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Intratracheal Administration of Hyaluronan-Cisplatin Conjugate Nanoparticles Significantly Attenuates Lung Cancer Growth in Mice

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Abstract

Purpose

To determine aerosol administration capability and therapeutic efficacy of the new formulation of hyaluronan cisplatin conjugates, HylaPlat™ (HA-Pt), for lung cancer treatment.

Methods

In vitro formulation stability test, 2D and 3D spheroid cell culture and in vivo efficacy studies using mouse orthotopic allograft models were conducted.

Results

The HA-Pt effectively attenuated cell growth in 2D and 3D cultures with IC50 of 2.62 and 5.36 μM, respectively, which were comparable to those with unconjugated control cisplatin-dependent growth inhibition (IC50 1.64 and 4.63 μM, respectively). A single dose of either 7.5 or 15 mg/kg HA-Pt (cisplatin equivalent) by intratracheal aerosol spray 7 days after Lewis lung carcinoma (LLC) cell inoculation markedly inhibited growth of LLC allografts in mouse lungs and resulted in a 90 or 94% reduction of tumor nodule numbers, respectively, as compared to those from the PBS control. Cancer stem cells and cisplatin resistant cells marker, CD44 expression decreased in the tumor nodules of the HA-Pt but not in those of cisplatin treated groups.

Conclusions

The current study suggests that an intratracheal aerosol administration of the HA-Pt nanoparticles offers an effective strategy for lung cancer treatment and this treatment may induce only limited cisplatin resistance.

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Abbreviations

2D:

Two dimensional

3D:

Three dimensional

cfu:

Colony forming units

EU:

Endotoxin units

FBS:

Fetal bovine serum

HA:

Hyaluronan

HAdase:

Hyaluronidase

HA-Pt:

Hyaluronan-cisplatin nanoconjugate

IT:

Intratracheal

LLC:

Lewis Lung carcinoma

SEC:

Size exclusion chromatography

Tg :

Glass transition temperature

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

USP:

US Pharmacopeia

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was also supported in part by Kansas State University Johnson Cancer Research Center (MT), Kansas Bioscience Authority Research grant (MLF) and NIH grant 1R01CA173292 (MLF).

We are grateful to Dr. Raelene Wouda (Department of Clinical Science, Kansas State University) for constructive comments during the preparation of the manuscript. We also thank Mr. Joel Sannemann (Department of Anatomy and Physiology, Kansas State University) for his technical support on the confocal microscope.

M.L. Forrest, W.C. Forrest, S. Cai and T. Zhang are employees and/or have ownership interest in HylaPharm, which has licensed HylaPlat technologies from the University of Kansas. No potential conflicts of interest were disclosed by the other authors.

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    Authors and Affiliations

    1. Department of Anatomy & Physiology, College of Veterinary Medicine, Kansas State University, 210 Coles Hall, Manhattan, Kansas, 66506, USA

      Susumu Ishiguro, Deepthi Uppalapati, Katie Turner & Masaaki Tamura

    2. Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas, 66047, USA

      Shuang Cai, Ti Zhang & M. Laird Forrest

    3. HylaPharm LLC, Lawrence, Kansas, 66047, USA

      Shuang Cai, Wai Chee Forrest & M. Laird Forrest

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    1. Susumu Ishiguro
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    Correspondence to Masaaki Tamura.

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    Susumu Ishiguro and Shuang Cai contributed equally to this work.

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    Ishiguro, S., Cai, S., Uppalapati, D. et al. Intratracheal Administration of Hyaluronan-Cisplatin Conjugate Nanoparticles Significantly Attenuates Lung Cancer Growth in Mice. Pharm Res 33, 2517–2529 (2016). https://doi.org/10.1007/s11095-016-1976-3

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    • DOI: https://doi.org/10.1007/s11095-016-1976-3

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