Glycol chitosan nanoparticles as specialized cancer therapeutic vehicles: Sequential delivery of doxorubicin and Bcl-2 siRNA

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Abstract

Conventional chemotherapy is plagued with adverse side effects because cancer treatments are subject to numerous variations, most predominantly from drug resistance. Accordingly, multiple or multistage chemotherapeutic regimens are often performed, combining two or more drugs with orthogonal and possibly synergistic mechanisms. In this respect, glycol chitosan (GC)-based nanoparticles (CNPs) serve as an effective platform vehicle that can encapsulate both chemotherapeutics and siRNA to achieve maximal efficacy by overcoming resistance. Herein, DOX-encapsulated CNPs (DOX-CNPs) or Bcl-2 siRNA-encapsulated CNPs (siRNA-CNPs) exhibited similar physicochemical properties, including size, surface properties and pH sensitive behavior, regardless of the different physical features of DOX and Bcl-2 siRNA. We confirmed that the CNP platform applied to two different types of drugs results in similar in vivo biodistribution and pharmacokinetics, enhancing treatment in a dose-dependent fashion.

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Drug resistance and the solid tumor microenvironment.

Olivier Trédan, Carlos M. Galmarini, Krupa Patel … (2007)

Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.

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Mechanisms of action of Bcl-2 family proteins.

Aisha Shamas-Din, Justin Kale, Brian Leber … (2013)

The Bcl-2 family of proteins controls a critical step in commitment to apoptosis by regulating permeabilization of the mitochondrial outer membrane (MOM). The family is divided into three classes: multiregion proapoptotic proteins that directly permeabilize the MOM; BH3 proteins that directly or indirectly activate the pore-forming class members; and the antiapoptotic proteins that inhibit this process at several steps. Different experimental approaches have led to several models, each proposed to explain the interactions between Bcl-2 family proteins. The discovery that many of these interactions occur at or in membranes as well as in the cytoplasm, and are governed by the concentrations and relative binding affinities of the proteins, provides a new basis for rationalizing these models. Furthermore, these dynamic interactions cause conformational changes in the Bcl-2 proteins that modulate their apoptotic function, providing additional potential modes of regulation.

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Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance.

Alina Shapira, Yoav Livney, Henk Broxterman … (2011)

Anticancer drug resistance almost invariably emerges and poses major obstacles towards curative therapy of various human malignancies. In the current review we will distinguish between mechanisms of chemoresistance that are predominantly mediated by ATP-driven multidrug resistance (MDR) efflux transporters, typically of the ATP-binding cassette (ABC) superfamily, and those that are independent of such drug efflux pumps. In recent years, multiple nanoparticle (NP)-based therapeutic systems have been developed that were rationally designed to overcome drug resistance by neutralizing, evading or exploiting various drug efflux pumps and other resistance mechanisms. NPs are being exploited for selective drug delivery to tumor cells, to cancer stem/tumor initiating cells and/or to the supportive cancer cell microenvironment, i.e. stroma or tumor vasculature. Some of these NPs are currently undergoing preclinical in vivo studies as well as advanced stages of clinical evaluation with promising results. Nanovehicles harboring a payload of therapeutic drug combinations for the selective targeting and elimination of tumor cells as well as the simultaneous overcoming of mechanisms of drug resistance are a subject of intense research efforts, some of which are expected to enter clinical trials in the near future. In the present review we highlight novel approaches to selectively target cancer cells and overcome drug resistance phenomena, through the use of various nanometric drug delivery systems. In the near future, it is anticipated that innovative theragnostic nanovehicles will be developed which will harbor four major components: (1) a selective targeting moiety, (2) a diagnostic imaging aid for the localization of the malignant tumor and its micro- or macrometastases, (3) a cytotoxic, small molecule drug(s) or novel therapeutic biological(s), and (4) a chemosensitizing agent aimed at neutralizing a resistance mechanism, or exploiting a molecular "Achilles hill" of drug resistant cells. We propose to name these envisioned four element-containing nanovehicle platform, "quadrugnostic" nanomedicine. This targeted strategy holds promise in paving the way for the introduction of highly effective nanoscopic vehicles for cancer therapeutics while overcoming drug resistance. Copyright © 2011 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 03 November 2014

Publication date Collection: 2014

Volume: 4

Electronic Location Identifier: 6878

Affiliations

[1 ]Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST) , Seoul 136-791, South Korea

[2 ]School of Chemical Engineering, Sungkyunkwan University , Suwon 440-746

[3 ]The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine , Baltimore, Maryland 21287, USA

[4 ]Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins School of Medicine , Baltimore, Maryland 21287, USA

[5 ]KU-KIST School, Korea University , Seoul 136-701, South Korea

Author notes

[a ] kim@ 123456kist.re.kr

[b ] mpomper@ 123456jhmi.edu

[*]

These authors contributed equally to this work.

Article

Publisher Item ID: srep06878

DOI: 10.1038/srep06878

PMC ID: 4217108

PubMed ID: 25363213

SO-VID: ec0236a9-f74b-466c-af45-34aa38236df6

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

History

Date received : 17 June 2014

Date accepted : 24 September 2014

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Glycol chitosan nanoparticles as specialized cancer therapeutic vehicles: Sequential delivery of doxorubicin and Bcl-2 siRNA

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Abstract

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RNA drug delivery

Most cited references 23

Drug resistance and the solid tumor microenvironment.

Mechanisms of action of Bcl-2 family proteins.

Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance.

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