In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles.
Nanoparticles with pH-sensitive behavior may enhance the success of chemotherapy in many cancers by efficient intracellular drug delivery. Here, we investigated the effect of a bioactive surfactant with pH-sensitive properties on the antitumor activity and intracellular behavior of methotrexate-loaded chitosan nanoparticles (MTX-CS-NPs). NPs were prepared using a modified ionotropic complexation process, in which was included the surfactant derived from N(α),N(ε)-dioctanoyl lysine with an inorganic lithium counterion. The pH-sensitive behavior of NPs allowed accelerated release of MTX in an acidic medium, as well as membrane-lytic pH-dependent activity, which facilitated the cytosolic delivery of endocytosed materials. Moreover, our results clearly proved that MTX-CS-NPs were more active against the tumor HeLa and MCF-7 cell lines than the free drug. The feasibilty of using NPs to target acidic tumor extracellular pH was also shown, as cytotoxicity against cancer cells was greater in a mildly acidic environment. Finally, the combined physicochemical and pH-sensitive properties of NPs generally allowed the entrapped drug to induce greater cell cycle arrest and apoptotic effects. Therefore, our overall results suggest that pH-sensitive MTX-CS-NPs could be potentially useful as a carrier system for tumor and intracellular drug delivery in cancer therapy.
Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
Daniele Rubert
DR
Nogueira
Lorena
L
Tavano
Montserrat
M
Mitjans
Lourdes
L
Pérez
M Rosa
MR
Infante
M Pilar
MP
Vinardell
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D048271:Chitosan / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D005240:Feasibility Studies; D005452:Fluoresceins; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry; D061986:MCF-7 Cells; D008727:Methotrexate / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry*; D013501:Surface-Active Agents / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D005452:Fluoresceins; D013501:Surface-Active Agents; C433469:dioctanoyl lysine; D048271:Chitosan; D008239:Lysine; C007740:fluorexon; D008727:Methotrexate