Targeted Intravenous Nanoparticle Delivery: Role of Flow and Endothelial Glycocalyx Integrity

Cheng, Ming; Mitra, Ronodeep; Okorafor, Chinedu C.; Nersesyan, Alina; Harding, Ian C.; Bal, Nandita N.; Kumar, Rajiv; Jo, Hanjoong; Sridhar, Srinivas; Ebong, Eno E.

doi:10.1007/s10439-020-02474-4

Cited by 18 publications

(13 citation statements)

References 33 publications

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“…We plan to address this in the future by increasing the sample size. Second, as shown in Figure S8E,F, we relied on another in vivo study conducted by our research group, which confirms the link between DF conditions (induced by partial ligation of the carotid arteries) and degradation of GCX coverage and thickness, as compared to a link between UF conditions and robust GCX (Harding et al and Cheng et al Our previously conducted study of GCX under DF conditions in vivo suggests that GCX is, indeed, degraded in the branched (DF) areas of the mouse ear vessels, enabling the endothelium covered vessel walls to recruit CTCs, as indicated by the reduction in CTC speed and the increased CTC attachment that we see.…”

Section: Discussionsupporting

confidence: 58%

Flow‐regulated endothelial glycocalyx determines metastatic cancer cell activity

et al. 2020

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Cancer metastasis and secondary tumor initiation largely depend on circulating tumor cell (CTC) and vascular endothelial cell (EC) interactions by incompletely understood mechanisms. Endothelial glycocalyx (GCX) dysfunction may play a significant role in this process. GCX structure depends on vascular flow patterns, which are irregular in tumor environments. This work presents evidence that disturbed flow (DF) induces GCX degradation, leading to CTC homing to the endothelium, a first step in secondary tumor formation. A 2‐fold greater attachment of CTCs to human ECs was found to occur under DF conditions, compared to uniform flow (UF) conditions. These results corresponded to an approximately 50% decrease in wheat germ agglutinin (WGA)‐labeled components of the GCX under DF conditions, vs UF conditions, with undifferentiated levels of CTC‐recruiting E‐selectin under DF vs UF conditions. Confirming the role of the GCX, neuraminidase induced the degradation of WGA‐labeled GCX under UF cell culture conditions or in Balb/C mice and led to an over 2‐fold increase in CTC attachment to ECs or Balb/C mouse lungs, respectively, compared to untreated conditions. These experiments confirm that flow‐induced GCX degradation can enable metastatic CTC arrest. This work, therefore, provides new insight into pathways of secondary tumor formation.

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Section: Discussionsupporting

confidence: 58%

Flow‐regulated endothelial glycocalyx determines metastatic cancer cell activity

et al. 2020

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“…Degradation of the vascular endothelial glycocalyx significantly increased endothelial cell uptake of nanoparticle vehicles designed for drug delivery compared to the intact glycocalyx [ 126 ]. Ultra-small gold nanospheres coated with polyethylene glycol were successfully delivered intravenously in the glycocalyx degradation mouse model [ 127 ]. These lines of evidence suggest that vascular endothelial glycocalyx dysfunction induced by SARS-CoV-2 may be targeted for enhanced drug delivery, offering a new therapeutic approach for COVID-19.…”

Section: Possible Therapeutic Targets On Covid-19 Associated With Thementioning

confidence: 99%

Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19

Yamaoka‐Tojo

2020

Biomedical Journal

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In atherosclerosis patients, vascular endothelial dysfunction is commonly observed alongside damage of the vascular endothelial glycocalyx, an extracellular matrix bound to and encapsulating the endothelial cells lining the blood vessel wall. Although atherosclerotic risk factors have been reported in severe patients with coronavirus disease 2019 (COVID-19), the exact mechanisms are unclear. The mortality associated with the COVID-19 outbreak is increased by comorbidities, including hypertension, diabetes, obesity, chronic obstructive pulmonary disease (COPD), and cardiovascular disease. Besides, older individuals and smokers have significantly worse outcomes. Interestingly, these comorbidities and risk factors are consistent with the pathophysiology that causes vascular endothelial glycocalyx damage. Moreover, vascular glycocalyx dysfunction causes microvascular leakage, which results in interstitial pulmonary abnormal shadows (multiple patchy shadows with a ground glass inter-pneumonic appearance). This is frequently followed by severe acute respiratory distress syndrome (ARDS), closely related to coagulo-fibrinolytic changes contributing to disseminated intravascular coagulation (DIC) and Kawasaki disease shock syndrome, as well as inducing activation of the coagulation cascade, leading to thromboembolism and multiple organ failure. Notably, SARS-CoV-2, the causative virus of COVID-19, binds to ACE2, which is abundantly present not only in human epithelia of the lung and the small intestine, but also in vascular endothelial cells and arterial smooth muscle cells. Moreover, COVID-19 can induce severe septic shock, and sepsis can easily lead to systemic degradation of the vascular endothelial glycocalyx. In the current review, we propose new concepts and therapeutic goals for COVID-19-related vascular endothelial glycocalyx damage, based on previous vascular endothelial medicine research.

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“…For future optimization of EC GCX regeneration, researchers must consider implementing strategies to specifically deliver GCX regeneration therapies to the right place. First, strategies are needed for delivery of GCX regeneration therapies specifically to the endothelium, which is a component of the complex systemic vasculature that contains multiple cell types, each of which possesses a GCX, and a plethora of extracellular components, which may resemble the GCX. ,− Second, strategies are needed to deliver GCX regeneration therapies to only the endothelium of the disease-prone regions of the vasculature where GCX is most eroded, such as the branches of the coronary arteries and the curves of the aortic arch. , Executing these strategies could increase the efficacy and reduce side effects of the GCX regeneration therapies. − …”

Section: Endothelial Glycocalyx Regenerationmentioning

confidence: 99%

Regeneration and Assessment of the Endothelial Glycocalyx To Address Cardiovascular Disease

Banerjee

Mwangi

Stanley

et al. 2021

Ind. Eng. Chem. Res.

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Endothelial cell (EC) glycocalyx (GCX) loss permits blood circulating particle infiltration of the vessel walls and leads to vascular dysfunction, atherosclerosis, and serious downstream cardiovascular events, motivating EC GCX regeneration to treat cardiovascular disease. This review discusses the benefits and drawbacks of current options for EC GCX regeneration and assessment. Existing pharmaceutical therapies are being explored for their applicability to EC GCX regeneration, while nutraceuticals are under development as primary EC GCX regeneration approaches, and novel therapies continue to emerge. Promotion of increased efficacy of these therapies by using novel targeted drug delivery approaches is proposed. In addition, development of intravital (and intravascular, if possible) detection tools for assessment of GCX health and GCX regeneration efficacy is recommended. The work presented in this review encourages continued development of GCX regeneration and detection approaches, which could lead to breakthrough solutions for addressing cardiovascular disease.

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Targeted Intravenous Nanoparticle Delivery: Role of Flow and Endothelial Glycocalyx Integrity

Cited by 18 publications

References 33 publications

Flow‐regulated endothelial glycocalyx determines metastatic cancer cell activity

Flow‐regulated endothelial glycocalyx determines metastatic cancer cell activity

Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19

Regeneration and Assessment of the Endothelial Glycocalyx To Address Cardiovascular Disease

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