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Contact-dependent signaling, as the name suggests, requires that communicating cells be in direct contact with each other. This is achieved either through receptor-ligand interactions or by specialized cytoplasmic channels that allow the flow of small molecules between cells. In animal cells, channels called gap junctions facilitate contact-dependent signaling in certain tissues, whereas, plasmodesmata perform a similar function in plants.
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Multicellular organisms employ a variety of ways for cells to communicate with each other. Gap junctions are specialized proteins that form pores between neighboring cells in animals, connecting the cytoplasm between the two, and allowing for the exchange of molecules and ions. They are found in a wide range of invertebrate and vertebrate species, mediate numerous functions including cell differentiation and development, and are associated with numerous human diseases, including cardiac and...
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Drugs need to permeate cell membranes to reach their target sites after administration. Orally administered drugs must transcend intestinal epithelial membrane barriers to infiltrate the systemic circulation. Drugs with a molecular weight of less than 500 Daltons diffuse through gaps between neighboring cells, called paracellular pathways.
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Drug delivery methods like oral inhalation, nasal sprays, transdermal patches, eye drops, intravitreal injection,  and rectal administration provide localized effects with reduced toxicity.
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The selection of a drug's delivery route depends upon its physicochemical properties, including lipid or water solubility and ionization, as well as the therapeutic requirement, such as immediate or sustained effect. These routes can be divided into three primary categories: enteral, parenteral, and topical.
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Drugs must traverse multiple biological barriers, such as multi-layered skin, single-layered intestinal epithelium, and the plasma membrane, to reach their target sites within the body. The plasma membrane, a highly structured composite of phospholipids, carbohydrates, and proteins, is the cell's protective boundary, facilitating selective substance exchange.
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Cell Squeezing as a Robust, Microfluidic Intracellular Delivery Platform
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Gap Junction-Mediated Delivery of Polymeric Macromolecules.

Andrea N Trementozzi1, Chi Zhao1, Hugh Smyth2

  • 1Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States.

ACS Biomaterials Science & Engineering
|March 10, 2022
PubMed
Summary

Gap junctions facilitate the transfer of large molecules like dextran (up to 40 kDa) between cells. Cell-derived vesicles called connectosomes efficiently deliver these membrane-impermeable molecules into the cell cytosol.

Keywords:
cellular deliveryconnectosomesconnexinsconnexon hemichannel poresgap junctionpolymeric macromolecules

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Area of Science:

  • Cell Biology
  • Biotechnology
  • Molecular Medicine

Background:

  • Cellular delivery of therapeutic macromolecules is hindered by inefficient plasma membrane transport.
  • Gap junction channels, formed by connexin proteins, enable small molecule transfer.
  • Emerging evidence suggests potential for larger molecule transfer, like microRNAs, via gap junctions.

Purpose of the Study:

  • To provide direct evidence for gap junction-mediated transfer of polymeric macromolecules.
  • To investigate the transport capacity of dextran chains through gap junctions.
  • To evaluate the efficacy of connectosomes in delivering macromolecules into cells.

Main Methods:

  • Examined dextran chain transport (10-70 kDa) across multiple cell layers.
  • Assessed dextran loading into connectosomes by opening connexon hemichannel pores.
  • Compared cytosolic delivery efficiency of dextran-loaded connectosomes versus free dextran.

Main Results:

  • Dextran chains up to 40 kDa diffused through five cell layers in a gap junction-dependent manner within 30 minutes.
  • 10 kDa dextran loaded into over 90% of connectosomes, with decreased loading for larger chains.
  • Connectosomes significantly enhanced delivery of 10 kDa dextran into the cellular cytosol compared to free dextran.

Conclusions:

  • Polymeric macromolecules can be delivered into cells via gap junctions.
  • The gap junction pathway offers a promising route for therapeutic delivery of nucleic acids and peptides.
  • Connectosomes represent an effective vehicle for intracellular delivery of membrane-impermeable molecules.