One-Step Synthesis of Nanoliposomal Copper Diethyldithiocarbamate and Its Assessment for Cancer Therapy
The metal complex copper diethyldithiocarbamate (CuET) induces cancer cell death by inhibiting protein degradation and induces proteotoxic stress, making CuET a promising cancer therapeutic. However, no clinical formulation of CuET exists to date as the drug is insoluble in water and exhibits poor b...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/3/640 |
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| author | Radu A. Paun Daciana C. Dumut Amanda Centorame Thusanth Thuraisingam Marian Hajduch Martin Mistrik Petr Dzubak Juan B. De Sanctis Danuta Radzioch Maryam Tabrizian |
| author_facet | Radu A. Paun Daciana C. Dumut Amanda Centorame Thusanth Thuraisingam Marian Hajduch Martin Mistrik Petr Dzubak Juan B. De Sanctis Danuta Radzioch Maryam Tabrizian |
| author_sort | Radu A. Paun |
| collection | DOAJ |
| description | The metal complex copper diethyldithiocarbamate (CuET) induces cancer cell death by inhibiting protein degradation and induces proteotoxic stress, making CuET a promising cancer therapeutic. However, no clinical formulation of CuET exists to date as the drug is insoluble in water and exhibits poor bioavailability. To develop a scalable formulation, nanoliposomal (LP) CuET was synthesized using ethanol injection as a facile one-step method that is suitable for large-scale manufacturing. The nanoparticles are monodispersed, colloidally stable, and approximately 100 nm in diameter with an encapsulation efficiency of over 80%. LP-CuET demonstrates excellent stability in plasma, minimal size change, and little drug release after six-month storage at various temperatures. Additionally, melanoma cell lines exhibit significant sensitivity to LP-CuET and cellular uptake occurs predominantly through endocytosis in YUMM 1.7 cancer cells. Intracellular drug delivery is mediated by vesicle acidification with more nanoparticles being internalized by melanoma cells compared with RAW 264.7 macrophages. Additionally, the nanoparticles preferentially accumulate in YUMM 1.7 tumors where they induce cancer cell death in vivo. The development and characterization of a stable and scalable CuET formulation illustrated in this study fulfils the requirements needed for a potent clinical grade formulation. |
| first_indexed | 2024-03-09T12:58:04Z |
| format | Article |
| id | doaj.art-9a7a1378cb3244ff93fef87229b73e23 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T12:58:04Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-9a7a1378cb3244ff93fef87229b73e232023-11-30T21:57:49ZengMDPI AGPharmaceutics1999-49232022-03-0114364010.3390/pharmaceutics14030640One-Step Synthesis of Nanoliposomal Copper Diethyldithiocarbamate and Its Assessment for Cancer TherapyRadu A. Paun0Daciana C. Dumut1Amanda Centorame2Thusanth Thuraisingam3Marian Hajduch4Martin Mistrik5Petr Dzubak6Juan B. De Sanctis7Danuta Radzioch8Maryam Tabrizian9Department of Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, 3775 Rue University, Montreal, QC H3A 2B6, CanadaResearch Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC H4A 3J1, CanadaResearch Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC H4A 3J1, CanadaDivision of Dermatology, Department of Medicine, Jewish General Hospital, McGill University, 3755 Cote Ste-Catherine, Montreal, QC H3T 1E2, CanadaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 1333/5, 77900 Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 1333/5, 77900 Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 1333/5, 77900 Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 1333/5, 77900 Olomouc, Czech RepublicResearch Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC H4A 3J1, CanadaDepartment of Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, 3775 Rue University, Montreal, QC H3A 2B6, CanadaThe metal complex copper diethyldithiocarbamate (CuET) induces cancer cell death by inhibiting protein degradation and induces proteotoxic stress, making CuET a promising cancer therapeutic. However, no clinical formulation of CuET exists to date as the drug is insoluble in water and exhibits poor bioavailability. To develop a scalable formulation, nanoliposomal (LP) CuET was synthesized using ethanol injection as a facile one-step method that is suitable for large-scale manufacturing. The nanoparticles are monodispersed, colloidally stable, and approximately 100 nm in diameter with an encapsulation efficiency of over 80%. LP-CuET demonstrates excellent stability in plasma, minimal size change, and little drug release after six-month storage at various temperatures. Additionally, melanoma cell lines exhibit significant sensitivity to LP-CuET and cellular uptake occurs predominantly through endocytosis in YUMM 1.7 cancer cells. Intracellular drug delivery is mediated by vesicle acidification with more nanoparticles being internalized by melanoma cells compared with RAW 264.7 macrophages. Additionally, the nanoparticles preferentially accumulate in YUMM 1.7 tumors where they induce cancer cell death in vivo. The development and characterization of a stable and scalable CuET formulation illustrated in this study fulfils the requirements needed for a potent clinical grade formulation.https://www.mdpi.com/1999-4923/14/3/640liposomescopper diethyldithiocarbamateethanol injectioncancer therapeuticsmelanomaprotein corona |
| spellingShingle | Radu A. Paun Daciana C. Dumut Amanda Centorame Thusanth Thuraisingam Marian Hajduch Martin Mistrik Petr Dzubak Juan B. De Sanctis Danuta Radzioch Maryam Tabrizian One-Step Synthesis of Nanoliposomal Copper Diethyldithiocarbamate and Its Assessment for Cancer Therapy Pharmaceutics liposomes copper diethyldithiocarbamate ethanol injection cancer therapeutics melanoma protein corona |
| title | One-Step Synthesis of Nanoliposomal Copper Diethyldithiocarbamate and Its Assessment for Cancer Therapy |
| title_full | One-Step Synthesis of Nanoliposomal Copper Diethyldithiocarbamate and Its Assessment for Cancer Therapy |
| title_fullStr | One-Step Synthesis of Nanoliposomal Copper Diethyldithiocarbamate and Its Assessment for Cancer Therapy |
| title_full_unstemmed | One-Step Synthesis of Nanoliposomal Copper Diethyldithiocarbamate and Its Assessment for Cancer Therapy |
| title_short | One-Step Synthesis of Nanoliposomal Copper Diethyldithiocarbamate and Its Assessment for Cancer Therapy |
| title_sort | one step synthesis of nanoliposomal copper diethyldithiocarbamate and its assessment for cancer therapy |
| topic | liposomes copper diethyldithiocarbamate ethanol injection cancer therapeutics melanoma protein corona |
| url | https://www.mdpi.com/1999-4923/14/3/640 |
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