Encapsulation and delivery of antitumor therapeutics is one of the challenges in targeted drug delivery.  We have exploited a 25-nm dodecahedron protein nanoparticle from the E2 subunit of pyruvate dehydrogenase to develop a universal strategy for encapsulating drug molecules through only non-covalent interactions. To enhance molecular encapsulation capacity for the model antitumor drug doxorubicin, a biomimetic hydrophobic microenvironment was engineered within the E2 scaffold cavity by mutating native hydrophilic residues to phenylalanines. The mutation sites were selected based on molecular structure modeling and computational analysis.  The resultant scaffold exhibited over a 35-fold increase in drug encapsulation relative to native E2 scaffold,  yielding high drug loading levels compared to conventional nanoparticle delivery systems.  Doxorubicin-loaded E2 nano-capsule demonstrated significant cellular uptake.  Intracellular release was shown by cytotoxicity against breast cancer cells, with an IC50 of 0.33 � 0.12 mM. Our novel protein engineering approach shows the promise of utilizing hydrophobic interactions to fabricate protein nano-capsule for molecular encapsulation and transport.

Design of a hydrophobically-enhanced protein nanocapsule for molecular encapsulation and transport

243rd National Meeting (2012)

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