The approval and mass vaccination of two COVID-19 mRNA vaccines have made everyone aware of the great potential of lipid nanoparticles (LNPs) as delivery vehicles. In addition to being used to deliver vaccines, nanoparticle (NP)-based therapies also hold great potential for personalized cancer treatment, with nanoparticles being able to encapsulate a range of goods, including small molecules, biological agents, nucleic acids and more. Thus, nanoparticles loaded with therapeutic drugs can be designed to prevent accidental degradation of therapeutic drugs during delivery, to increase their circulation time in the body, and to specifically deliver drugs to specific tissues such as tumors.
Although using nanoparticles as carriers to deliver anticancer drugs is a potential way to treat cancer and avoid the side effects of chemotherapy, only a few nanoparticle-based anticancer drugs have been approved by the FDA so far.
A major challenge for successful targeted delivery of nanoparticles is that the nanobiological interactions at the target site are not well understood, and the diversity of cancer types and targets means that a full understanding of which nanoparticle properties determine successful delivery and targeting is a formidable challenge.
On July 22, 2022, researchers from the Massachusetts Institute of Technology (MIT) and the Broad Institute published a research paper titled: Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery in the journal Science.
The study analyzed the interactions between 35 different types of nanoparticles and nearly 500 types of cancer cells, revealing thousands of biological features that influence the uptake of different types of nanoparticles by these cancer cells. This study identified the SLC46A3 protein as a negative regulator and potential biomarker of cellular uptake of lipid-based nanoparticles.
These findings help to better tailor drug delivery nanoparticle carriers to specific cancer types, or to customize novel nanoparticle carriers using the cellular biology of specific cancers, to overcome current barriers to the development of nanoparticle-based drugs.
Paula Hammond, the paper's corresponding author and professor at MIT and chair of the Department of Chemical Engineering, said she is excited about the findings, which can be used to determine which types of nanoparticles are suitable for targeting certain cell types, from cancer cells to immune cells and other types of cells of the healthy or diseased organs, and this is only a start.
The Paula Hammond lab has previously developed several types of nanoparticles that can be used to deliver drugs into cells. In further research, they found that different types of cancer cells often showed different responses to the same nanoparticle particles. They believe that biological differences between cells may be responsible for this different response.
To figure out the real reasons behind these different responses, the research team conducted a large-scale study to observe the interactions between a large number of different cells and many different types of nanoparticles.
The research team used the Broad Institute's PRISM platform, which rapidly screens thousands of drugs in hundreds of different cancer cell types simultaneously. The team adapted the PRISM platform from cell-drug interactions to screening cell-nanoparticle interactions to assess whether the genotypic characteristics of cells can predict the uptake of nanoparticles by cells.
The research team used 488 cancer cell lines from 22 different tissues. Each cancer cell type carries a unique "barcode" of DNA sequences so that these cells can be identified in subsequent screening. For each cancer cell type, extensive datasets on its gene expression profile and other biological characteristics are also available.
The researchers constructed 35 different types of nanoparticles, each with a core composed of liposomes, PLGA or polystyrene. The research team also coated these nanoparticles with different types of protective or targeting molecules, examples are polymers such as polyethylene glycol (PEG), antibodies, or polysaccharides, enabling the study of the effects of nanoparticle core components and nanoparticle surface chemistry.
The research team exposed these hundreds of different cancer cells to one of 35 different nanoparticles, each with a fluorescent tag, allowing the cells to be sorted using the amount of fluorescence emitted by the cell sorting technique 4 or 24 hours after exposure. Based on these measurements, each cancer cell line was assigned a score representing its affinity for each nanoparticle. The team then used machine learning algorithms to analyze these scores and all the other biological data available for each cancer cell line to identify the cellular characteristics that mediate nanoparticle transport.
The PRISM platform can help screen interactions between nanoparticles and cancer cells (Image source: Reference )
These analyses yielded thousands of signatures or biomarkers associated with the affinity of different types of nanoparticles. The study found that the main factor determining the uptake of nanoparticles by cancer cells is the core components of the nanoparticles, rather than the surface materials and modifications as previously thought.
And among these cancer cell biomarkers, many are genes encoding the cellular machinery needed to bind nanoparticles, bring them into cells, or dispose of them. Some of these genes are known to be involved in the transport of nanoparticles, but most of the related genes are newly discovered.
The research team selected a newly discovered biomarker, SLC46A3, for further study. SLC46A3 is a lysosomal transporter, and high expression of this protein is associated with low uptake of nanoparticles by cells. This study demonstrates that SLC46A3 protein is a negative regulator and potential biomarker of cellular uptake of lipid-based nanoparticles.
The biological characteristics of different cancer cells determine the degree of nanoparticle absorption (Image source Reference )
The research team further verified this in a mouse model of melanoma, so that the expression level of the SLC46A3 protein can be used as a biomarker to help determine whether cancer patients will respond to nanoparticle-based therapy.
The current FDA-approved nanoparticles for anticancer therapy are all liposomal formulations, therefore, SLC46A3 protein has great potential as a biomarker to help accelerate clinical trials of existing nanoparticles.
According to the research team, the mechanism by which SLC46A3 regulates cellular uptake of nanoparticles is now being explored. If we can find a good way to reduce SLC46A3 protein levels, it will help to improve the efficiency of nanoparticle delivery to cancer cells, thereby helping to better treat cancer.
Finally, the research team concluded that this study represents a high-throughput study exploring nanoparticle-cancer cell interactions through multi-omics. It provides a broad blueprint for the scientific community to study more nanoparticles and other unknown biomarkers, promote nano-biological interaction research, and advance the rational design of nanoparticle carriers.
Nanomedicine may revolutionize cancer immunotherapy, and the continuous development and optimization of nanomedicine by researchers is bound to accelerate the application of nanomedicine in cancer immunotherapy. As a leading and reliable PEG supplier, Biopharma PEG has been focusing on the development of a full range of medical applications and technologies for nanocarrier systems (including various types of nanoparticles, liposomes, micelles, etc.), and it also offers a wide range of PEG-lipid conjugates (DSPE PEG) incorporating various functionalized PEG terminal, like Biotin, Amine, Carboxylic acid, Azide, Aldehyde, Thiol, and Hydroxy.
 How different cancer cells respond to drug-delivering nanoparticles.
 One step closer to cancer nanomedicine.
 Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery.
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