Diameter-dependent release of a cisplatin pro-drug from small and large functionalized carbon nanotubes

Abstract

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.

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

“…The explicit dependence of platinum(IV) prodrug release on the diameter of the MWCNTs was recently probed. 423 Smaller MWCNTs, once loaded with the prodrug, release platinum more slowly, as expected given the smaller size of the opening through which it must diffuse in order to escape. In addition to delivering a prodrug that only releases cisplatin, dual-threat prodrugs can also be loaded into MWCNTs.…”

Core–shell polymer nanoparticles for prevention of GSH drug detoxification and cisplatin delivery to breast cancer cells

“…13 PEGylated block copolymers of poly(isobutylene-maleic acid) 14 and polyacrylates [15][16][17][18][19][20] are some of the important polymer systems that were explored for cisplatin conjugation. 25 Folic acid-conjugated platinum nanoparticles, 26 PEGylated mesoporous silica nanoparticles, 27 functionalized carbon nanotubes 28 and graphenes, [29][30] lipids [31][32] and amphiphilic oligomer based micelles, 33 cyclic tripeptides, 34 and gold nanoparticles [35][36] are some of the other approached developed for cisplatin delivery. Kataoka and co-workers used PEGylated-poly(L-glutamic acid) copolymers for cisplatin conjugation and the resultant micellar drug conjugates were found to be effective in suppressing the growth of solid tumours.…”

Nano-Based Systems and Biomacromolecules as Carriers for Metallodrugs in Anticancer Therapy

“…Several carbon nanotube-based carriers have been developed for Pt(IV) prodrug delivery [78][79][80][81][82][83]. In one example, two different diameters of multi-walled carbon nanotubes were examined to deliver Pt(IV) to HeLa cells [82]. The cells internalized the CNTs-Pt effectively, with the larger diameter CNTs-Pt showing higher cytotoxicity than the smaller one or free drugs.…”