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Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules

Abstract

Purpose

To develop drug-combination nanoparticles (DcNPs) composed of hydrophilic gemcitabine (G) and hydrophobic paclitaxel (T) and deliver both drugs to metastatic cancer cells.

Methods

GT DcNPs were evaluated based on particle size and drug association efficiency (AE%). The effect of DcNP on GT plasma time-course and tissue distribution was characterized in mice and a pharmacokinetic model was developed. A GT distribution study into cancer nodules (derived from 4 T1 cells) was performed.

Results

An optimized GT DcNP composition (d = 59.2 nm ±9.2 nm) was found to be suitable for IV formulation. Plasma exposure of G and T were enhanced 61-fold and 3.8-fold when given in DcNP form compared to the conventional formulation, respectively. Mechanism based pharmacokinetic modeling and simulation show that both G and T remain highly associated to DcNPs in vivo (G: 98%, T:75%). GT DcNPs have minimal distribution to healthy organs with selective distribution and retention in tumor burdened tissue. Tumor bearing lungs had a 5-fold higher tissue-to-plasma ratio of gemcitabine in GT DcNPs compared to healthy lungs.

Conclusions

DcNPs can deliver hydrophilic G and hydrophobic T together to cancer nodules and produce long acting exposure, likely due to stable GT association to DcNPs in vivo.

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Abbreviations

DcNP:

Drug combination nanoparticle

CrEL:

Cremophor El suspension

AUC:

Area under the curve

C0 :

Concentration at time 0

T1/2 :

Half-life

Dose/AUC:

Apparent clearance

Vss :

Volume of distribution at steady state

MRT:

Mean residence time

AUMC:

Area under the moment curve

GT:

Gemcitabine and paclitaxel combination

G:

Gemcitabine

T:

Paclitaxel

MBPK :

Mechanism-based pharmacokinetic model

K:

rate constant

dFdU:

2′,2′-difluoro-deoxyuridine

CDA:

Cytidine deaminase

dCK:

deoxycytidine kinase

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Financial Support

This work was supported in part by NIH grants UM1 AI120176, R61 AI149665, U01 AI1448055 and T32 GM007750 Pharmacological training for J Yu.

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Correspondence to Rodney JY Ho.

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Yu, J., Mu, Q., Perazzolo, S. et al. Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules. Pharm Res 37, 197 (2020). https://doi.org/10.1007/s11095-020-02888-8

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Key Words

  • breast cancer
  • mechanism based pharmacokinetic modeling
  • nanoparticles
  • pharmacokinetics
  • tumor distribution