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WIREs Nanomed Nanobiotechnol
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Crosslinked polymer nanocapsules for therapeutic, diagnostic, and theranostic applications

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Abstract Crosslinked polymer nanocapsules (CPNCs) are hollowed nanoparticles with network‐like polymeric shells stabilized by primary bonds. CPNCs have drawn broad and significant interests as nanocarriers for biomedical applications in recent years. As compared with conventional polymeric nanoparticles systems without cavity and/or crosslinking architectures, CPNCs possess significant biomedical relevant advantages, including (a) superior structural stability against environmental conditions, (b) high loading capacity and ability for region‐specific loading of multiple cargos, (c) tuneable cargo release rate via crosslinking density, and (d) high specific surface area to facilitate surface adsorption, modification, and interactions. With appropriate base polymers and crosslinkages, CPNCs can be biocompatible and biodegradable. While CPNC‐based biomedical nanoplatforms can possess relatively stable physicochemical properties owing to their crosslinked architectures, various biomedically relevant stimuli‐responsivities can be incorporated with them through specific structural designs. CPNCs have been studied for the delivery of small molecule drugs, genes, proteins, and other therapeutic agents. They have also been investigated as diagnostic platforms for magnetic resonance imaging, ultrasound imaging, and optical imaging. Moreover, CPNCs have been utilized to carry both therapeutics and bioimaging agents for theranostic applications. This article reviews the therapeutic, diagnostic and theranostic applications of CPNCs, as well as the preparation of these CPNCs, reported in the past decade. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Implantable Materials and Surgical Technologies > Nanomaterials and Implants Diagnostic Tools > in vivo Nanodiagnostics and Imaging
(a) Ultrasound (US) triggered pH/redox‐responsive doxorubicin (DOX) release profiles from DOX‐loaded PMAA‐PFH crosslinked polymer nanocapsules (CPNCs) under pH 7.4 (top) and pH 5.0 (bottom). (b) In vitro US imaging for PBS control, PMAA‐40 CPNCs and PMAA‐PFH CPNCs under B‐mode and power Doppler mode. Source: Reprinted with permission from Yang et al. (2014). Copyright 2014 Elsevier
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Polylactide‐based zwitterionic crosslinked polymer nanocapsules for near‐infrared fluorescence cancer imaging. Source: Adapted with permission from Sun et al. (2019). Copyright 2019, American Chemical Society
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(a) Schematic illustration of preparing protein‐encapsulated crosslinked polymer nanocapsules (CPNCs) with sustained release capability. (b) In vivo fusion score using a rat spinal fusion model at 8 weeks (nMBP‐2: BMP‐2‐encapsulated CPNC with BMP‐2 concentration equivalent to 1.5 μg BMP‐2). (c) Quantified relative bone volume (BV/TV) resulted from the nBMP‐2 versus BMP‐2. (d) Quantified inflammatory reaction volume and area caused by nBMP‐2 versus BMP‐2, as measured by MRI and histology, respectively. **p < .01; ***p < .001. Source: Adapted with permission from Tian et al. (2016). Copyright 2016, American Chemical Society
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(a) Synthesis of Cas9 ribonucleoprotein (RNP)‐encapsulating nanocapsules (NCs) (i.e., crosslinked polymer nanocapsules). (b) Optimizing the NC formulation in vitro using mCherry‐expressing HEK 293 (mCherry‐HEK 293) cells. (c) Gene editing in mCherry‐HEK 293 cells with RNP‐encapsulating NCs, as compared to unencapsulated RNP, optimized Lipofectamine (Lipo) system and untransfected control sample (UT). (d) Deep sequencing of HEK 293 cells to examine in vitro gene editing efficiency with RNP‐encapsulating NCs with and without decoration using cell‐penetrating peptide (CPP). (e) In vivo gene editing efficiency expressed as the percentage area of whole muscle tissue showing confocal fluorescent signal for a genome editing reporter (tdTomato+) 12 days after the intramuscular injection of genome editors. Source: Adapted with permission from Chen et al., 2019
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(a) Schematic illustration of crosslinked polymer nanocapsules as DNA cassettes. (b) sh1005 DNA cassette versus siRNA 1,005 lipofectamine complex in the knockdown of CCR5‐Luciferase in HEK‐293T cells. (c) A time profile for knockout of EGFP expression by DNA cassette‐encoded gRNA as determined by flow cytometry. (d) Ex‐vivo culture of cytokine‐mobilized CD34 + cells for 6 days after delivery of miR‐125b DNA cassette versus controls. Source: Adapted with permission from Yan et al. (2015). Copyright 2015, Public Library of Science
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(a) Schematic illustration of the synthesis and cellular uptake of doxorubicin (DOX)‐loaded poly(ethylene glycol)‐poly(propylene sulfide)‐cRGD crosslinked polymer nanocapsules. (b) MTT assay of SCC‐15 cells after incubation with for 24 hr (***p < .001). (c) DOX concentrations in various organs and tumor tissue. Source: Reproduced with permission from Zhang et al. (2017). Copyright 2017, The Royal Society of Chemistry
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(a) Schematic illustration of the preparation of doxorubicin (DOX)‐loaded and DOX/siRNA‐loaded cationic polylactide (CPLA) nanocapsules (NCs, that is, crosslinked polymer nanocapsules). (b) Fluorescence quantification of DOX uptake by MCF7/ADR cells via free DOX and DOX‐CPLA NCs. (c) MTS cell viability assay of MCF7/ADR cells after 48 hr incubation with free DOX and DOX‐CPLA NCs. (d) Confocal images of PC3 cells after incubation with DOX/IL‐8‐siRNAFAM‐CPLA NCs for 4 hr. (e) MTS cell viability assay of PC3 cells after incubation with DOX‐CPLA NCs and DOX/IL‐8‐siRNA CPLA NCs for 72 hr ([siRNA]0 = 0.1 μM; WDOX/WNCs = 0.116). Source: Adapted with permission from Chen, Law, et al. (2014)
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Schematic illustration of synthetic approaches of crosslinked polymer nanocapsules: (a) cavitation of shell‐crosslinked nanostructures, (b) vesicle‐based crosslinking, and (c) emulsion‐based interfacial crosslinking
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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Implantable Materials and Surgical Technologies > Nanomaterials and Implants
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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