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WIREs Nanomed Nanobiotechnol
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Multifunctional nanoparticle composites: progress in the use of soft and hard nanoparticles for drug delivery and imaging

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With continued advancements in nanoparticle (NP) synthesis and in the interfacing of NPs with biological systems has come the exponential growth in the use of NPs for therapeutic drug delivery and imaging applications. In recent years, the advent of NP multifunctionality—the ability to perform multiple, disparate functions on a single NP platform—has garnered much excitement for the potential realization of highly functional NP‐mediated drug delivery for use in the clinical setting. This Overview will survey the current state of the art (reports published within the last 5 years) of multifunctional NPs for therapeutic drug delivery, imaging or a combination thereof. We provide extensive examples of both soft (micelles, liposomes, polymeric NPs) and hard (noble metals, quantum dots, metal oxides) NP formulations that have been used for multimodal drug delivery and imaging. The criteria for inclusion, herein, is that there must be at least two therapeutic drug cargos or imaging agents or a combination of the two. We next offer an assessment of the cytotoxicity of therapeutic NP constructs in biological systems. We then conclude with a forward‐looking perspective on how we expect this field to develop in the coming years. WIREs Nanomed Nanobiotechnol 2017, 9:e1466. doi: 10.1002/wnan.1466 This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vitro Nanoparticle-Based Sensing Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Multifunctional nanoparticles (NPs) for the dual delivery of therapeutic drugs. (a) (i) Schematic of multifunctional gold NP (AuNP) the combined delivery of methotrexate and anti‐TGF‐β1 antibody. AuNPs show differential cellular uptake that is dependent upon both (ii) cell line and (iii) AuNP size. (iv) The efficiency of cell killing mediated by AuNP dual drug conjugates requires an optimal ratiometric mix of AuNP, targeting folate moiety and methotrexate. (Reprinted with permission from Ref . Copyright 2016 IOP Publishing, Ltd.). (b) Liposomes for dual drug delivery of paclitaxel and artemether for treatment of invasive brain glioma. (i) The two drugs are incorporated into the lipid bilayer of the NP and mannose (MAN) and phospholipid (DSPE) derivatives mediate endocytosis and crossing of the blood–brain barrier. (ii) Cytotoxicity of different liposome formulations on brain glioma C6 stem cells after 48 h of treatment. (iii) Kaplan–Meier survival curves showing in vivo survivability of various liposomal formulations. b, saline; c, taxol; d, paclitaxel liposomes; e, paclitaxel/artemether liposomes; f, MAN‐targeted paclitaxel/artemether liposomes; g, dequalinium (DQA)‐targeted paclitaxel/artemether liposomes; h, dual targeted paclitaxel/ artemether liposomes. (Reprinted with permission from Ref . Copyright 2014 Elsevier). (c) Multiblock copolymer micelle NP system for enhanced doxorubicin (DOX) killing in drug‐resistant cells. (i) A poly(ethylene oxide)‐block‐poly(ε‐caprolactone) (PEO‐b‐PCL) copolymer system condenses siRNA with polyamines and incorporates DOX into the core. RGD and TAT peptides mediate cellular uptake. (ii) Full ensemble micelles bearing RGD and TAT show enhanced DOX‐mediated cell necrosis when combined with siRNA for P‐glycoprotein down regulation. (Reprinted with permission from Ref . Copyright 2011 ACS). (d) Copolymer NP‐mediated codelivery of antiapoptotic siRNA and DOX in a rat model of glioma. NPs composed of caprolactone/poly(ethyleneimine) (PEI) were conjugated to folic acid (FA) for targeting. Upon injection, the full ensemble NPs (D‐PCE‐/BCL‐2/FA, far left) showed significant reduction in imaged tumor size (i) and volume (ii) compared with control formulations (e.g., non‐targeted (NFA); scrambled siRNA (SCR)). (iii) Survival curves show the significant protective effect of the full ensemble conjugates that avail survival beyond the time parameters of the study. (Reprinted with permission from Ref . Copyright 2012 Elseveir). (e) Gel‐liposome NPs for dual delivery of protein and small molecule drugs. (i) Schematic of the TRAIL/DOX gelipo combination NP. (ii) In vivo fluorescence imaging of MDA‐MD‐231 tumor‐bearing nude mice at 4, 24, 48 h after injection of various formulations showing distribution. (iii) MDA‐MB‐231 tumor growth curves after iv injections of different DOX formulations. TRAIL/Dox‐Gelipo showed the greatest inhibitory effect on tumor growth. (Reprinted with permission from Ref . Copyright 2014 WILEY‐VCH Verlag GmbH & Co.)
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Key considerations for implementing multifunctional therapeutic nanoparticles (NPs). The successful implementation of multifunctional NPs for therapeutic applications in vitro and in vivo depends on a number of critical factors including: 1‐the NP type/form (hard versus soft versus multi‐NP hybrid); 2‐the method of cargo incorporation and actuation; 3‐NP targeting and specificity. These factors combine to determine the level of control afforded to various NP constructs. This Overview discusses these issues while highlighting current examples of multifunctional NPs for the combinatorial delivery of imaging agents and therapeutic drugs.
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Multifunctional nanoparticles (NPs) for the dual delivery of imaging agents. (a) Schematic illustration of gadolinium‐loaded dendrimer‐entrapped gold NPs (Gd‐Au DENPs) for magnetic resonance imaging (MRI)/computed tomography (CT) dual mode imaging. T1‐weighted magnetic resonance (MR) and CT images of mouse kidney before and 45 min after iv injection of Gd‐Au DENPs in a rat model. (Reprinted with permission from Ref . Copyright 2013 Elsevier). (b) Schematic illustration of the synthesis of Gd‐doped CuInS/ZnS core/shell quantum dots (QDs) for dual mode (MRI/PL) imaging. In vivo fluorescence imaging and T1‐weighted images of U87 tumor‐bearing mice 18 h postinjection via tail vein. (Reprinted with permission from Ref Copyright 2015 ACS). (c) Schematic of PEG‐encapsulated NaYF4:Yb,Er:Fe3O4@Au NPs for MR/PL imaging and targeted photothermal therapy. In vivo upconversion (UC) fluorescence images of 4T1 mammary tumor‐bearing Balb/c mice taken 2 h after injection of NPs with (under MF) and without (no MF) magnetic field. Also shown are T2‐weighted MR images of tumor‐bearing mice at the same time points. (Reprinted with permission from Ref . Copyright 2012 Elsevier). (d) Schematic illustration of microbubbles containing PLGA‐Fe3O4 NPs and doxorubicin (DOX) targeted to lymph vasculature coupled with DOX release triggered by low intensity sonication. Bottom; In vivo ultrasound (US) images of rabbit tumor lymph nodes before and 5 min after administration of saline (a1) or NPs (c4). Right; in vivo MR‐assisted lymphosonography of rabbit tumor lymph nodes (arrows) before (c1) and after (c2) injection of the NPs, respectively. (Reprinted with permission from Ref . Copyright 2013 Elsevier)
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Multifunctional nanoparticles (NPs) for the dual delivery of imaging agents and therapeutic drugs‐ part 2. (a) (i) Schematic of the effects of the chlorin‐e6 conjugated PEG‐b‐poly(diisopropanol amino ethyl methacrylate cohydroxyl methacrylate) (PDPA) micelle NPs under normal internalization processes (left). Decreased intracellular pH induces protonation of the PDPA and subsequent cell killing upon laser excitation. Presence of the vascular inhibitor bafilomycin A1 (Baf‐A1) inhibits NP release, resulting in cellular protection (right). (ii/iii) Confocal laser scanning microscopy images of in vitro intracellular ROS generation in cells exposed to PDPA micelles alone (ii) and PDPA micelles stimulated with light in the absence of the protective BFA‐A1 (iii). Perinuclear red staining in (ii) are PDPA micelles in the lysosomes. The yellow color in (iii) emanates from red PDPA micelles released into the cytosol merged with green fluorescence corresponding to the ROS probe. (iv) Fluorescence images of MCF‐7/ADR tumor‐bearing mice post iv‐injection of the PDPA micelles; bottom panel shows the ex vivo images at 4 h postinjection. Scale bar is 50 µm. (Reprinted with permission from Ref Copyright 2016 Elsevier). (b) (i) Schematic of folate‐decorated PEG‐PLGA nanopolymersomes with encapsulated doxorubicin (DOX) and quantum dots (QDs). Ex vivo fluorescent images of excised tumor tissue from polymersome‐DOX‐QD NP‐injected mice (ii) and FA‐polymersome‐QD NP‐injected mice (iii). The significantly higher QD uptake (green) in the folate(+) NPs shows the specificity of the targeting. (iv) Survival curves of subcutaneous mouse model of 4T1 mouse mammary tumors after treatment with DOX‐QD NPs, FA‐DOX‐QD NPs, free DOX, free QD, and saline. A 100% survival rate was observed for the targeted DOX‐QD NP constructs while untargeted DOX‐QD NPs showed less than 50% survival. (Reprinted with permission from Ref . Copyright 2016 Elsevier). (c) Schematic of polypyrrole NPs with encapsulated Fe3O4 NPs and DOX. The Fe3O4 in the core avails magnetic resonance (MR) imaging, the pyrrole shell mediates near‐infrared (NIR)‐induced release of DOX and the PEG shell increases circulation time. Confocal imaging of 4T1 tumor cells incubated without (ii) and with (iii) magnetic targeting. Increased uptake and diffuse intracellular distribution of the NPs is evident by the DOX (red) staining. Nuclei are in blue. NIR (808 nm) irradiation of NP‐loaded cells shows enhanced triggered release (v) compared with non‐irradiated cells (iv). Graph of the average mass of tumors treated with (1) PBS+NIR excitation (2) Fe3O4 NPs+NIR and (3) Fe3O4 NPs‐DOX+NIR. ***P < 0.001, *P < 0.05. Scale bar is 50 µm. (Reprinted with permission from Ref . Copyright 2013 Elsevier)
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Multifunctional nanoparticles (NPs) for the dual delivery of imaging agents and therapeutic drugs‐part 1. (a) (i) Schematic of tocopheryl polyethylene glycol 1000 succinate (TPGS)‐coated NaYbF4‐UCNPs with doxorubicin (DOX) appended to the surface. (ii) Upconversion fluorescence of NPs upon excitation with 980‐nm laser. (iii) Fluorescence image of MCF‐7 cells after 6‐h incubation with DOX‐loaded NPs. (iv) Cytotoxicity of DOX‐resistant MCF‐7 cells after treatment with free DOX versus DOX‐loaded UCNPs. The NP form of DOX displayed enhanced cell killing coupled with magnetic resonance (MR) imaging. (Reprinted with permission from Ref . Copyright 2015 Elsevier). (b) (i) Folic acid (FA)‐decorated iron oxide NP (IONP)‐fullerene composites avail tumor‐targeted MR imaging, radiofrequency thermal therapy (RTT) and reactive oxygen species (ROS)‐based photodynamic therapy. (ii) Visualization of ROS generation in MCF‐7 cells 24 h after treatment with 16 µg/mL of FA‐IONP‐fullerene conjugates. (iii) In vivo T2‐weighted MR images of mice treated with conjugates postapplication of magnetic field. (iv) Tumor volume (V) (expressed V/V0) over 2 weeks posttreatment with various iterations of IONP‐fullerene conjugates. The full complement of NP+RTT+PDT+ magnetic field resulted in minimal tumor growth. (Reprinted with permission from Ref . Copyright 2014 Elsevier). (c) (i) Prussian Blue (PB)‐coated AuNPs (Au@PB NPs) for combined fluorescence imaging and photoacoustic/computed tomography (CT)/photothermal ablation of tumors. (ii) Reconstructed CT image of Ht‐29 tumor bearing nude mouse 24 h after treatment with Au@PB NPs. (iii) Photoacoustic imaging of HT‐29 tumor bearing mice 22 h after tail vein injection of Au@PB NPs. (iv) Cell viability assay of HeLa cells demonstrates enhanced cell killing mediated by Au@PB NPs in conjunction with laser‐induced heating as compared to control. (Reprinted with permission from Ref Copyright 2014 Elsevier)
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