Tunable, Ultrasensitive pH‐Responsive Nanoparticles Targeting Specific Endocytic Organelles in Living Cells

Zhou, Kejin; Wang, Yiguang; Huang, Xiaonan; Luby-Phelps, Katherine; Sumer, Baran D.; Gao, Jinming

doi:10.1002/anie.201100884

Cited by 520 publications

(453 citation statements)

References 67 publications

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“…Monomers including 2-(ethylpropylamino) ethyl methacrylate (EPA-MA), 2-(dipropylamino) ethyl methacrylate (DPA-MA), 2-(dibutylamino) ethyl methacrylate (DBA-MA) and 2-(dipentylamino) ethyl methacrylate (D5A-MA), 2-(pentamethyleneimino)ethyl methacrylate (C6A-MA), 2-(hexamethyleneimino)ethyl methacrylate (C7A-MA) were synthesized following previous publications 34,35 . New monomers including 2-(heptamethyleneimino)ethyl methacrylate (C8A-MA), 2-(4-methylpiperidineleneimino)ethyl methacrylate (C6S1A-MA), 2-(3,5-dimethylpiperidineleneimino)ethyl methacrylate (C6S2A-MA) were synthesized following a previously published procedure 35 .…”

Section: Methodsmentioning

confidence: 99%

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A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

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Generation of tumor-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells (APCs) with innate stimulation. Here we report a minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression. Mechanistically, PC7A NP achieved efficient cytosolic delivery of tumor antigens to APCs in draining lymph nodes leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect was dependent on STING but not Toll-like receptor or MAVS pathway. Nanovaccine produced potent tumor growth inhibition in melanoma, colon cancer, and human papilloma virus-E6/E7 tumor models. Combination of PC7A nanovaccine with an anti-PD-1 antibody showed great synergy with 100% survival over 60 days in a TC-1 tumor model. Rechallenging of these tumor-free animals with TC-1 cells led to complete inhibition of tumor growth, suggesting generation of long-term antitumor memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumor immunity for cancer immunotherapy.

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Section: Methodsmentioning

confidence: 99%

“…AMA-MA was introduced in the PEG- b -PR copolymers for the conjugation of dyes followed the similar procedure 34,35 . After synthesis, PEG- b -(PR- r -AMA) (10 mg) and Dye-NHS (1.5 equivalences) was both dissolved in DMF.…”

Section: Methodsmentioning

confidence: 99%

A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

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“…Nanoparticles were not able to enter the cell in the media at pH 7.4, whilst at pH between 6.3 and 5.4 were found be enabled in different cellular pH compartments, such as lysosomes or early endosomes [37] which could be used in drug delivery applications.…”

Section: Hepatocytesmentioning

confidence: 98%

Nanoparticle Technology as a Double-Edged Sword: Cytotoxic, Genotoxic and Epigenetic Effects on Living Cells

Jennifer¹,

Wnuk²

2013

JBNB

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Nanoparticles are considered as powerful tools in nanotechnological applications. Due to their unique physicochemical properties, their interactions with different biological systems have been shown. Nanomaterials have been successfully used as coating materials or treatment and diagnosis tools. Nevertheless, toxic effects of nanoparticles in vitro and in vivo have also been reported. Here, we summarize the current state of knowledge on exposure routes, cellular uptake and toxicological activities of the commonly used nanoparticles. In this context, we discuss the mechanisms of toxicity of nanoparticles involving perturbation of redox milieu homeostasis and cellular signaling pathways.

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“…Such dependence is highly reversible. As shown in figure 2D, by repeating switching pH from 6 to 10, very little variation in the ratio, which is different from those irreversible pH sensors derived from micelle or avidin loaded with TARMA [11,14] and other known ratiometric pH indicators [15] . The pH response of TG-AuNPs was still independent of the concentration ( Figure S3), indicating the changes in the fluorescence intensity at different values were not induced by the aggregation of AuNPs.…”

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confidence: 94%

Dimerization of Organic Dyes on Luminescent Gold Nanoparticles for Ratiometric pH Sensing

et al. 2016

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Synergistic effects arising from the conjugation of organic dyes onto non-luminescent metal nanoparticles (NPs) have greatly broadened their applications in both imaging and sensing. Herein, we report that conjugation of a well-known pH-insensitive dye, tetramethyl-rhodamine (TAMRA), to pH-insensitive luminescent gold nanoparticles (AuNPs) can lead to an ultrasmall nanoindicator that can fluorescently report local pH in a ratiometric way. Such synergy originated from the dimerization of TAMRA on AuNPs, of which geometry was very sensitive to surface charges of the AuNPs and can be reversely modulated through protonation of surrounding glutathione ligands. Not limited to pH-insensitive dyes, this pH-dependent dimerization can also enhance the pH sensitivity of fluorescein, a well-known pH-sensitive dye, within a larger pH range, opening up a new pathway to design ultrasmall fluorescent ratiometric nanoindicators with tunable wavelengths and pH response ranges. KeywordsGold Nanoparticle; Luminescence; Dimerization; Dye; pH Metal nanoparticles (NPs) generally do not fluoresce because of their large density of states; as a result, conjugation of organic dyes to non-luminescent metal NPs is essential for visualizing them in fluorescence imaging systems. [1] . For instance, Chan et al. conjugated organic dyes such as Cyto633 to different sized non-luminescent gold NPs (AuNPs), so that these AuNPs can be readily monitored in real time in vivo [2] . Moreover, this simple approach also creates many synergistic effects that can further broaden imaging and sensing applications of both organic dyes and metal NPs. For example, by loading organic dyes onto plasmonic metal NPs, giant Raman scattering with specific molecular signatures of organic dyes has been used for multispectral cancer imaging [3] . By taking advantage of the fluorescence quenching effect of AuNPs, dye-AuNP complexes can be used as sensors for detecting ssDNA, proteins, small toxins, etc [4] .Correspondence to: Jie Zheng. ‡ These authors contributed equally to this work HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptDifferent from conventional non-luminescent metal NPs, a new class of metal NPs that can give intrinsic fluorescence without being labeled with organic dyes has also emerged in the past decade [5] . By tuning particle size, crystallinity, surface ligands and valance states, we and others were able to create a large number of luminescent metal NPs with tunable emission ranging from UV to NIR [6] . Complementary to dye-labeled non-luminescent metal NPs, metal NPs with intrinsic emissions have also found many applications in imaging and sensing. For instance, red-emitting AuNPs have been used to detect small metal ions, toxin and reactive oxygen species [7] . More recent studies show that NIR-emitting AuNPs can serve as a new class of renal clearable contrast agents for rapid tumor diagnosis and kidney functional imaging [8] . While the emergence of these luminescent metal NPs suggests that or...

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Tunable, Ultrasensitive pH‐Responsive Nanoparticles Targeting Specific Endocytic Organelles in Living Cells

Cited by 520 publications

References 67 publications

A STING-activating nanovaccine for cancer immunotherapy

A STING-activating nanovaccine for cancer immunotherapy

Nanoparticle Technology as a Double-Edged Sword: Cytotoxic, Genotoxic and Epigenetic Effects on Living Cells

Dimerization of Organic Dyes on Luminescent Gold Nanoparticles for Ratiometric pH Sensing

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