Nanoparticle elasticity directs tumor uptake

Guo, Peng; Liu, Daxing; Subramanyam, Kriti S.; Wang, Biran; Yang, Jiang; Huang, Jing; Auguste, Debra T.; Moses, Marsha A.

doi:10.1038/s41467-017-02588-9

Cited by 294 publications

(292 citation statements)

References 44 publications

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“…Elasticity of nanoparticles is another feature to direct tumor accumulation. For instance, nanolipogels with a high elasticity (Young's modulus < 1.6 MPa) are preferentially internalized by neoplastic cells whereas the rigid counterparts (Young's modulus > 13.8 MPa) are mainly entrapped within the liver cells . The results from a nanoporous membrane deformability assay and an endothelial barrier assay suggest that the internalization of soft particles depends predominantly on fusion while particles with higher moduli enter cells strictly via clathrin‐mediated endocytosis pathway.…”

Section: Key Features Of Nanoparticles Required For Efficient Cancermentioning

confidence: 99%

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

Liu

Zhang

2019

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109

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Cancer immunotherapy is a promising cancer terminator by directing the patient's own immune system in the fight against this challenging disorder. Despite the monumental therapeutic potential of several immunotherapy strategies in clinical applications, the efficacious responses of a wide range of immunotherapeutic agents are limited in virtue of their inadequate accumulation in the tumor tissue and fatal side effects. In the last decades, increasing evidences disclose that nanotechnology acts as an appealing solution to address these technical barriers via conferring rational physicochemical properties to nanomaterials. In this Review, an imperative emphasis will be drawn from the current understanding of the effect of a nanosystem's structure characteristics (e.g., size, shape, surface charge, elasticity) and its chemical modification on its transport and biodistribution behavior. Subsequently, rapid‐moving advances of nanoparticle‐based cancer immunotherapies are summarized from traditional vaccine strategies to recent novel approaches, including delivery of immunotherapeutics (such as whole cancer cell vaccines, immune checkpoint blockade, and immunogenic cell death) and engineered immune cells, to regulate tumor microenvironment and activate cellular immunity. The future prospects may involve in the rational combination of a few immunotherapies for more efficient cancer inhibition and elimination.

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Section: Key Features Of Nanoparticles Required For Efficient Cancermentioning

confidence: 99%

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

Liu

Zhang

2019

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109

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“…To validate this hypothesis, we characterized the nanostructure of ICAM1-FusoNLP and ICAM1-EndoNLG using transmission electron microscopy (TEM) (29). In Figure 2a, it is clear that ICAM1-FusoNLPs feature a soft and hollow lipid bilayer shell, whereas ICAM1-EndoNLGs exhibit a more rigid and crosslinked alginate core inside the lipid bilayer.…”

Section: Resultsmentioning

confidence: 92%

“…In order to facilitate these ICAM1 antibody-directed nanomedicines to enter MDA-MB-231 cells via different cell entry routes, we tuned the particle elasticity of ICAM1-FusoNLP and ICAM1-EndoNLG by encapsulating either PBS (low elasticity) or crosslinked alginate hydrogel (high elasticity), respectively. We previously reported that nanoparticle elasticity directly regulates its cell entry route (29). Here, we hypothesized that ICAM1-FusoNLP and ICAM1-EndoNLG can be engineered with identical particle size, shape, and surface chemistry, and the only viable factor between ICAM1-FusoNLP and ICAM1-EndoNLG is their cell entry routes from receptor-mediated membrane fusion to receptor-mediated endocytosis (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…ICAM1 is a cell membrane receptor for host cell entry of human rhinovirus (26) and has been recently identified as a molecular target for human triple negative breast cancer (27). We previously reported that nanoparticle elasticity directly regulates its cell entry route (29). In this study, ICAM1 antibody was selected as the actively targeting ligand covalently conjugated to the surfaces of ICAM1-FusoNLP and ICAM1-EndoNLG.…”

Section: Resultsmentioning

confidence: 99%

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Quantitative Analysis of Different Cell Entry Routes of Actively Targeted Nanomedicines Using Imaging Flow Cytometry

et al. 2019

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A rapid, high-throughput, and quantitative method for cell entry route characterization is still lacking in nanomedicine research. Here, we report the application of imaging flow cytometry for quantitatively analyzing cell entry routes of actively targeted nanomedicines. We first engineered ICAM1 antibody-directed fusogenic nanoliposomes (ICAM1-FusoNLPs) and ICAM1 antibody-directed endocytic nanolipogels (ICAM1-EndoNLGs) featuring highly similar surface properties but different cell entry routes: receptor-mediated membrane fusion and receptor-mediated endocytosis, respectively. By using imaging flow cytometry, we characterized their intracellular delivery into human breast cancer MDA-MB-231 cells. We found that ICAM1-FusoNLPs mediated a 2.8-fold increased cell uptake of fluorescent payload, FITC-dextran, with a 2.4-fold increased intracellular distribution area in comparison with ICAM1-EndoNLGs. We also investigated the effects of incubation time and endocytic inhibitors on the cell entry routes of ICAM1-FusoNLP and ICAM1-EndoNLG.Our results indicate that receptor-mediated membrane fusion is a faster and more efficient cell entry route than receptor-mediated endocytosis, bringing with it a significant therapeutic benefit in a proof-of-principle nanomedicine-mediated siRNA transfection experiment. Our studies suggest that cell entry route may be an important design parameter to be considered in the development of next-generation nanomedicines.NANOMEDICINES have emerged as a revolutionary therapeutic approach for treating many diseases including cancer (1-3). They take advantage of rapidly developed nanomaterials to engineer "virus-like" nanovectors that circulate in the body and deliver a variety of therapeutic, diagnostic, and theranostic agents to disease sites. To date, more than 20 nanomedicines (e.g., Doxil, Abraxane, and Onivyde) have been approved by the United States Food and Drug Administration (U.S. FDA) and the European Medical Agency (EMA) for clinical indications due to their fewer adverse effects and better safety profiles than conventional drug formulations(4,5). Moreover, actively targeted nanomedicines (e.g., MM310 and BIND-014) have been under intense pre-clinical and clinical investigations as next-generation targeted therapeutics for cancer treatment. These nanomedicines utilize molecularly targeting ligands (e.g., antibodies, peptides, and aptamers) to guide nanovectors to precisely recognize and ablate cancer cells while sparing normal organs and tissues (4).Cell entry route plays a critical role in the intracellular delivery of actively targeted nanomedicines. In general, nanomedicines are hypothesized to enter cells through two major routes: endocytosis and membrane fusion (6,7). Most actively targeted nanoparticles rely on receptor-mediated endocytosis to enter targeted

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“…Mammary epithelial cells and breast cancer cells more avidly took up lipid-alginate particles with lower Young’s moduli (as controlled by alginate crosslinking density). In vivo , the highly flexible lipid-alginate particles successfully targeted tumors in an orthotopic model, while concurrently manifesting reduced liver uptake, relative to rigid counterparts [111]. …”

Section: General Aspects Of Dds Toxicologymentioning

confidence: 99%

Unintended effects of drug carriers: Big issues of small particles

Parhiz

Khoshnejad

Myerson

et al. 2018

Advanced Drug Delivery Reviews

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Humoral and cellular host defense mechanisms including diverse phagocytes, leukocytes, and immune cells have evolved over millions of years to protect the body from microbes and other external and internal threats. These policing forces recognize engineered sub-micron drug delivery systems (DDS) as such a threat, and react accordingly. This leads to impediment of the therapeutic action, extensively studied and discussed in the literature. Here, we focus on side effects of DDS interactions with host defenses. We argue that for nanomedicine to reach its clinical potential, the field must redouble its efforts in understanding the interaction between drug delivery systems and the host defenses, so that we can engineer safer interventions with the greatest potential for clinical success.

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Nanoparticle elasticity directs tumor uptake

Cited by 294 publications

References 44 publications

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

Quantitative Analysis of Different Cell Entry Routes of Actively Targeted Nanomedicines Using Imaging Flow Cytometry

Unintended effects of drug carriers: Big issues of small particles

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