Diameter-dependent release of a cisplatin pro-drug from small and large functionalized carbon nanotubes.
The use of platinum-based chemotherapeutic drugs in cancer therapy still suffers from severe disadvantages, such as lack of appropriate selectivity for tumor tissues and insurgence of multi-drug resistance. Moreover, drug efficacy can be attenuated by several mechanisms such as premature drug inactivation, reduced drug uptake inside cells and increased drug efflux once internalized. The use of functionalized carbon nanotubes (CNTs) as chemotherapeutic drug delivery systems is a promising strategy to overcome such limitations due to their ability to enhance cellular internalization of poorly permeable drugs and thus increase the drug bioavailability at the diseased site, compared to the free drug. Furthermore, the possibility to encapsulate agents in the nanotubes' inner cavity can protect the drug from early inactivation and their external functionalizable surface is useful for selective targeting. In this study, a hydrophobic platinum(IV) complex was encapsulated within the inner space of two different diameter functionalized multi-walled CNTs (Pt(IV)@CNTs). The behavior of the complexes, compared to the free drug, was investigated on both HeLa human cancer cells and RAW 264.7 murine macrophages. Both CNT samples efficiently induced cell death in HeLa cancer cells 72 hours after the end of exposure to CNTs. Although the larger diameter CNTs were more cytotoxic on HeLa cells compared to both the free drug and the smaller diameter nanotubes, the latter allowed a prolonged release of the encapsulated drug, thus increasing its anticancer efficacy. In contrast, both Pt(IV)@CNT constructs were poorly cytotoxic on macrophages and induced negligible cell activation and no pro-inflammatory cytokine production. Both CNT samples were efficiently internalized by the two types of cells, as demonstrated by transmission electron microscopy observations and flow cytometry analysis. Finally, the platinum levels found in the cells after Pt(IV)@CNT exposure demonstrate that they can promote drug accumulation inside cells in comparison with treatment with the free complex. To conclude, our study shows that CNTs are promising nanocarriers to improve the accumulation of a chemotherapeutic drug and its slow release inside tumor cells, by tuning the CNT diameter, without inducing a high inflammatory response.
CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et Chimie Thérapeutique, Strasbourg, France. a.bianco@ibmc-cnrs.unistra.fr.
Laura
L
Muzi
Cécilia
C
Ménard-Moyon
Julie
J
Russier
Jian
J
Li
Chee Fei
CF
Chin
Wee Han
WH
Ang
Giorgia
G
Pastorin
Gianfranco
G
Risuleo
Alberto
A
Bianco
D065966:Absorption, Physicochemical; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry*; D004058:Diffusion; D006367:HeLa Cells; D006801:Humans; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D037742:Nanotubes, Carbon / Q000737:chemistry* / Q000648:ultrastructure*; D010316:Particle Size; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D037742:Nanotubes, Carbon; D011355:Prodrugs; D002945:Cisplatin