Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients
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Obesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate the relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer.
Hormone and chemokine mediators in obese and normal weight ovarian and endometrial cancer patients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancer patients.
Univariate analysis revealed a significant relationship between serum estradiol and body mass index (OR 8.64, 95% CI 2.67–28.0, p < 0.001). Estrone and testosterone concentrations were positively correlated with MPS function (ρ = 0.57 and 0.53, p = 0.14 and 0.18, respectively) and inversely correlated with PLD PK exposure (ρ = − 0.75 and − 0.76, respectively, p = 0.02 for both).
Higher MPS function resulting in reduced PLD exposure is a potential mechanism for reduced efficacy of PLD and other nanoparticles observed in obese patients with cancer. PK simulations suggest higher doses of PLD are required in obese patients to achieve similar exposures as standard dosing in normal weight patients.
KeywordsNanoparticle Pharmacology Obesity Ovarian cancer Endometrial cancer Estradiol
American Society of Clinical Oncology
Area under the concentration versus time curve
Body mass index
Biospecimen processing core facility
Coefficient of variance
Cytochrome P450 Family 19
Enhanced permeability and retention effect
Mean fluorescent intensity
Mononuclear phagocyte system
PEGylated liposomal doxorubicin
Reactive oxygen species
PEGylated liposomal formulation of CKD-602
- UNC CSC
UNC Health Registry/Cancer Survivorship Cohort
World Health Organization
The authors thank the UNC Health Registry/Cancer Survivorship Cohort (HR/CSC) participants for their important contributions. The HR/CSC is funded in part by the UNC Lineberger Comprehensive Cancer Center’s University Cancer Research Fund. This project was reviewed and approved by the Human Research Protections Program (IRB Number: 09-0605) at the University of North Carolina at Chapel Hill. The authors would also like to acknowledge the UNC Biospecimen Facility for our blood processing, and storage and sample disbursement (genome.unc.edu/bsp).
The sera analyses as part of this study were funded by a Developmental Research Award from the University of North Carolina Lineberger Comprehensive Cancer Center. The pharmacology study as part of this study was funded by a University Cancer Research Fund Grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Compliance with ethical standards
Conflict of interest
Brittney Roberts Starling has no conflicts of interest to report. Parag Kumar has no conflicts of interest to report. Andrew T. Lucas has no conflicts of interest to report. David Barrow has no conflicts of interest to report. Laura Farnan has no conflicts of interest to report. Laura Hendrix has no conflicts of interest to report. Hugh Giovinazzo has no conflicts of interest to report. Gina Song has no conflicts of interest to report. Paola Gehrig has no conflicts of interest to report. Jeannette T. Bensen has no conflicts of interest to report. William C. Zamboni has no conflicts of interest to report.
This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Studies were approved by the University of North Carolina Institutional Review Board (UNC IRB# 08-1204 & UNC IRB# 14-2078).
Informed consent was obtained from all individual participants included in the study.
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