A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats.
By focusing on rat glioma, we elucidated whether new lipid nanocapsules (LNC) were able to improve anticancer hydrophobic drug bioavailability while also overcoming multidrug resistance. Blank LNCs and LNCs loaded with the antineoplastic agent paclitaxel were formulated by an emulsion inversion phase process. Expression of efflux pumps by rat glioma cells was assessed by reverse transcription-PCR, Western blot, and immunohistochemistry, and their activity was followed using the tracer (99)Tc(m)-methoxyisobutylisonitrile. Modalities of LNC action were addressed by using confocal microscopy detection of fluorescently labeled LNCs, fluorescence-activated cell sorting, high-performance liquid chromatography measurement of paclitaxel release, and analysis of tumor cell growth. This revealed an interaction between LNCs and efflux pumps that resulted in an inhibition of multidrug resistance in glioma cells, both in culture and in cell implants in animals. LNCs were able to target the intracellular compartment of glioma cells, a mechanism that was abrogated by using intracellular cholesterol inhibitors but not by clathrin-coated pit or caveolae uptake inhibitors. This result can be correlated to the LNC inhibitory effects on efflux pump activity that is itself known to be stimulated by intracellular cholesterol. In parallel, we showed that paclitaxel-loaded LNCs were active reservoirs from which paclitaxel could be released. Finally, we established that paclitaxel-loaded LNCs were more efficient than the commercially available paclitaxel formulation (Taxol) for clinical use, thus reducing tumor expansion in vitro and in vivo. Considering the physiologically compatible nature of LNC excipients, these data may represent an important step towards the development of new clinical therapeutic strategies against cancers.
Garcion
Emmanuel
E
Institut National de la Santé et de la Recherche Medicale Unité 646, 10 rue André Boquel, 49100 Angers, France. emmanuel.garcion@univ-angers.fr
Lamprecht
Alf
A
Heurtault
Béatrice
B
Paillard
Archibald
A
Aubert-Pouessel
Anne
A
Denizot
Benoît
B
Menei
Philippe
P
Benoît
Jean-Pierre
JP
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002214:Capsules / Q000008:administration & dosage / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004705:Endocytosis; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D049329:Nanostructures / Q000737:chemistry*; D009570:Nitriles / Q000032:analysis; D017239:Paclitaxel / Q000008:administration & dosage; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002214:Capsules; D004337:Drug Carriers; D009570:Nitriles; D017239:Paclitaxel; D012333:RNA, Messenger; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C055887:2-methoxyisobutylisonitrile