Overcoming the Reticuloendothelial System Barrier to Drug Delivery with a “Don’t-Eat-Us” Strategy

Tang, Yixuan; Wang, Xiaoyou; Li, Jie; Nie, Yu; Liao, Guojian; Ye, Yu; Li, Chong

doi:10.1021/acsnano.9b05679

Cited by 203 publications

(171 citation statements)

References 47 publications

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“…The implementation of these strategies is to reduce the involvement of the immune system, which may lead to thrombogenicity and complement activation, resulting in altered biodistribution of NP and potential toxicity. More recently, a RES-specific blocking system based on a CD47-derived peptide ligand was utilized as a pre-treatment prior to intravenous injection of NP, resulting in a longer half-life and reduced uptake by macrophages [24]. This report strongly suggested that NP clearance could be reduced by altering the recognition of NP by phagocytes.…”

Section: Challenges In Sirna Delivery: Physiological and Intracellulamentioning

confidence: 99%

Lipid and Polymer-Based Nanoparticle siRNA Delivery Systems for Cancer Therapy

2020

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RNA interference (RNAi) uses small interfering RNAs (siRNAs) to mediate gene-silencing in cells and represents an emerging strategy for cancer therapy. Successful RNAi-mediated gene silencing requires overcoming multiple physiological barriers to achieve efficient delivery of siRNAs into cells in vivo, including into tumor and/or host cells in the tumor micro-environment (TME). Consequently, lipid and polymer-based nanoparticle siRNA delivery systems have been developed to surmount these physiological barriers. In this article, we review the strategies that have been developed to facilitate siRNA survival in the circulatory system, siRNA movement from the blood into tissues and the TME, targeted siRNA delivery to the tumor or specific cell types, cellular uptake, and escape from endosomal degradation. We also discuss the use of various types of lipid and polymer-based carriers for cancer therapy, including a section on anti-tumor nanovaccines enhanced by siRNAs. Finally, we review current and recent clinical trials using NPs loaded with siRNAs for cancer therapy. The siRNA cancer therapeutics field is rapidly evolving, and it is conceivable that precision cancer therapy could, in the relatively near future, benefit from the combined use of cancer therapies, for example immune checkpoint blockade together with gene-targeting siRNAs, personalized for enhancing and fine-tuning a patient’s therapeutic response.

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Section: Challenges In Sirna Delivery: Physiological and Intracellulamentioning

confidence: 99%

Lipid and Polymer-Based Nanoparticle siRNA Delivery Systems for Cancer Therapy

2020

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“…This approach is achieved by reversibly blocking MPS‐mediated phagocytosis using empty liposomes or directly depleting MPS macrophages using chemical agents [24–27]. However, the rapid elimination of conventional liposomes from the MPS and the systematic toxicity induced by the chemical materials hamper the clinical usefulness of this strategy [5,28].…”

Section: Introductionmentioning

confidence: 99%

A combined “eat me/don't eat me” strategy based on extracellular vesicles for anticancer nanomedicine

Belhadj

Deng

et al. 2020

J of Extracellular Vesicle

134

109

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A long-term and huge challenge in nanomedicine is the substantial uptake and rapid clearance mediated by the mononuclear phagocyte system (MPS), which enormously hinders the development of nanodrugs. Inspired by the natural merits of extracellular vesicles, we therefore developed a combined "eat me/don't eat me" strategy in an effort to achieve MPS escape and efficient drug delivery. Methodologically, cationized mannan-modified extracellular vesicles derived from DC2.4 cells were administered to saturate the MPS (eat me strategy). Then, nanocarriers fused to CD47-enriched exosomes originated from human serum were administered to evade phagocytosis by MPS (don't eat me strategy). The nanocarriers were also loaded with antitumor drugs and functionalized with a novel homing peptide to promote the tumour tissue accumulation and cancer cell uptake (eat me strategy). The concept was proven in vitro as evidenced by the reduced endocytosis of macrophages and enhanced uptake by tumour cells, whereas prolonged circulation time and increased tumour accumulation were demonstrated in vivo. Specially, the strategy induced a 123.53% increase in tumour distribution compared to conventional nanocarrier. The study both shed light on the challenge overcoming of phagocytic evasion and provided a strategy for significantly improving therapeutic outcomes, potentially permitting active drug delivery via targeted nanomedicines.

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“…The RES-specific blocking systems (like enzyme-resistant peptide ligands on liposomes or the codisposition of chitosan-based nanoparticles by macrophages) can utilize a “don’t-eat-us” strategy. 65,66 Moreover, another problem is that 30% to 99% of administered nanoparticles will accumulate and sequester in the liver after administration into the body. This phenomenon can cause reduced delivery to the targeted diseased tissue and potentially leads to increased toxicity at the hepatic cellular level.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Polymer Coating of Gold Nanoparticles on Oxidative Stress and DNA Damage

et al. 2020

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Gold nanoparticles (AuNPs) have been widely used in many biological and biomedical applications. In this regard, their surface modification is of paramount importance in order to increase their cellular uptake, delivery capability, and optimize their distribution inside the body. The aim of this study was to examine the effects of AuNPs on cytotoxicity, oxidant/antioxidant parameters, and DNA damage in HepG2 cells and investigate the potential toxic effects of different surface modifications such as polyethylene glycol (PEG) and polyethyleneimine (PEI; molecular weights of 2,000 (low molecular weight [LMW]) and 25,000 (high molecular weight [HMW]). The study groups were determined as AuNPs, PEG-coated AuNPs (AuNPs/PEG), low-molecular weight polyethyleneimine-coated gold nanoparticles (AuNPs/PEI LMW), and high-molecular weight polyethyleneimine-coated gold nanoparticles (AuNPs/PEI HMW). After incubating HepG2 cells with different concentrations of nanoparticles for 24 hours, half maximal inhibitory concentrations (the concentration that kills 50% of the cells) were determined as 166.77, 257.73, and 198.44 µg/mL for AuNPs, AuNPs/PEG, and AuNPs/PEI LMW groups, respectively. Later, inhibitory concentration 30 (IC30, the concentration that kills 30% of the cells) doses were calculated, and further experiments were performed on cells that were exposed to IC30 doses. Although intracellular reactive oxygen species levels significantly increased in all nanoparticles, AuNPs as well as AuNPs/PEG did not cause any changes in oxidant/antioxidant parameters. However, AuNPs/PEI HMW particularly induced oxidative stress as evidence of alterations in lipid peroxidation and protein oxidation. These results suggest that at IC30 doses, AuNPs do not affect oxidative stress and DNA damage significantly. Polyethylene glycol coating does not have an impact on toxicity, however PEI coating (particularly HMW) can induce oxidative stress.

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Overcoming the Reticuloendothelial System Barrier to Drug Delivery with a “Don’t-Eat-Us” Strategy

Cited by 203 publications

References 47 publications

Lipid and Polymer-Based Nanoparticle siRNA Delivery Systems for Cancer Therapy

Lipid and Polymer-Based Nanoparticle siRNA Delivery Systems for Cancer Therapy

A combined “eat me/don't eat me” strategy based on extracellular vesicles for anticancer nanomedicine

The Effects of Polymer Coating of Gold Nanoparticles on Oxidative Stress and DNA Damage

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