Mucus as a Barrier for Biopharmaceuticals and Drug Delivery Systems

Zhang, Hongbo; Shahbazi, Mohammad‐Ali; Almeida, Patrick; Santos, Hélder A.

doi:10.1007/978-1-4614-9524-6_3

Cited by 8 publications

(8 citation statements)

References 172 publications

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“…The decreased mucus trapping could also be explained thermodynamically. MSN@PLA–PEG with the smoother surface, from AFM images, led to a larger excluded volume and lower contact area, according to the mechanical theory . Thus, lower conformational entropy and interfacial free energy could provide steric repulsion against mucin and other mucous constituents.…”

Section: Resultsmentioning

confidence: 92%

“…MSN@PLA−PEG with the smoother surface, from AFM images, led to a larger excluded volume and lower contact area, according to the mechanical theory. 5 Thus, lower conformational entropy and interfacial free energy could provide steric repulsion against mucin and other mucous constituents. As stated above, the deceased interaction and steric repulsion with mucus could contribute to lower mucous trapping.…”

Section: Resultsmentioning

confidence: 99%

“…Thereinto, mucin, a major component of mucus, consists of core proteins and side chains with charged groups, such as sialic acid and ester sulfate, and can link together to form secreted mucins in the lumen or anchor to intestinal epithelial cells. Cell-associated mucins such as the surficial glycocalyx have unique sea-urchin sperm protein, enterokinase, and agrin (SEA) domains, and two hydrophobic patches on external SEA domains are potential hydrophobic sites for trapping of nanoparticles or macromolecules . In addition to mucins, other compositions such as lipids also exist in mucus layers and, thus, foreign nanoparticles or macromolecular drugs can be trapped in mucus via electrostatic or hydrophobic interactions, eliminate via fast intestinal turnover, and as a result low contact with intestinal cells.…”

Section: Introductionmentioning

confidence: 99%

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Hydrophilic and Electroneutral Nanoparticles to Overcome Mucus Trapping and Enhance Oral Delivery of Insulin

et al. 2020

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The oral delivery of macromolecules using nanoparticles is limited by secreted mucus, resulting in low contact or internalization via intestinal cells and, thus, both mucus trapping and further low cellular uptake need to be overcome. Here, hydrophilic and electroneutral nanoparticles were developed to overcome mucus trapping and enhance the oral delivery of macromolecules. Mesoporous silica nanoparticles (MSNs) were synthesized and modified with a hydrophilic block polymer (poly(lactic acid)−methoxy poly(ethylene glycol), PLA−PEG), and then an overall electroneutrality and promoted cellular uptake were achieved by sequential modification with cell-penetrating peptides (CPPs). Reduced hydrophobic and electrostatic interactions of MSN@PLA−PEG-CPP with mucus decreased mucus trapping by 36.0%, increased the cellular uptake of MSN@PLA−PEG-CPP by 2.3-folds in mucous conditions via active heparan sulfate proteoglycan receptor (HSPG)-mediated and caveolae-mediated endocytosis and electrostatic interactions. Furthermore, insulin, a model macromolecular drug, was successfully loaded into the nanoparticles (INS@MSN@PLA−PEG-CPP). Compared with insulin solution, in vitro cellular uptake in mucous conditions and in vivo pharmacodynamic effects were significantly increased by 9.1-and 14.2-folds, respectively. As well, all nanoparticles with or without insulin loading presented negligible in vitro and in vivo toxicity. Herein, hydrophilic and electroneutral nanoparticles with sequential PEG and CPP modification could promote cellular uptake against mucus trapping and finally show good prospects for oral insulin delivery.

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hydrophilic and Electroneutral Nanoparticles to Overcome Mucus Trapping and Enhance Oral Delivery of Insulin

et al. 2020

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“…Most notably, protein-based therapies are unable to regulate intracellular proteins, including many potential targets identified by disease genetics and recent studies of the mechanisms that regulate immune cell development and function [6-8]. Also, while systemic administration of blocking antibodies or decoy receptors can effectively neutralize individual cytokines in circulation, these effects can be undermined by functional redundancy among inflammatory cytokines or limited delivery of protein-based reagents to mucosal tissues [5,9]. Finally, biopharmaceuticals are expensive to produce and lack oral availability, often necessitating administration by specialists.…”

Section: Introductionmentioning

confidence: 99%

Small-molecule control of cytokine function: new opportunities for treating immune disorders

Sundberg¹,

Xavier²,

Schreiber³

et al. 2014

Current Opinion in Chemical Biology

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Manipulating cytokine function with protein-based drugs has proven effective for treating a wide variety of autoimmune and auto-inflammatory disorders. However, the limited ability of protein-based drugs to modulate intracellular targets, including many implicated by studies of the genetics and physiology of these diseases, and to coordinately neutralize redundant inflammatory cytokines, suggest an important and complementary role for small molecules in immunomodulatory drug development. The recent clinical approval of Janus kinase and phosphodiesterase inhibitors, along with emerging evidence from other compound classes, firmly establish small molecules as effective tools for modulating therapeutically relevant proteins that give rise to aberrant cytokine signaling or mediate its downstream consequences.

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“…[91] They reported an 8000 fold higher in diffusion of 200nm and 500nm PEG-polystyrene in CVM than smaller sized Herpes simplex virus (HSV; 180 nm) of enveloped hydrophobic surfaces. [92][93][94]…”

Section: Muco-adhesive and Muco-penetratingmentioning

confidence: 99%

Studies of insulin transport across intestinal epithelium using nano-encapsulation for oral delivery

Zhang¹

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First, I would like to thank my advisor Professor Subbu S. Venkatraman for providing the opportunity for me to work on this project. His valuable insights and constructive criticisms throughout the course of study has shaped the project in the right direction. I am grateful for his constant help and support whenever I encountered any difficulties. The project would not have been possible without him. Next, I would also like to thank my co-supervisor Professor Bernhard Boehm for his patience in guiding me through the disease fundamental part of the project. I am thankful for his constant sharing of useful resources about the disease fundamentals. I would like to extend my thanks to Assistant Professor Yusuf Ali for his invaluable time in guiding me through the experimental part since the beginning of the project. I would like to thank Dr. Huang yingying for leading the project in the right direction and providng valuable feedbacks through various disscusions throughout my PhD. My appreciation also extends to Dr. Gordon Xiong for sacrificing his time mentoring and discussing with me whenever needed. Also Dr. Lim Wei Shan for helping me during the difficult times of my PhD candidature. My thanks extend to all the members of ADDeC lab including my intern student Abigail Goh and technicians in the Organic Materials Service lab, the FACTS lab. I would like to thank Miss Kathy Wong for helping with the last minute experiments and her time and patience in proof reading my thesis during the thesis submission period. I am also thankful for my scholarship funding from Interdisplinary Graduate School, Health Technologies. I would like to thank Professor Kim Donghwan for bringing me into the field of research and his support while I was working in his lab. I would like to ackowledge

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Mucus as a Barrier for Biopharmaceuticals and Drug Delivery Systems

Cited by 8 publications

References 172 publications

Hydrophilic and Electroneutral Nanoparticles to Overcome Mucus Trapping and Enhance Oral Delivery of Insulin

Hydrophilic and Electroneutral Nanoparticles to Overcome Mucus Trapping and Enhance Oral Delivery of Insulin

Small-molecule control of cytokine function: new opportunities for treating immune disorders

Studies of insulin transport across intestinal epithelium using nano-encapsulation for oral delivery

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