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WIREs Nanomed Nanobiotechnol
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Dextran–doxorubicin/chitosan nanoparticles for solid tumor therapy

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Abstract Chemotherapy is a major therapeutic approach for the treatment of localized and metastasized cancers. Whereas potent chemotherapeutic agents seem promising in the test tube, clinical trials often fail due to unfavorable pharmacokinetics, poor delivery, low local concentrations, and limited accumulation in the target cell. The pathophysiology of the tumor vasculature and stromal compartment presents a major obstacle to effective delivery of agents to solid tumors. Poor perfusion of the tumor, arterio‐venous shunting, necrotic and hypoxic areas, as well as a high interstitial fluid pressure work against favorable drug uptake. Thus, targeted drug delivery using long‐circulating particulate drug carriers such as hydrogels of controlled size (<100 nm diameter) holds immense potential to improve the treatment of cancer by selectively providing therapeutically effective drug concentrations at the tumor site [through enhanced permeability and retention (EPR) effect] while reducing undesirable side effects. This review focuses on the progress of targeted delivery of nanoparticulated anticancer drug such as doxorubicin chemically conjugated with dextran and encapsulated in chitosan nanoparticles to solid tumor with reduced side effect of drug. Regulated particle size and long circulation of these hydrogel nanoparticles in blood help them accumulate in tumor tissue through EPR effect as evident from the significant regression of the tumor volume. The cardiotoxicity of doxorubicin can be minimized by coupling the drug with dextran and encapsulating it in chitosan nanoparticles. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease

Schematic representation of anatomical differences between normal and tumor tissues. Hyper‐permeable tumor vasculature allows preferential extravasation of the circulating macromolecular drug carriers due to enhanced permeability and retention (EPR) effect.

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Survival of tumor‐bearing mice with = 8 animals per group. Results of five treatment arms are shown: Control, Empty chitosan nanoparticles, doxorubicin (DXR), dextran–doxorubicin (DEX–DXR), and DEX–DXR loaded in chitosan nanoparticles, respectively.

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Tumor regression studies with: control‐treatment (Series 1), empty chitosan nanoparticles (Series 2), doxorubicin (DXR) (Series 3), dextran–doxorubicin (DEX–DXR) (Series 4), and DEX–DXR in chitosan nanoparticles (Series 5) with n = 8 mice per treatment arm. Average tumor volumes are plotted as means and standard deviations. Arrows indicate the days of drug administration.

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Representative quasi‐elastic laser light scattering (QELS) of dextran–doxorubicin (DEX–DXR) loaded chitosan nanoparticles.

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Confocal images of (a) free doxorubicin (DXR) after 30 min of incubation, (b) DXR‐loaded nanoparticles (overnight incubation). All confocal studies were performed in A375 melanoma cells at a drug concentration of 5µg/ml DXR equivalent. Magnification: X630 (a, b). Arrows in the figure represents intracellular uptake of free drug and drug‐loaded chitosan nanoparticles.

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Chemical structure of doxorubicin (DXR).

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Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease

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