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Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 1, pp 61–70 | Cite as

Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients

  • Brittney R. Starling
  • Parag Kumar
  • Andrew T. Lucas
  • David Barrow
  • Laura Farnan
  • Laura Hendrix
  • Hugh Giovinazzo
  • Gina Song
  • Paola Gehrig
  • Jeannette T. Bensen
  • William C. ZamboniEmail author
Original Article
  • 95 Downloads

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

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.

Keywords

Nanoparticle Pharmacology Obesity Ovarian cancer Endometrial cancer Estradiol 

Abbreviations

17β-HSD

17β-Hydroxysteroid dehydrogenase

ASCO

American Society of Clinical Oncology

AUC

Area under the concentration versus time curve

BMI

Body mass index

BSP

Biospecimen processing core facility

CMA

Carrier-mediated agents

CV%

Coefficient of variance

CYP19

Cytochrome P450 Family 19

DHT

Dihydrotestosterone

EPR

Enhanced permeability and retention effect

MFI

Mean fluorescent intensity

MPS

Mononuclear phagocyte system

NP

Nanoparticles

PD

Pharmacodynamics

PK

Pharmacokinetics

PLD

PEGylated liposomal doxorubicin

ROS

Reactive oxygen species

S-CKD-602

PEGylated liposomal formulation of CKD-602

UNC CSC

UNC Health Registry/Cancer Survivorship Cohort

WHO

World Health Organization

Notes

Acknowledgements

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).

Funding

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.

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Brittney R. Starling
    • 1
  • Parag Kumar
    • 1
    • 2
  • Andrew T. Lucas
    • 1
  • David Barrow
    • 3
  • Laura Farnan
    • 4
  • Laura Hendrix
    • 4
  • Hugh Giovinazzo
    • 1
    • 5
  • Gina Song
    • 1
    • 6
  • Paola Gehrig
    • 7
  • Jeannette T. Bensen
    • 4
    • 8
  • William C. Zamboni
    • 1
    • 4
    • 9
    Email author
  1. 1.Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Clinical PharmacologyOtsuka Pharmaceutical CompaniesRockvilleUSA
  3. 3.UNC Cytokine and Biomarker Core Facility, UNC School of DentistryUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.UNC Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillUSA
  5. 5.Department of Pharmacology and Molecular SciencesJohns Hopkins University School of MedicineBaltimoreUSA
  6. 6.ScitoVation LLCResearch Triangle ParkUSA
  7. 7.Department of Gynecologic Oncology, UNC School of MedicineUniversity of North Carolina Medical CenterChapel HillUSA
  8. 8.Department of Epidemiology, UNC Gillings School of Public HealthUniversity of North Carolina at Chapel HillChapel HillUSA
  9. 9.Carolina Center of Cancer Nanotechnology ExcellenceUniversity of North Carolina at Chapel HillChapel HillUSA

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