Nanoparticle treatment starves cancer cells effectively
Researchers at the LKS Faculty of Medicine, the University of Hong Kong (HKUMed), have pioneered a new cancer-treatment strategy that amplifies cancer cell starvation for amino acids.
The study found that cancer cells can survive in nutrient-deprived environments by internalizing extracellular proteins via macropinocytosis and degrading them through the proteasomal pathway. Leveraging this discovery, the HKUMed researchers engineered pH-responsive polymeric nanoparticles that release drugs to block both protein uptake and degradation, effectively achieving tumor starvation therapy.
The research findings were published in Advanced Science and a US patent application has been filed.
According to Hong Kong Cancer Statistics of 2022 from the Hong Kong Cancer Registry, lung cancer remains the most prevalent malignancy, accounting for 16.1% of all new cancer cases in Hong Kong. Tumors with poor blood supply often exhibit nutrient-deficient microenvironments, lacking critical resources like amino acids and glucose.
Previous studies indicated that cancer cells can scavenge extracellular proteins for survival through the lysosomal pathway, providing a source of amino acids for the cancer cells. However, whether other protein degradation systems also play a role in the utilization of extracellular nutrients remained unclear.
The research team identified the macropinocytosis-proteasome pathway as a compensatory system for extracellular protein metabolism in cancer cells.
Under amino acid starvation, cancer cells activated macropinocytosis to engulf extracellular proteins and degraded them via proteasomes. To disrupt this process, the research team developed pH-responsive nanoparticles for the co-delivery of macropinocytosis inhibitors and proteasome inhibitors.
In an experiment, the nanoparticles were injected into a lung tumor-bearing mouse model. The research team found that the nanoparticles effectively released drugs to simultaneously inhibit protein internalization and proteasomal degradation in acidic tumor microenvironments, achieving synergistic tumor starvation.
Professor Wang Weiping, Associate Professor in the Department of Pharmacology and Pharmacy and the Dr. Li Dak-Sum Research Center at HKUMed, and Principal Investigator of the State Key Laboratory of Pharmaceutical Biotechnology, said, "Our work has uncovered the macropinocytosis-proteasome axis as another critical nutrient supply route for extracellular protein uptake and degradation—distinct from the classical lysosomal degradation pathway.
"This finding reveals the macropinocytosis-proteasome system as a novel therapeutic target for starvation therapy."
To expedite the clinical translation of this strategy, the research team developed novel pH-responsive polymeric nanoparticles that suppress the amino acid level in cancer cells, thereby achieving therapeutic tumor starvation.
He added, "Our pH-responsive nanoparticles offer a new strategy for blocking cancer nutrient scavenging, thus advancing precise starvation therapy."
More information:
Tianyi Wang et al, Amino Acid‐Starved Cancer Cells Utilize Macropinocytosis and Ubiquitin‐Proteasome System for Nutrient Acquisition, Advanced Science (2023). DOI: 10.1002/advs.202304791
Provided by The University of Hong Kong
