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Cited by 127Nanoparticle-Based Drug DeliveryRNA Interference and Gene DeliveryUltrasound and Hyperthermia Applications

Binding and interstitial penetration of liposomes within avascular tumor spheroids

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Kostarelos, Kostas, Emfietzoglou, Dimitris, Papakostas, Alexandros, Yang, Wei‐Hong, Ballangrud, Åse, Sgouros, George·2004·International Journal of Cancer
DOI 10.1002/ijc.20457
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Abstract

The liposomal delivery of cancer therapeutics, including gene therapy vectors, is an area of intense study. Poor penetration of liposomes into interstitial tumor spaces remains a problem, however. In this work, the penetration of different liposomal formulations into prostate carcinoma spheroids was examined. Spheroid penetration was assessed by confocal microscopy of fluorescently labeled liposomes. The impact of liposomal surface charge, mean diameter, lipid bilayer fluidity and fusogenicity on spheroid penetration was examined. A variety of different liposome systems relevant to clinical or preclinical protocols have been studied, including classical zwitterionic (DMPC:chol) and sterically stabilized liposomes (DMPC:chol:DOPE‐PEG 2000), both used clinically, and cationic liposomes (DMPC:DOPE:DC‐chol and DOTAP), forming the basis of the vast majority of nonviral gene transfer vectors tested in various cancer trials. Surface interactions between strongly cationic vesicles and the tumor cells led to an electrostatically derived binding‐site barrier effect, inhibiting further association of the delivery systems with the tumor spheroids (DMPC:DC‐chol). However, inclusion of the fusogenic lipid DOPE and use of a cationic lipid of lower surface charge density (DOTAP instead of DC‐chol) led to improvements in the observed intratumoral distribution characteristics. Sterically stabilized liposomes did not interact with the tumor spheroids, whereas small unilamellar classical liposomes exhibit extensive distribution deeper into the tumor volume. Engineering liposomal delivery systems with a relatively low charge molar ratio and enhanced fusogenicity, or electrostatically neutral liposomes with fluid bilayers, offered enhanced intratumoral penetration. This study shows that a delicate balance exists between the strong affinity of delivery systems for the tumor cells and the efficient penetration and distribution within the tumor mass, similar to previous work studying targeted delivery by ligand‐receptor interactions of monoclonal antibodies. Structure‐function relationships from the interaction of different liposome systems with 3‐dimensional tumor spheroids can lead to construction of delivery systems able to target efficiently and penetrate deeper within the tumor interstitium and act as a screening tool for a variety of therapeutics against cancer. © 2004 Wiley‐Liss, Inc.

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  • Organoids are embedded in extracellular matrix, which constitutes a barrier for efficient transfection.

    “One limitation is that organoids are embedded in extracellular matrix and grow into compact structures that hinder transfection using traditional techniques.”

    From Direct transfection of clonal organoids in Matrigel microbeads: a promising approach toward organoid-based genetic screens (2018) · cites this paper as [7]

    The paper’s introductory passage (indexed under Abstract; page not supplied) says tumor spheroids contain extracellular matrix, and its Abstract and Discussion report barriers to liposome penetration into those spheroids. It does not study organoids or establish that extracellular matrix is the barrier to their transfection; the barrier it identifies for strongly cationic liposomes is electrostatic binding at the spheroid surface. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Organoids grow into dense and compact structures that impede diffusion, penetration and cellular accumulation of genetic material, making transfection via traditional techniques difficult.

    “Moreover, organoids grow into dense and compact structures that impede diffusion, penetration and cellular accumulation of genetic material, which makes transfection via traditional techniques difficult (7–9).”

    From Direct transfection of clonal organoids in Matrigel microbeads: a promising approach toward organoid-based genetic screens (2018) · cites this paper as [7]

    The Abstract and Discussion (page numbers unavailable) describe three-dimensional tumor spheroids and show that some liposomes penetrate only their outer cell layers; the paper also identifies cationic liposomes as gene-delivery vectors. It studies tumor spheroids, not organoids, and does not show that genetic material fails to accumulate in cells or that traditional transfection techniques are difficult to use in organoids. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Direct 3D transfection on already formed organoids remains challenging.

    “However, direct 3D transfection on already formed organoids remains challenging.”

    From Direct transfection of clonal organoids in Matrigel microbeads: a promising approach toward organoid-based genetic screens (2018) · cites this paper as [7]

    The Abstract says poor liposome penetration into tumor tissue remains a problem, and the Results show that some liposomes remained at the surface of already formed 3D tumor spheroids. This supports a delivery challenge, but the paper measures liposome binding and penetration in spheroids, not transfection success in organoids; its findings do not establish the claim at that broader level. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Lipofection and electroporation have been proven relatively inefficient in transfecting 3D cultures, with transfection efficiencies lower than 5% and 20%, respectively.

    “However, they have been proven to be relatively inefficient in transfecting 3D cultures with transfection efficiencies lower than 5 and 20%, respectively (7–9).”

    From Direct transfection of clonal organoids in Matrigel microbeads: a promising approach toward organoid-based genetic screens (2018) · cites this paper as [7]

    The Results and Discussion examine how liposomes bind to and penetrate prostate tumor spheroids, not how efficiently lipofection or electroporation transfects 3D cultures. Searches for electroporation and the stated 5% and 20% transfection efficiencies found no passage supporting those figures in our copy. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Authors
Kostarelos, K., Emfietzoglou, D., Papakostas, A., Yang, W., Ballangrud, Å., & Sgouros, G.
Affiliations
  • Imperial College London (GB)
  • University of Ioannina (GR)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Sgouros, George
ORCID
Venue
International Journal of Cancer
Publisher
Wiley
Published
2004-06-30
Volume
112
Issue
4
Pages
713-721
ISSN
  • 0020-7136 (ISSN-L)
  • 1097-0215
DOI
10.1002/ijc.20457
OpenAlex
W2096391616
Cited by
127
References
65
Citations by year
2025: 5 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 11 · 2020: 8 · 2019: 8 · 2018: 6 · 2017: 6 · 2016: 5 · 2015: 10 · 2014: 9 · 2013: 7 · 2012: 7
FWCI
1.82
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • International Journal of Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • National Institutes of Health (5r01ca072683-03)
  • National Cancer Institute (R01CA62444, R01 CA72683, R01CA062444)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
Keywords
liposomal drug delivery, tumor spheroids, electrostatic interactions, surface charge, DOTAP, cationic liposomes, PEGylated liposomes, lipid bilayer fluidity, prostate cancer, intratumoral distribution
MeSH terms
Antibodies, Monoclonal, Engineering, Humans, Ligands, Liposomes, Male, Neoplasm Metastasis, Prostatic Neoplasms, Tumor Cells, Cultured, Drug Design, Drug Delivery Systems, Spheroids, Cellular

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