Polypeptide-based Micelles for Delivery of Irinotecan: Physicochemical and In vivo Characterization
Irinotecan (IRI) is a broad spectrum chemotherapeutic agent used individually or in combination to treat multiple malignancies. Present study aimed at developing polypeptide-based block ionomer complex (BIC) micelles to improve the pharmacokinetic and antitumor response of IRI.
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.
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.
Taken together, BIC micelles could be a potentially useful nanovehicle with promising applicability in systemic tumor treatment.
KEY WORDSanticancer block ionomer complex irinotecan polypeptide self-assembly
Acetate buffered saline
The area under the drug concentration–time curve from 0 to 24 h
Block ionomer complex
The peak concentration of drug
Dynamic light scattering
Enhanced permeation and retention effect
Fourier transform infrared spectroscopy
Elimination rate constant
Mean retention time
Phosphate buffered saline
Poly(ethylene glycol)-b-poly(aspartic acid)
Transmission electron microscope
The time to reach the peak concentration
Volume of distribution
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).
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