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WIREs Nanomed Nanobiotechnol
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Drug nanocrystals for cancer therapy

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Drug nanocrystals (NCs) with fascinating physicochemical properties have attracted great attention in drug delivery. High drug‐loading efficiency, great structural stability, steady dissolution, and long circulation time are a few examples of these properties, which makes drug NCs an excellent formulation for efficient cancer therapy. In the last two decades, there are a lot of hydrophobic or lipophilic drugs, such as paclitaxel (PTX), camptothecin (CPT), thymectacin, busulfan, cyclosporin A, 2‐devinyl‐2‐(1‐hexyloxyethyl) pyropheophorbide (HPPH), and so on, which have been formulated into drug NCs for cancer therapy. In this review, we summarized the recent advances in drug NCs‐based cancer treatment. So far, there are main three methods to synthesize drug NCs, including top‐down, bottom‐up, and combination methods. The characterization methods of drug NCs were also elaborated. Furthermore, the applications and mechanisms of drug NCs were introduced by their administration routes. At the end, we gave a brief conclusion and discussed the future perspectives of drug NCs in cancer therapy.

Intracellular transport of nanoparticles (NPs). NPs were internalized by one or more of the endocytic pathways across the cell membrane, then NPs were transported by various endosomes, endoplasmic reticulum (ER), microtubule‐organizing center, and multivesicular bodies.(Reprinted with permission from Ref . Copyright 2011 Royal Society of Chemistry).
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Confocal images of KB cells incubated with 100 μg/mL polymer‐treated nanocrystals (NCs) for 3 h (a) of (A) PTX NCs, (B) SRB‐PTX‐NCs, (C) Dp‐PTX‐NCs, (D) FA‐PEG‐Dp‐PTX NCs, (E) FA‐PEG‐PTX‐NCs, and (F) F68‐PTX‐NCs, Scale bar = 10 μm. Percentage of dosed paclitaxel (PTX) internalized in KB cells of Taxol (soluble PTX) and NCs (PTX NCs) at 4 and 37°C (b) and cellular uptake measurement of PTX in KB cells of pure and polymer‐treated drug NCs incubated for 3 h (c).(Reprinted with permission from Ref . Copyright 2015 Springer).
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Transmission electron microscope (TEM) image of ursolic acid (UA) nanocrystals (NCs) (a), dissolution profiles of the UA NCs and the physical mixture (b), and dose/time dependent growth inhibition of MCF‐7 cells by free UA and UA NCs at 12 (c) and 48 h (d).(Reprinted with permission from Ref . Copyright 2014 Springer).
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Schematic illustration of multi‐inlet vortex mixer (MIVM) technique (a), transmission electron microscope (TEM) image of 70 nm curcumin (CUR) nanocrystals (NCs) prepared by MIVM method (b) and size distributions (c) of CUR NCs.(Reprinted with permission from Ref . Copyright 2016 Elsevier).
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Overview and close‐up of a three dimensional (3D) glass capillary device to prepare superfast structured core/shell nanocomposites (a). Transmission electron microscope (TEM) image of paclitaxel (PTX) core/shell structure (b), impact of Reynold number on particle size and size distribution, obtained from dynamic light scattering (DLS) (c).(Reprinted with permission from Ref . Copyright 2017 American Chemical Society).
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Representation of laser fragmentation in the vertical (a) and the horizontal (b) configurations. Scanning electron microscope (SEM) images of untreated water‐exposed megestrol acetate (MA) (c), femtosecond laser fragmented MA (250 mW, 30 min, 2 mL) (d) and nanosecond laser fragmented MA (2.5 W, 60 min, 10 mL) (e). Size distribution analysis by laser diffraction (f).(Reprinted with permission from Ref . Copyright 2011 Elsevier).
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In vitro dissolution profiles (a) of Taxol™ (▴), paclitaxel (PTX) coarse suspension ( ) and PTX NCs (●); saturation solubility of PTX in aqueous phase from coarse suspension and PTX NCs (b). Caco‐2 cell uptake of PTX NCs and Taxol™ at 25, 50, and 100 μg/mL (n = 6, **P < 0.01, ***P < 0.001 PTX‐NC vs Taxol™) after 4 h (c). Plasma concentration profiles of PTX after oral administration of Taxol™ and PTX‐NC at dose equivalent of 10 mg/kg PTX in male Wistar rats (d).(Reprinted with permission from Ref . Copyright 2015 Elsevier).
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Construction of a hydrophobic drug nanocrystal/hydrogel composite system (a), transmission electron microscope (TEM) images of PTX NCs (b) and PTX NCs‐Gel (c), in vivo near‐infrared reflection (NIR) imaging (d) and ex vivo fluorescence images (e) of mice injected with PTX/DiR hybrid NCs Gel and PTX/DiR hybrid NCs and Crem/ethanol solubilized 1,1‐dioctadecyltetramethyl indotricarbocyanine iodide (DiR) at 4T1 tumor‐bearing mice, in vivo antitumor activity against 4T1 tumor‐bearing BALB/C mice (f) and MCF‐7 tumor‐bearing nude mice (g) after a single i.t. injection of PTX NCs gel, PTX NCs, Taxol, and saline.(Reprinted with permission from Ref . Copyright 2014 Elsevier).
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Schematic illustration of the preparation of PEG‐PTX NCs (a), Scanning electron microscope (SEM) image of PEG‐PTX NCs (b), tumor volume change in MDA‐MB‐231/luc bearing nude mice after being treated with different formulations (c), bioluminescence images of nude mice treated with different formulations (d).(Reprinted with permission from Ref . Copyright 2015 Royal Society of Chemistry).
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Chemical structures of drugs in Table .
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Schematic of nanoparticle trafficking process and fate upon i.v. administrations (step I), followed by exposure to blood plasma proteins (step II), clearance organs of the mononuclear phagocyte system (step III), accumulation in the tumor cells (step IV), and transportation in lymphatics and lymph nodes (step V) in a tumor‐bearing mouse.(Reprinted with permission from Ref . Copyright 2013 American Chemical Society).
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Scanning electron microscope (SEM) image (a) of HTCC‐NP:PTX, in vivo near‐infrared fluorescence imaging of N‐((2‐hydroxy‐3‐trimethylammonium) propyl) chitosan chloride (HTCC) nanoparticles’ biodistribution after oral administration in subcutaneous LLC tumor‐bearing mice (b), tumor images and the corresponding cell nuclear of different groups after treatment (c), tumor volumes (d), and survival (e) of mice in different groups (scale bar: 10 μm).(Reprinted with permission from Ref . Copyright 2011 American Chemical Society).
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Oral administration of drugs in the whole body including absorption, distribution, metabolism, and excretion process (a), structure of intestine and transmission electron microscope (TEM) image of villi (b), and transport processes of drugs across intestine lumen (c).(Reprinted with permission from Ref . Copyright 2013 American Chemical Society).
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Mauro Ferrari

Mauro Ferrari

started out in mechanical engineering and became interested in nanotechnology with his studies on nanomechanics and nanofluidics. His research work and involvement with setting up some of the premier nano centers and alliances in the world, bringing together universities, hospitals, and federal agencies, showcases interdisciplinarity at work.

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