Clickable protein nanocapsules for targeted delivery of recombinant p53 protein
Muxun Zhao1, Yarong Liu, Renee S Hsieh
1Department of Chemical and Biomolecular Engineering and Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
Abstract:
Encapsulating anticancer protein therapeutics in nanocarriers is an attractive option to minimize active drug destruction, increase local accumulation at the disease site, and decrease side effects to other tissues. Tumor-specific ligands can further facilitate targeting the nanocarriers to tumor cells and reduce nonspecific cellular internalization. Rationally designed non-covalent protein nanocapsules incorporating copper-free "click chemistry" moieties, polyethylene glycol (PEG) units, redox-sensitive cross-linker, and tumor-specific targeting ligands were synthesized to selectively deliver intracellular protein therapeutics into tumor cells via receptor-mediated endocytosis. These nanocapsules can be conjugated to different targeting ligands of choice, such as anti-Her2 antibody single-chain variable fragment (scFv) and luteinizing hormone releasing hormone (LHRH) peptide, resulting in specific and efficient accumulation within tumor cells overexpressing corresponding receptors. LHRH-conjugated nanocapsules selectively delivered recombinant human tumor suppressor protein p53 and its tumor-selective supervariant into targeted tumor cells, which led to reactivation of p53-mediated apoptosis. Our results validate a general approach for targeted protein delivery into tumor cells using cellular-responsive nanocarriers, opening up new opportunities for the development of intracellular protein-based anticancer treatment.
Insights
Researchers developed novel nanocapsules for targeted protein delivery to cancer cells. These nanocarriers enhance therapeutic protein accumulation at tumor sites, minimizing side effects and reactivating cancer cell apoptosis.
Area of Science:
- Biotechnology
- Nanomedicine
- Oncology
Background:
- Protein therapeutics offer targeted cancer treatment but face challenges like degradation and systemic toxicity.
- Nanocarriers can improve drug delivery by protecting proteins and concentrating them at disease sites.
- Tumor-specific ligands enhance nanocarrier targeting to cancer cells, reducing off-target effects.
Purpose of the Study:
- To design and synthesize novel non-covalent protein nanocapsules for targeted intracellular delivery of protein therapeutics.
- To incorporate tumor-specific ligands for enhanced selectivity and receptor-mediated endocytosis into cancer cells.
- To evaluate the efficacy of these nanocapsules in delivering therapeutic proteins and inducing apoptosis in tumor cells.
Main Methods:
- Synthesis of nanocapsules using copper-free click chemistry, PEGylation, and redox-sensitive cross-linkers.
- Conjugation of tumor-specific ligands (e.g., anti-Her2 scFv, LHRH peptide) to nanocapsules.
- In vitro and in vivo studies to assess targeting specificity, cellular uptake, and therapeutic protein delivery (e.g., p53).
Main Results:
- Successfully synthesized targeted protein nanocapsules with tunable ligand conjugation.
- Demonstrated specific and efficient accumulation of nanocapsules in tumor cells overexpressing target receptors.
- Showcased selective delivery of therapeutic proteins (p53) leading to reactivation of apoptosis in targeted cancer cells.
Conclusions:
- Validated a versatile platform for targeted intracellular protein delivery using cellular-responsive nanocarriers.
- Opened new avenues for developing advanced intracellular protein-based cancer therapies.
- Highlighted the potential of ligand-conjugated nanocapsules for precise and effective cancer treatment.
