Journal article
Combining Doxorubicin-Loaded PEGylated Poly(Lactide-co-glycolide) Nanoparticles with Checkpoint Inhibition Safely Enhances Therapeutic Efficacy in a Melanoma Model
ACS biomaterials science & engineering, Vol.6(5), pp.2659-2667
05/11/2020
DOI: 10.1021/acsbiomaterials.9b01108
PMID: 33463284
Abstract
Doxorubicin (DOX) has been widely used for the treatment of various cancers, however, the use of soluble DOX is limited by its low therapeutic index and improved formulations are therefore sought. Aside from its tumoricidal properties, DOX has also been shown to cause an immunogenic form of cell death, however, it is becoming abundantly clear that in situ immune stimulation alone is insufficient to cause significant immune based antitumor activity and that immune checkpoint modulation is also required. In this study, DOX-loaded nanoparticles were made by nanoprecipitation of DOX with a PEGylated poly(lactide-
-glycolide) copolymer (DOX-PLGA-PEG NPs) and were then tested in combination with immune checkpoint blockade (antiprogrammed death (anti-PD-1)) in a murine melanoma model to enhance antitumor effectiveness. Results showed the prepared particles to be approximately 134 nm in diameter (zeta potential -22 mV) with a loading of 1.75 μg DOX/mg NPs. In vitro release studies (of DOX) revealed the NPs to exhibit a 12 h burst release phase, followed by a slower release phase for up to 200 h. Survival studies of mice challenged with B16.F10 melanoma cells, revealed 60% of mice treated with the combination of DOX-PLGA-PEG NPs plus anti-PD-1 were tumor-free at the completion of the study. This combination therapy demonstrated higher antitumor efficacy in vivo compared to control, soluble DOX, and monotherapy of DOX-PLGA-PEG NPs or anti-PD-1 solution (
< 0.05). Moreover, in vivo safety studies (mouse weight/histopathological/toxicity) were investigated and results suggested that the combination therapy was safe. In conclusion, this study demonstrates the successful fabrication of DOX-loaded NPs by a nanoprecipitation method, and when combined with checkpoint inhibition could provide significant therapy in a murine melanoma model, suggesting that the DOX-PLGA-PEG NPs may be generating immune stimulation in situ and that benefit from this combination may be obtained in a clinical setting in the future.
Details
- Title: Subtitle
- Combining Doxorubicin-Loaded PEGylated Poly(Lactide-co-glycolide) Nanoparticles with Checkpoint Inhibition Safely Enhances Therapeutic Efficacy in a Melanoma Model
- Creators
- Khanidtha Chitphet - University of IowaSean M Geary - University of IowaCarlos H F Chan - University of IowaAndrean L Simons - University of IowaGeorge J Weiner - University of IowaAliasger K Salem - University of Iowa
- Resource Type
- Journal article
- Publication Details
- ACS biomaterials science & engineering, Vol.6(5), pp.2659-2667
- DOI
- 10.1021/acsbiomaterials.9b01108
- PMID
- 33463284
- NLM abbreviation
- ACS Biomater Sci Eng
- ISSN
- 2373-9878
- eISSN
- 2373-9878
- Grant note
- DOI: 10.13039/100000054, name: National Cancer Institute, award: P30 CA086862; DOI: 10.13039/501100004283, name: Office of the Civil Service Commission; DOI: 10.13039/100008893, name: University of Iowa
- Language
- English
- Date published
- 05/11/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Oral Pathology, Radiology and Medicine; Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Surgery; Radiation Oncology; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering; Internal Medicine
- Record Identifier
- 9984186654802771
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