Run Meng, Shilei Hao, Changfa Sun, Zongkun Hou, Yao Hou, Lili Wang, Peiying Deng, Jia Deng, Yaying Yang, Haijian Xia, Bochu Wang, Rui Qing, Shuguang Zhang. "Reverse-QTY code design of active human serum albumin self-assembled amphiphilic nanoparticles for effective anti-tumor drug doxorubicin release in mice." PNAS.
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Publication
Reverse-QTY code design of active human serum albumin self-assembled amphiphilic nanoparticles for effective anti-tumor drug doxorubicin...
Abstract
Reverse-QTY code design of active human serum albumin self-assembled amphiphilic nanoparticles for effective anti-tumor drug doxorubicin release in mice
Human serum albumin (HA) is a highly water-soluble protein with 67% alpha-helix content and 3 distinct domains (I, Il and III). HSA offers a great promise in drug delivery with enhanced permeability and retention effect. But it is hindered by protein denaturation during drug entrapment or conjugation that result in distinct cellular transport pathways and reduction of biological activities. Here we report using a protein design approach named reverse-QTY (QTY) code to convert specific hydrophilic alpha-helices to hydrophobic to alpha-helices. The designed HSA undergo self-assembly of well-ordered nanoparticles with highly biological actives. The hydrophilic amino acids, asparagine (N), glutamine (Q), threonine (T), and tyrosine (Y) in the helical B-subdomains of HSA were systematically replaced by hydrophobic leucine (L), valine (V), and phenylalanine (F). HSArQTY nanoparticles exhibited efficient cellular internalization through the cell membrane albumin binding protein GP60, or SPARC (secreted protein, acidic and rich in cysteine) mediated pathways. The designed HSAQTY variants displayed superior biological activities including: i) encapsulation of drug doxorubicin, i) receptor-mediated cellular transport, iii) tumor cell-targeting and iv) anti-tumor efficiency compare to denatured HA nanoparticles. HSArQTY nanoparticles provided superior tumor targeting and anti-tumor therapeutic effects compared to the albumin nanoparticles fabricated by antisolvent precipitation method. We believe that the rQTY code is a robust platform for specific hydrophobic modification of functional hydrophilic proteins with clear-defined binding interfaces.
Why this research matters
QTY code has been successfully used to significantly improve the solubility of water-insoluble integral transmembrane proteins. They include G protein-coupled receptors (GPCRs), cytokine receptors, glucose transporters, and solute carrier transporters through systematically replacing the hydrophobic leucine (L), valine (V), isoleucine (I), and phenylalanine (F) in the transmembrane domains by glutamine (Q), threonine (T), and tyrosine (Y).
Here we reverse the QTY code as the rQTY code to improve the hydrophobicity of the specific alpha-helices on HSA for self-assembly into well-defined nanoparticles. The rQTY code has significant implications for design of specific hydrophobic domains of highly water-soluble proteins to design their self-assembly for diverse applications including encapsulate hydrophobic drugs, receptor-mediated sustained drug release, and target drug transport across cell membranes.
Researchers have been doing controlled and sustained drug delivery for over four decades. These delivery technologies can be called “general delivery,” namely, the molecular medicine can be sustained and controlled delivery into the body for weeks, months, perhaps even years. These molecular drugs can go to most parts of the body. The current PNAS paper report is for “specific delivery” through the specific receptor-mediate delivery, like UPS or USPS delivery follows the specific zip code and specific location address. This current research could open a new avenue of study that will eventually lead to more targeted delivery to treat particularly diseased cells.
Image caption: Reverse-QTY designed HSA nanoparticle is a specific receptor-mediated cellular internalization and tumor targeting through the cell receptor GP60 together with SPARC pathways. a, The reverse-QTY code how each amino acid is changed from water-soluble Q, N, T, Y to water-insoluble L, V, F. b, Self-assembly of rQTY-designed HSA into defined nanoparticles for spontaneous encapsulating anti-cancer drug. c, How these HSArQTY nanoparticles enter the blood vein circulation. d, Cellular transport of HSArQTY nanoparticle specifically mediated by the GP60 cell surface receptor. e, HSArQTY nanoparticle deliver the drug to tumor cells through the SPARC-dependent pathway.