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Optimizing Antitumor Efficacy and Adverse Effects of Pegylated Liposomal Doxorubicin by Scheduled Plasmapheresis: Impact of Timing and Dosing
- Source :
- Current Drug Delivery
- Publication Year :
- 2018
- Publisher :
- Bentham Science Publishers, 2018.
-
Abstract
- Background Nanoscale drug delivery systems accumulate in solid tumors preferentially by the enhanced permeation and retention effect (EPR-effect). Nevertheless, only a miniscule fraction of a given dosage reaches the tumor, while >90% of the given drug ends up in otherwise healthy tissues, leading to the severe toxic reactions observed during chemotherapy. Once accumulation in the tumor has reached its maximum, extracorporeal elimination of circulating nanoparticles by plasmapheresis can diminish toxicities. Objective In this study, we investigated the effect of dosing and plasmapheresis timing on adverse events and antitumor efficacy in a syngeneic rat tumor model. Methods MAT-B-III cells transfected with a luciferase reporter plasmid were inoculated into female Fisher rats, and pegylated liposomal doxorubicin (PLD) was used for treatment. Plasmapheresis was performed in a discontinuous manner via centrifugation and subsequent filtration of isolated plasma. Results Bioluminescence measurements of tumor growth could not substitute caliper measurements of tumor size. In the control group, raising the dosage above 9 mg PLD/kg body weight did not increase therapeutic efficacy in our fully immunocompetent animal model. Plasmapheresis was best done 36 h after injecting PLD, leading to similar antitumor efficacy with significantly less toxicity. Plasmapheresis 24 h after injection interfered with therapeutic efficacy, while plasmapheresis after 48 h led to fewer side effects but also to increased weight loss. Conclusion Long-circulating nanoparticles offer the unique possibility to eliminate the excess of circulating particles after successful accumulation in tumors by EPR, thereby reducing toxicities and likely toxicity-related therapeutic limitations.
- Subjects :
- Drug
liposomes
Cancer therapy
Surface Properties
medicine.medical_treatment
media_common.quotation_subject
Pharmaceutical Science
EPR-effect
02 engineering and technology
Pharmacology
Article
Polyethylene Glycols
03 medical and health sciences
0302 clinical medicine
pegylated liposomal doxorubicin
Tumor Cells, Cultured
Medicine
Animals
Humans
Dosing
Particle Size
Adverse effect
media_common
Cell Proliferation
Liposome
Chemotherapy
Antibiotics, Antineoplastic
Dose-Response Relationship, Drug
business.industry
toxicity
Neoplasms, Experimental
Plasmapheresis
021001 nanoscience & nanotechnology
adverse events
Rats, Inbred F344
Rats
Disease Models, Animal
Doxorubicin
030220 oncology & carcinogenesis
Drug delivery
Toxicity
Luminescent Measurements
Female
Drug Screening Assays, Antitumor
0210 nano-technology
business
Subjects
Details
- Language :
- English
- ISSN :
- 18755704 and 15672018
- Volume :
- 15
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Current Drug Delivery
- Accession number :
- edsair.doi.dedup.....2a06086a5db1f28dd0435d55a307dad4