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Engineering liposomal nanoparticles of cholesterol-tethered amphiphilic Pt(iv) prodrugs with prolonged circulation time in blood.
- Source :
-
Dalton transactions (Cambridge, England : 2003) [Dalton Trans] 2020 Jun 23; Vol. 49 (24), pp. 8107-8113. - Publication Year :
- 2020
-
Abstract
- Cisplatin is a platinum-based chemotherapeutic agent widely used in the treatment of various solid tumors. However, a major challenge in the use of cisplatin and in the development of cisplatin derivatives, namely Pt(iv) prodrugs, is their premature reduction in the bloodstream before reaching cancer cells. To circumvent this problem, we designed liposomal nanoparticles coupled with a cholesterol-tethered amphiphilic Pt(iv) prodrug. The addition of cholesterol served to stabilize the formation of the liposome, while selectively incorporating cholesterol as the axial ligand also allowed the Pt(iv) prodrug to readily migrate into the liposomal bilayer. Notably, upon embedding into the nanoparticles, the Pt(iv) prodrug showed marked resistance against premature reduction in human plasma in vitro. Pharmacokinetic analysis in a mouse model also showed that the nanoparticles significantly extend the half-life of the Pt(iv) prodrug to 180 min, which represents a >6-fold increase compared to cisplatin. Importantly, such lipid modification did not compromise the genotoxicity of cisplatin, as the Pt(iv) prodrug induced DNA damage and apoptosis in ovarian cancer cell lines efficiently. Taken together, our strategy provides a novel insight as to how to stabilize a platinum-based compound to increase the circulation time in vivo, which is expected to enhance the efficacy of drug treatment.
- Subjects :
- Antineoplastic Agents blood
Antineoplastic Agents chemistry
Apoptosis drug effects
Cell Proliferation drug effects
Cholesterol blood
Cholesterol chemistry
Cholesterol pharmacology
Cisplatin blood
Cisplatin chemistry
Cisplatin pharmacology
DNA Damage
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Liposomes blood
Liposomes chemistry
Molecular Structure
Nanoparticles metabolism
Organoplatinum Compounds blood
Organoplatinum Compounds chemistry
Prodrugs chemistry
Prodrugs metabolism
Structure-Activity Relationship
Surface-Active Agents chemistry
Surface-Active Agents metabolism
Time Factors
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Nanoparticles chemistry
Organoplatinum Compounds pharmacology
Prodrugs pharmacology
Surface-Active Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9234
- Volume :
- 49
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Dalton transactions (Cambridge, England : 2003)
- Publication Type :
- Academic Journal
- Accession number :
- 32490446
- Full Text :
- https://doi.org/10.1039/d0dt01297a