Prolonged intracellular accumulation of light-inducible nanoparticles in leukemia cells allows their remote activation
Open accessAbstract
Leukaemia cells that are resistant to conventional therapies are thought to reside in protective niches. Here, we describe light-inducible polymeric retinoic acid (RA)-containing nanoparticles (NPs) with the capacity to accumulate in the cytoplasm of leukaemia cells for several days and release their RA payloads within a few minutes upon exposure to blue/UV light. Compared to NPs that are not activated by light exposure, these NPs more efficiently reduce the clonogenicity of bone marrow cancer cells from patients with acute myeloid leukaemia (AML) and induce the differentiation of RA-low sensitive leukaemia cells. Importantly, we show that leukaemia cells transfected with light-inducible NPs containing RA can engraft into bone marrow in vivo in the proximity of other leukaemic cells, differentiate upon exposure to blue light and release paracrine factors that modulate nearby cells. The NPs described here offer a promising strategy for controlling distant cell populations and remotely modulating leukaemic niches.
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Light-activatable nanoparticles containing RA that disassemble in minutes after activation by a blue laser at 405 nm have been prepared.
“In that sense, light-activatable nanoparticles containing RA that disassemble in minutes after activation by a blue laser at 405 nm have been prepared25,26,60.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
Uptake between 25 and 80 pg of nanoparticles containing RA per cell has been described.
“Uptake between 25 and 80 pg of nanoparticles containing RA per cell has been described25.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
Formulations that escaped the endolysosomal compartment accumulated in the cytoplasm in less than 24 h.
“Formulations that escaped the endolysosomal compartment accumulated in the cytoplasm in less than 24 h25,45.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
The intracellular concentration of formulations containing RA was dependent on the initial formulation loading, type of formulation, and type of cell.
“The intracellular concentration of formulations containing RA was dependent on the initial formulation loading, type of formulation, and type of cell25,45.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
The cellular uptake of some RA-containing nanoparticles has been demonstrated to take <12 h by clathrin-mediated endocytosis and macropinocytosis.
“The cellular uptake of some RA-containing nanoparticles has been demonstrated to take <12 h44 by clathrin-mediated endocytosis and macropinocytosis25.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
Light-activatable formulations presented higher activity than formulations in which RA was released by passive diffusion because they rapidly saturated nuclear receptors.
“Importantly, these formulations presented higher activity than formulations in which RA was released by passive diffusion (not light triggered) because they rapidly saturated nuclear receptors.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
In vitro tests showed that ATRA-containing liposomes or ATRA-containing polymeric nanoparticles were 100-1000 times more active than soluble ATRA in cultured tumor cells or neural stem cells.
“In vitro tests showed that ATRA-containing liposomes69 or ATRA-containing polymeric nanoparticles25,44 were 100–1000 times more active than soluble ATRA in cultured tumor cells25,69 or neural stem cells (NSC)44.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
The formulation was highly internalized by leukemia-initiating cells and accumulated in the cell cytoplasm.
“The formulation was highly internalized by leukemia-initiating cells and accumulated in the cell cytoplasm.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
Irradiation of bone marrow with a blue light induced photo-disassembly of the nanoparticles within the cells and consequently their differentiation.
“The irradiation of bone marrow with a blue light induced photo-disassembly of the nanoparticles within the cells and consequently their differentiation.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
Once leukemia-initiating cells transfected with light-activatable nanoparticles containing RA were administered intravenously in leukemic mice they tend to home in the bone marrow, in the proximity of other leukemia cells.
“Once leukemia-initiating cells transfected with light-activatable nanoparticles containing RA were administered intravenously in leukemic mice they tend to home in the bone marrow, in the proximity of other leukemia cells.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
These cells then secreted extracellular vesicles containing ATRA that interfered with cells supporting the stem cell niche.
“These cells then secreted extracellular vesicles containing ATRA that interfered with cells supporting the stem cell niche.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
We have developed a new platform to target bone marrow, based on light-activatable nanoparticle formulations containing ATRA.
“Recently, we have developed a new platform to target bone marrow, based on light-activatable nanoparticle formulations containing ATRA25,26.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
Linkers may be cleaved by an external trigger such as light, with consequent release of RA.
“In addition, linkers may be cleaved by an external trigger, such as light with the consequent release of RA25,26.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [25]
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References 36 · Cited by 28
- Authors
- Boto, C., Quartin, E., Cai, Y., Martín-Lorenzo, A., Cenador, M. B. G., Pinto, S., Gupta, R., Enver, T., Sánchez-García, I., Hong, D., Pires das Neves, R., & Ferreira, L.
- Affiliations
- University of Coimbra (PT)
- Shanghai Jiao Tong University (CN)
- Universidad de Salamanca (ES)
- University College London (GB)
- Corresponding author
- Ferreira, Lino
- Venue
- Nature Communications
- Published
- 2017-05-11
- Volume
- 8
- Issue
- 1
- Pages
- 15204-15204
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5437273
- OpenAlex
- W2613011298
- Cited by
- 28
- References
- 36
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 1 · 2018: 4
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by)
- Funders
- Cancer Research UK (12796)
- CHILDREN with CANCER UK (17-250)
- Medical Research Council (MR/M009033/1, MR/N000838/1)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- retinoic acid, acute myeloid leukemia, leukemia cells, remote activation, blue light, ultraviolet radiation, bone marrow engraftment, leukemia microenvironment, paracrine signaling, clonogenicity, differentiation therapy, polymeric nanoparticles
- MeSH terms
- Aged, Aged, 80 and over, Animals, Benzene Derivatives, Drug Compounding, Female, Formates, Humans, Leukocytes, Light, Male, Polyethyleneimine, Tretinoin, Leukemia, Promyelocytic, Acute, Mice, Inbred NOD, Photosensitizing Agents, U937 Cells, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Nanoparticles, Human Umbilical Vein Endothelial Cells
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