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1.
Cancer Med ; 6(6): 1240-1254, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28544814

RESUMO

The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK-N-SH, IMR-32 and LAN-1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper-drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio engendered significant increases in drug retention. Dose-range finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug-to-lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/Chol liposomal topotecan exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC0-24 h when compared with Hycamtin administered at equivalent doses (5 mg/kg). In contrast to the great extension in exposure time, SM/Chol liposomal topotecan increased the life span of mice with established LAN-1 neuroblastoma tumors only modestly in a subcutaneous and systemic model. The extension in exposure time may still not be sufficient and the formulation may require further optimization. In the future, liposomal topotecan will be assessed in combination with high-dose radiotherapy such as 131 I-metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy.


Assuntos
Neuroblastoma/tratamento farmacológico , Inibidores da Topoisomerase I/administração & dosagem , Topotecan/administração & dosagem , Animais , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Lipossomos , Masculino , Camundongos , Neuroblastoma/metabolismo , Distribuição Tecidual , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacocinética , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/química , Topotecan/farmacocinética , Topotecan/uso terapêutico
2.
Drug Deliv Transl Res ; 7(4): 544-557, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28432657

RESUMO

Topotecan is a drug that is under investigation for the treatment of neuroblastoma and has been encapsulated into liposomes to improve its therapeutic efficacy. However, liposomal formulations still need to be optimized for drug retention and new techniques to measure drug release are required to better understand this process. Here, a novel in vitro method based on fluorescence de-quenching and an automated microscopy imaging platform were developed for monitoring, in real time, the release of topotecan from a liposomal formulation. Drug release from liposomes was monitored for up to 15 h under different conditions including topotecan concentrations, fetal bovine serum amounts (0-20%), and temperatures (25 and 37 °C). A cell-based assay was used to assess liposome association with cells in culture and to quantify amounts of topotecan internalized into cells after release from liposomes. Our results show that the liposomal topotecan concentration had an influence on drug release kinetics: there was a reduction in release rate as a function of increasing concentration. Our data also show that topotecan release from the liposomal formulation was dependent on serum concentration where faster release was observed at higher serum concentrations, and on temperature where faster release was found at 37 °C. This real-time liposomal drug release assay allows for better understanding of the factors important in governing release of topotecan. The assay will be essential towards designing liposomal formulations of topotecan (and potentially of other camptothecin derivatives such as irinotecan) with optimized retention times and better therapeutic efficacy for testing in the clinic.


Assuntos
Inibidores da Topoisomerase I/administração & dosagem , Topotecan/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Humanos , Cinética , Lipossomos , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Topotecan/química , Topotecan/farmacologia , Transcitose
3.
J Drug Target ; 24(9): 787-796, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27145072

RESUMO

As a tribute to Pieter R. Cullis, this manuscript identifies a liposomal formulation that bears his initials: the PRCosomes. "Pretty" Reactive Complexes within liposomes were observed, while the senior author of this manuscript completed his Ph.D. thesis under Pieter's supervision. The dye (safranine) was used as a tool to measure the magnitude of the transmembrane gradient generated with liposomes. The dye's redistribution is easily detected by eye and correlates with >98% encapsulation of the dye. This observation became the basis from which remote drug loading methods developed. Remote loading methodology involves the addition of drugs to pre-formed liposomes with a transmembrane gradient, which results in drug redistribution to the liposome interior. Doxorubicin, as an example drug candidate, complexes manganese trapped within the liposome. A color change accompanied drug encapsulation as the solution went from an orange to purple. This manuscript reviews and adds a novel perspective on the use of metal complexation reactions to prepare PRCosomes. The technology described provides a versatile method to form metal-drug complexed within liposomes. The purpose of this work is to differentiation between drug candidate loading that is caused by metal-drug complexation and loading driven by formation of a pH gradient.


Assuntos
Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Lipossomos/química , Metais/química , Antibióticos Antineoplásicos/química , Lipídeos de Membrana
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