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Polypeptide-based Micelles for Delivery of Irinotecan: Physicochemical and In vivo Characterization

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Abstract

Purpose

Irinotecan (IRI) is a broad spectrum chemotherapeutic agent used individually or in combination to treat multiple malignancies. Present study aimed at develo** polypeptide-based block ionomer complex (BIC) micelles to improve the pharmacokinetic and antitumor response of IRI.

Methods

Irinotecan-loaded BIC micelles (IRI-BIC) was prepared and evaluated in terms of various physicochemical and biological parameters including size, shape, release, cytotoxicity, and pharmacokinetic analysis. In vivo antitumor efficacy was investigated in SCC-7 bearing xenograft tumor model.

Results

IRI was successfully incorporated into the ionic cores of poly(ethylene glycol)-b-poly(aspartic acid) (PEG-b-PAA) with a high drug loading capacity (~80%). The electrostatically assembled BIC micelles were nanosized (~50 nm) with uniform size distribution pattern (PDI~0.1). The BIC micelles exhibited pH-sensitiveness with limited release of IRI at physiological conditions and significantly enhanced the release rate at acidic conditions, making it an ideal delivery system for tumor targeting. The IRI-BIC showed a dose-dependent cytotoxicity in SCC-7 and A-549 cancer cell lines. Pharmacokinetic studies clearly showed that BIC micelles improved the IRI blood circulation time and decreased its elimination rate constant, while that of free IRI, rapidly eliminated from the central compartment. Moreover, IRI-BIC showed superior therapeutic performance with no toxicity in BALB/c nude xenograft mice. The micelle treated group showed an inhibition rate of ~66% compared to free IRI treated group.

Conclusions

Taken together, BIC micelles could be a potentially useful nanovehicle with promising applicability in systemic tumor treatment.

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Abbreviations

ABS:

Acetate buffered saline

AUC:

The area under the drug concentration–time curve from 0 to 24 h

BIC:

Block ionomer complex

Cl:

Clearance

Cmax :

The peak concentration of drug

DLS:

Dynamic light scattering

EPR:

Enhanced permeation and retention effect

FT-IR:

Fourier transform infrared spectroscopy

IRI:

Irinotecan

IRI-BIC:

Irinotecan-loaded BIC

K el :

Elimination rate constant

MRT:

Mean retention time

PBS:

Phosphate buffered saline

PDI:

Polydispersity index

PEG-b-PAA:

Poly(ethylene glycol)-b-poly(aspartic acid)

t 1/2 :

Half-life

TEM:

Transmission electron microscope

Tmax :

The time to reach the peak concentration

V ss :

Volume of distribution

XRD:

X-ray diffractometer

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Acknowledgments and Disclosures

This research was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (No. 2012R1A2A2A02044997 and No.2012R1A1A1039059).

Author information

Authors and Affiliations

  1. College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan, 712-749, South Korea

    Thiruganesh Ramasamy, Ju Yeon Choi, Hyuk Jun Cho, Chul Soon Yong & Jong Oh Kim

  2. St. Paul’s College of Pharmacy, Osmania University, Hyderabad, Andhra Pradesh, India

    Subbaih Kandasamy Umadevi

  3. College of Pharmacy, Catholic University of Daegu, Gyeongsan, 712-702, South Korea

    Beom Soo Shin

  4. College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan, 426-791, South Korea

    Han-Gon Choi

Authors
  1. Thiruganesh Ramasamy
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  7. Chul Soon Yong
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Corresponding authors

Correspondence to Chul Soon Yong or Jong Oh Kim.

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Ramasamy, T., Choi, J.Y., Cho, H.J. et al. Polypeptide-based Micelles for Delivery of Irinotecan: Physicochemical and In vivo Characterization. Pharm Res 32, 1947–1956 (2015). https://doi.org/10.1007/s11095-014-1588-8

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  • DOI: https://doi.org/10.1007/s11095-014-1588-8

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