Combinatorially Designed Lipid-like Nanoparticles for Intracellular Delivery of Cytotoxic Protein for Cancer Therapy

• Published in: Angewandte Chemie International Edition Vol. 53; no. 11; pp. 2893 - 2898
• Main Authors: Wang, Ming, Alberti, Kyle, Sun, Shuo, Arellano, Carlos Luis, Xu, Qiaobing
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 10.03.2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Aconitic Acid - analogs & derivatives; Aconitic Acid - chemistry; Alkanes - chemistry; Amines - chemistry; Animals; Antineoplastic Agents - administration & dosage; Cancer; cancer therapy; Cationic; Cell growth; Cell Line, Tumor; Cell Survival - drug effects; Combinatorial analysis; Cytotoxicity; Humans; lipidoids; Lipids - chemistry; Mathematical models; Mice; Nanoparticles; Nanoparticles - chemistry; Neoplasms - drug therapy; Platforms; protein delivery; Proteins; Ribonuclease, Pancreatic - metabolism; Ribonuclease, Pancreatic - therapeutic use; Ribonuclease, Pancreatic - toxicity; Ribosome Inactivating Proteins, Type 1 - metabolism; Ribosome Inactivating Proteins, Type 1 - therapeutic use; Ribosome Inactivating Proteins, Type 1 - toxicity; Tumors; cancer therapy; lipidoids; nanoparticles; protein delivery
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201311245

An efficient and safe method to deliver active proteins into the cytosol of targeted cells is highly desirable to advance protein‐based therapeutics. A novel protein delivery platform has been created by combinatorial design of cationic lipid‐like materials (termed “lipidoids”), coupled with a reversible chemical protein engineering approach. Using ribonuclease A (RNase A) and saporin as two representative cytotoxic proteins, the combinatorial lipidoids efficiently deliver proteins into cancer cells and inhibit cell proliferation. A study of the structure–function relationship reveals that the electrostatic and hydrophobic interactions between the lipidoids and the protein play a vital role in the formation of protein–lipidoid nanocomplexes and intracellular delivery. A representative lipidoid (EC16‐1) protein nanoparticle formulation inhibits cell proliferation in vitro and suppresses tumor growth in a murine breast cancer model. A protein delivery platform that combines a library of lipid‐like nanoparticles and a reversible chemical protein modification approach is presented. With ribonuclease A (RNase A) and saporin as representative cytotoxic proteins, the nanoparticles deliver proteins into cancer cells and inhibit cell proliferation. A representative lipidoid protein nanoparticle formulation inhibits tumor cell proliferation in vitro and suppresses tumor growth.