in the past to enhance accumulation in tumor tissue by passive targeting. Accordingly, commercially available liposomal formulations of sterically stabilized liposomal doxorubicin (Caelyx, Doxil, Lipodox) are associated with improved off-target profiles. However, these preparations are still not capable to selectively bind to target cells. Thus, in an attempt to further optimize existing treatment schemes immunoliposomes have been established to enable active targeting of tumor tissues. Recently, we have provided evidence for therapeutic efficacy of anti-IGF1R-targeted, surface modified doxorubicin loaded liposomes. Our approach involved a technique, which allows specific post-modifications of the liposomal surface by primed antibody-anchor conjugates thereby facilitating personalized approaches of commercially available liposomal drugs. In the current study, post-modification of sterically stabilized liposomal Dox was thoroughly investigated including the influence of different modification techniques (PIT, SPIT, SPIT60), lipid composition (SPC/Chol, HSPC/Chol), and buffers (HBS, SH). As earlier in vivo experiments did not take into account the presence of non-integrated ab-anchor conjugates this was included in the present study. Our experiments provide evidence that post-modification of commercially available liposomal preparations for active targeting is possible. Moreover, lyophilisation represents an applicable method to obtain a storable precursor of surface modifying antibody-anchor conjugates. Thus, these findings open up new approaches in patient individualized targeting of chemotherapeutic therapies.
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology and Biopharmacy, Albert Ludwig University Freiburg, Freiburg, Germany.
Judith
J
Jakoby
Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Felix
F
Beuschlein
Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Susanne
S
Mentz
Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Constanze
C
Hantel
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology and Biopharmacy, Albert Ludwig University Freiburg, Freiburg, Germany.
Regine
R
Süss
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
Caelyx®; IGF1 receptor; liposomal targeting; surface modification