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WIREs Nanomed Nanobiotechnol
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Advances in the synthesis and application of nanoparticles for drug delivery

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The continuous development of drug delivery systems (DDSs) has been extensively researched by the need to maximize therapeutic efficacy while minimizing undesirable side effects. Nanoparticle technology was recently shown to hold great promise for drug delivery applications in nanomedicine due to its beneficial properties, such as better encapsulation, bioavailability, control release, and lower toxic effect. Despite the great progress in nanomedicine, there remain many limitations for clinical application. To overcome these limitations, advanced nanoparticles for drug delivery have been developed to enable the spatially and temporally controlled release of drugs in response to specific stimuli at disease sites. Furthermore, the controlled self‐assembly of organic and inorganic materials may enable their use in theranostic applications. This review presents an overview of a recent advanced nanoparticulate system that can be used as a potential drug delivery carrier and focuses on the potential applications of nanoparticles in various biomedical fields for human health care. WIREs Nanomed Nanobiotechnol 2015, 7:494–508. doi: 10.1002/wnan.1325 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Cancer‐recognizable MRI contrast agents using pH‐responsive polymeric micelle. (a) Schematic representation of the preparation of the cancer‐recognizable MRI contrast agents (CR‐CAs); Amphiphilic block copolymers (i.e., PEG‐p(l‐LA)‐DTPA‐Gd and PEG‐p(l‐His) self‐assemble into micelles in an aqueous solution at pH 7.4. (b) Schematic representation of pH‐dependent structural transformation and related MR signal change in CR‐CAs. Inset: Chemical structural representation of the protonation of imidazole groups in PEG‐p(l‐His) at acidic pH. (c) Schematic representation of the tumor‐accumulation behavior of (1) conventional micelle‐based CAs and (2) CR‐CAs. PEG‐p(l‐His) = methoxy poly(ethylene glycol)‐b‐poly(l‐histidine), PEG‐p(l‐LA)‐DTPA‐Gd = methoxy poly(ethylene glycol)‐b‐poly(l‐lactic acid)‐diethylenetriaminopentaacetic acid dianhydride‐gadolinium chelate. (d) Temporal color‐coded in vivo T1‐weighted MR images of CT26 murine tumor bearing Balb/c mice after the intravenous injection of CR‐CAs. (e) Contrast enhancement efficacy of CR‐CAs and Ins‐Cas (Control group) in the liver and tumor tissues (the contrast enhancement (%)/the concentration of the total amounts of Gd3+ distributed in the organs) (n = 3, *p < 0.05). (Reprinted with permission from Ref . Copyright 2014 Elsevier B.V.)
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Photo‐activatable ternary complex (PTC) to deliver nucleic acids for cancer treatment. (a) Chemical structure of the multifunctional shielding material (MSM) composed of a photosensitizer (PS) and acetylated chondroitin sulfate (CS) and a schematic view of the PTCs. (b) Schematic illustration of PS‐mediated transfection into HCT116 to silence the EGFR gene, leading to therapeutic anti‐tumor effects. (c) Confocal microscopic images of green fluorescent protein (GFP) expression in vivo by PS‐mediated transfection of PTC with 0, 10, 30 and 50 J cm−2 of laser irradiation. (d) Tumor growth inhibition by PS‐mediated transfection with EGFR‐shRNAPTC. (Reprinted with permission from Ref . Copyright 2013 Elsevier B.V.)
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Charge‐conversional polymeric nanoparticles for protein‐delivery system into cytoplasm. (a) Schematic illustration of the preparation of charge‐conversional polyionic complex (PIC) micelles containing cytochrome c (Cyt c) and (b) di‐block copolymer PEG‐pAsp(DET), in which the ionic portion can interact with Cyt c‐forming micelles. (c) Schematic illustration of the charge‐conversional PIC micelles containing immunoglobulin G (IgG) and PEG‐pAsp(DET) for cytosolic delivery. (d) Recognition of NPC in fixed human hepatoma (HuH‐7) cells by anti‐NPC IgG‐Cit after 4 h of incubation at (i) pH 7.4 and (ii) pH 5.5. Anti‐NPC IgG‐Cit was applied to the cells after fixation. The cell nuclei were stained by Hoechst 33258 (blue), and the anti‐NPC IgG‐Cit was detected by a secondary antibody (green). Scale bars: 20 mm. PEG‐pAsp(DET) = polyethylenglycol‐poly[N‐[N′‐(2‐aminoethyl)‐2‐aminoethyl]aspartamide]. (Reprinted with permission from Refs . Copyright 2009 and 2010 Wiley‐VCH)
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Chitosan‐based nanoparticles (CNPs) for PDT. (a) Schematic illustration of PS‐loaded CNPs. (b) Photodynamic therapeutic efficacy of PS‐loaded CNPs in tumor‐bearing mice. (Reprinted with permission from Ref . Copyright 2009 Elsevier Ltd)
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Multistage nanoparticle delivery system for deep penetration into tumor tissue. (a) Schematic of 100‐nm QDGelNPs changing size to 10‐nm QD NPs by cleaving away the gelatin scaffold with MMP‐2, a protease that is highly expressed in tumor tissue. (b) In vivo images of QDGelNPs (MMP‐2 cleavable nanoparticles) and SilicaQDs (non‐cleavable nanoparticles) after intratumoral co‐injection into the HT‐1080 tumor. QDGelNPs imaged 1 (b‐1), 3 (b‐2), and 6 h (b‐3) after injection. SilicaQDs imaged 1 (b‐4), 3 (b‐5), and 6 h (b‐6) after injection (Scale bar: 100 µm). (Reprinted with permission from Ref . Copyright 2011 PNAS)
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Differences between tumor and normal tissues that explain the passive targeting of nanoparticles by the enhanced permeability and retention (EPR) effect. (Reprinted with permission from Ref . Copyright 2013 Clond et al.)
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General scheme of the stimuli‐responsive release of a drug from a nanoparticle. (Reprinted with permission from Ref . Copyright 2012 Elsevier B.V.)
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Schematic illustration of various types of nanoparticles for drug delivery.
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pH‐sensitive magnetic nanogrenades (PMNs). (a) Schematic representation of pH‐responsive, ligand‐assisted self‐assembly of extremely small iron oxide nanoparticles (ESIONs). (b and c) Schematic representation of tumor pH‐recognizable treatment Strategy using PMNs; PMNs are latent in the circulation and reverse their surface charge from negative to positive at the tumor extracellular pH (6.8) to facilitate tissue permeation in the tumor microenvironment, trigger cell internalization where the decreased pH (5.5) causes further disassembly to enhanced their MR contrast and photoactivity. (d and e) In vivo T1‐weighted MR (d) and NIR (e) imaging of nude mice bearing HCT116 tumors after intravenous injection of PMNs or pH‐insensitive nanoparticles (InS‐NPs, Control group). (f) In vivo tumor photodynamic therapy using PMNs. Group 1, saline; group 2, free Ce6; group 3, InS‐NPs; and group 4, PMNs treated (group 2, 3, and 4 included equivalent to 2 mg kg−1 body of Ce6). (Reprinted with permission from Ref . Copyright 2014 American Chemical Society)
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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