Macromolecular machines for highly targeted cancer drug delivery
Dr Cham-fai Leung has developed macromolecules with ‘mechanical arms’ that can actively control the delivery of drugs released to targeted cancer cells.
In a recent study published in Nature Communications, Dr Cham-fai Leung (Croucher Fellowship 2003) and his team from Hong Kong Baptist University have designed and synthesised a smart globular macromolecular machine vehicle that helps deliver cancer drugs specifically to tumour sites.
Molecular machines are assembled with their molecular counterparts that are responsive to specific stimuli (input) and produce mechanical movements (output). Rotaxane dendrimers are molecular interlocked molecules that combine hyperbranched macromolecules with molecular machines. Among various types of rotaxane dendrimer, type III-B possesses the most complicated molecular structure and exhibits the largest extension-contraction properties.
Current leukemia treatment can only kill leukemia cells present in blood and bone marrow, but not free-floating cancer cells in elsewhere.
By using molecular machines for delivering drug cargo, free-floating cancer cells can be targeted as these cells offer different inputs than normal tissue, thus enhancing drug efficacy.
The team reported a series of novel hyperbranched macromolecules with at most 15 mechanical bonds at the branching unit. Mechanical bonds are a novel and exciting class of non-covalent bonds similar to chains and hooks. These macromolecules can induce an overall extension-contraction molecular motion via collective and controllable molecular back-and-forth shuttling, providing the ability to encapsulate drug molecules and release them actively by acidic stimuli.
“In current leukemia treatment, drugs are delivered to kill leukemia cells that may be present in the blood and bone marrow. However, the amount of drugs released to kill the free-floating cancer cells cannot be effectively controlled,“ said Dr Leung. “The 15 mechanical bonds resemble 15 mechanical arms that actively control the delivery and amount of drugs released to targeted cancer cells.”
Dr Leung added that this smart material combines molecular machines and dendrimers with a new breakthrough in synthesis as well as controlled and active drug release. With its complexity and size, this synthetic molecule resembles a small virus. Due to the relatively low toxicity of this smart globular molecular vehicle, it can also serve as a potential ideal long-term drug delivery molecular machine submerged in the human body. The molecular masses of these new macromolecules were characterised by mass spectrometry, and their chemical structures and physical properties were also verified with supercomputer simulations.
This breakthrough gives insight to targeted therapy drugs such as Chlorambucil in the treatment of leukemia. The researchers hope that their method of synthesis and control of particle size will be useful for the development of more sophisticated molecular machines to be applied in functional materials and nanotechnology.
To view Dr Leung's Croucher profile, please click here.