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WIREs Nanomed Nanobiotechnol
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Cytolytic peptide nanoparticles (‘NanoBees’) for cancer therapy

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Abstract Cytolytic peptides are an attractive class of anticancer candidates because of their wide‐spectrum lytic properties. However, their therapeutic potential cannot be realized without a proper delivery vehicle, because of their off‐target toxicity, nonspecificity, and unfavorable pharmacokinetics. The physical properties of perfluorocarbon (PFC)‐core surfactant‐coated nanoparticles render them a highly promising delivery vehicle for targeted therapeutic applications of cytolytic peptides. This article provides an overview of the mechanism underlying the anticancer efficacy of cytolytic peptides, the limitations in clinic applications, and the advantages of PFC nanoparticles over traditional FDA‐approved nanocarriers such as liposomes. Recent reports of successful anticancer therapeutics delivered by PFC nanoparticles will be discussed, as well as new applications. WIREs Nanomed Nanobiotechnol 2011 3 318–327 DOI: 10.1002/wnan.126 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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Delivery of melittin from integrin αvβ3‐targeted nanoparticles to endothelial cells and cancer cells. A fivefold reduction in IC50 after specific targeting of melittin‐loaded nanoparticles to endothelial cells (a) and melanoma cells (b). Three‐hour cell proliferation was determined by the MTT assay. Incorporation of melittin onto nanoparticles produces a 25‐fold protection from free peptide (IC50 of 1–2 µM for free melittin and greater than 25 µM for nontargeted nanoparticles). Specific targeting of the nanoparticles to αvβ3 integrins produces a fivefold enhancement of melittin toxicity; IC50, 6–8 µM. Data are represented as mean ± SD. A typical permanganate‐fixed transmission picture (left) and platinum replica images (right) of C32 melanoma cells interacting with either nontargeted (c) or αvβ3 integrin‐targeted nanoparticles (d). (e) Selected higher magnification platinum replica images of nanoparticles on the plasma membrane and microvilli of C32 melanoma cells. Left two panels show nontargeted nanoparticles, and the right two panels show αvβ3 integrin‐targeted nanoparticles attached to microvilli. Scale bars: 200 nm. (Reprinted with permission from Ref 24. Copyright 2009 the American Society for Clinical Investigation.)

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Stable insertion of melittin in PFC nanoparticles. Transmission electron micrographs of liposomes and perfluorocarbon (PFC) nanoparticles of identical lipid compositions before (a) and after (b) incorporation of melittin. Scale bars correspond to 100 nm. (c) A schematic of the proposed structure of PFC nanoparticle with the melittin inserted in a monolayer of phospholipids, stabilizing the individual bead structure. Also shown is a diagram of a bilayer liposome disrupted because of melittin insertion. (Reprinted with permission from Ref 23. Copyright 2008 American Chemical Society.)

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Characterization of melittin‐loaded perfluorocarbon (PFC) nanoparticles. (a) Structure of melittin. Tryptophan:blue, proline:green, and arginine and lysine:pink. (b) Mean hydrodynamic diameter and ζ potential of nanoparticles before and after incorporation of melittin. (Reprinted with permission from Ref 23. Copyright 2008 American Chemical Society.)

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Targeting feature introduced by linker strategy enhanced Doxil™ effect. (a) Mean hydrodynamic diameter and ζ potential of Doxil with or without insertion of TCP1, respectively. (b) Cell killing induced after treatments with VCAM‐1 targeted or nontargeted Doxil at various volumes in 1 mL of final treatment volume. All data points represent mean ± SD (n = 3). (c and d) Confocal microscopic images of 2F2B endothelial cells treated VCAM‐1 targeted (c) or nontargeted (d) Doxil. (Reprinted with permission from Ref 40. Copyright 2010 the Federation of American Societies for Experimental Biology.)

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Regression of precancerous epidermal dysplastic lesions in the ears of K14‐HPV16 mice by αγβ3‐targeted melittin nanoparticles. (a) Fluorescence microscopy pictures of mouse ear sections showing the extensive overlay with FITC‐lectin (shown by arrows) of αγβ3‐targeted rhodamine nanoparticles compared to nontargeted ones. (b) Representative H&E stained pictures of K14‐HPV16 mouse ear sections after treatment with seven doses of melittin nanoparticles (melittin dose 13 mg/kg). Note the regression of papillae (shown by arrows) in the group treated with αγβ3‐targeted melittin nanoparticles. Bars indicate 100 µm. (c) Chart showing the specific effect of targeted melittin nanoparticles on regression of severe papillae (greater than 100 µm). Data are represented as mean (n = 5) ± SEM. ∗︁P < 0.05. (Reprinted with permission from Ref 24. Copyright 2009 the American Society for Clinical Investigation.)

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Therapeutic efficacy of melittin nanoparticles in syngeneic B16F10 mouse melanoma tumors. (a) Graph showing the increase in tumor volume of B16F10 melanoma tumors during the course of treatment with melittin nanoparticles (melittin dose 8.5 mg/kg) or controls (saline or nanoparticles alone, n = 5 each group). Note the dramatic difference in tumor volume at day 14 after four doses of melittin nanoparticles. Data are represented as mean ± SD. ∗︁∗︁P < 0.01. (b) Histological assessment of B16‐F10 melanoma tumors excised at day 14. Note the extensive nonproliferating dead areas in the treated tumors along with the markedly decreased vascularity. (Reprinted with permission from Ref 24. Copyright 2009 the American Society for Clinical Investigation.)

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