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Cooperativity Principles in Self-Assembled Nanomedicine

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Cooperativity Principles in Self-Assembled Nanomedicine Review Cite This: Chem. Rev. 2018, 118, 5359−5391 pubs.acs.org/CR Cooperativity Principles in Self-Assembled Nanomedicine † † ‡ † † Yang Li, Yiguang Wang, , Gang Huang, and Jinming Gao*, † Department of Pharmacology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States ‡ Beijing Key Laboratory of Molecular Pharmaceutics and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China ABSTRACT: Nanomedicine is a discipline that applies nanoscience and nano- technology principles to the prevention, diagnosis, and treatment of human diseases. Self-assembly of molecular components is becoming a common strategy in the design and syntheses of nanomaterials for biomedical applications. In both natural and synthetic self-assembled nanostructures, molecular cooperativity is emerging as an important hallmark. In many cases, interplay of many types of noncovalent interactions leads to dynamic nanosystems with emergent properties where the whole is bigger than the sum of the parts. In this review, we provide a comprehensive analysis of the cooperativity principles in multiple self-assembled nanostructures. We discuss the molecular origin and quantitative modeling of cooperative behaviors. In selected systems, we describe the examples on how to leverage molecular cooperativity to design nanomedicine with improved diagnostic precision and therapeutic efficacy in medicine. CONTENTS 4.2.2. Tunable Sol−Gel Transition Temperature 5367 4.3. Thermoresponsive Elastin Like Polypeptides 1. Introduction 5360 (ELPs) 5368 2. Conformation Change-Induced Cooperativity in 4.3.1. Cooperativity in Supramolecular Self- Natural Self-Assembled Nanostructures 5360 Assembly of ELPs 5368 2.1. Self-Organization of Protein and RNA 5360 4.3.2. Tunable Phase Transition Temperature 2.1.1. Protein Folding 5360 of ELPs 5368 2.1.2. Nucleic Acid Folding 5361 4.4. Ultra-pH Sensitive (UPS) Nanoparticles 5370 2.2. Allosteric Cooperativity 5361 4.4.1. Cooperativity in Reversible Protonation 2.2.1. Hemoglobin-Oxygen Binding 5361 of UPS Block Copolymers 5371 2.2.2. Cooperative Enzyme Catalysis 5361 4.4.2. Tunable pKa and pH Transition Sharp- 2.3. Multivalent Cooperativity and Molecular ness 5371 Recognition 5362 4.5. pH-(Low) Insertion Peptides (pHLIPs) 5372 2.4. Biomolecular Condensation and Phase Tran- 5. Molecular Mechanism of Supramolecular Coop- sition-Induced Cooperativity 5362 erativity 5373 3. Noncovalent Interactions: Molecular Basis of 5.1. Origin of Cooperativity 5374 Downloaded via UNIV OF TEXAS SW MEDICAL CTR on March 15, 2019 at 19:43:29 (UTC). Supramolecular Cooperativity 5363 See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. 5.1.1. Cooperative Folding of Proteins 5374 3.1. Hydrophobic Interaction 5363 5.1.2. Cooperative Activation of Ion Channels 5375 3.2. Hydrogen Bonding 5364 5.1.3. Cooperative Dehydration of Thermores- 3.3. Electrostatic Interaction 5364 π−π ponsive Polymers 5375 3.4. Stacking 5364 5.1.4. Hydrophobic Micellization-Driven Coop- 3.5. Cooperativity: Interplay of Noncovalent In- erative Protonation 5375 teractions 5364 5.2. Quantitative Analysis of Cooperativity 5375 4. Phase Transition-Induced Cooperativity in Syn- 6. Supramolecular Cooperativity in Addressing the thetic Self-Assembled Nanostructures 5364 Challenges in Medicine 5378 4.1. Oligonucleotides-Conjugated Gold Nanopar- 6.1. Targeted Drug Delivery 5378 ticles 5364 6.2. Biological Sensing and Molecular Imaging 5378 4.1.1. Cooperativity in Aggregation of Oligo- 6.3. Digitization of pH Signals by Threshold nucleotides-Conjugated Nanoparticles 5365 Sensors 5379 4.1.2. Tunable Phase Transition Temperature 5365 6.4. On Demand Drug Release 5379 4.2. Poly(acrylamide)-Based Thermoresponsive Hydrogels 5366 4.2.1. Cooperativity in Gelation of Thermores- Received: March 27, 2018 ponsive Polymers 5367 Published: April 25, 2018 © 2018 American Chemical Society 5359 DOI: 10.1021/acs.chemrev.8b00195 Chem. Rev. 2018, 118, 5359−5391 Chemical Reviews Review 7. Summary and Future Perspective 5380 Author Information 5382 Corresponding Author 5382 ORCID 5382 Notes 5382 Biographies 5382 Acknowledgments 5382 References 5382 1. INTRODUCTION Nanomaterials are rapidly evolving and impact a broad range of − applications in photonics, electronics, and medicine.1 6 In particular, they play an increasingly important role in medicine, where numerous nanosystems have been developed for biochemical sensing, molecular imaging, disease diagnosis, and − treatment.7 12 Various nanoplatforms have been extensively investigated to address challenges in medicine to overcome deficiencies in conventional small molecular sensors and drugs, resulting in the rapid growth of nanomedicine as a new − discipline.13 15 In contrast to “top-down” methods like lithography, a Figure 1. Supramolecular self-assembly for the development of “bottom-up” approach allows the formation of nanoscopic cooperative nanomedicine. architectures driven by noncovalent self-assembly of molecular 16−18 components. Self-assembly, which bridges the structures of molecules.25 The binding may display either positive or negative individual building blocks and the function of the obtained 19 cooperativity. Positive cooperativity is described as synergistic nanocomplex, is an essential part of nanotechnology. The (whole is bigger than the sum of the parts) and negative underlying supramolecular chemistry principles were described 26 20,21 cooperativity as interfering. In this section, we begin the by Lehn and Whitesides over two decades ago. Compared to discussion of biological cooperativity using well-established covalent chemistry, noncovalent self-assembly employs weak and protein/RNA folding and allosteric examples (e.g., hemoglo- polyvalent interactions to achieve a thermodynamically stable bin-O2 interactions), then move on to more complex multivalent nanostructure. This strategy can produce nanoscopic structures cell surface interactions, and finally present the emerging 4− 10 (10 10 Da) that are not easily synthesizable by covalent microphase separations of large protein signaling complexes. chemistry. The resulting system often has a faster temporal 2.1. Self-Organization of Protein and RNA response to environmental stimuli due to the lower energy fi barrier (e.g., dissociation of noncovalent complexes requires 2.1.1. Protein Folding. Adening characteristic of bio- lower energy than breaking of covalent bonds).22,23 logical systems is their capability to organize small molecular A hallmark of self-assembled systems is molecular coopera- components into supramolecular structures with extraordinary 21 fi tivity, where the system behaves quite differently as a whole precision and delity. Protein folding, where a polypeptide chain self-organizes into a perfectly folded three-dimensional structure, from the sum of parts acting in isolation. Positive cooperativity 27 has been identified in many biological and physiological is a great example. A newly synthesized chain of amino acids processes (e.g., oxygen transport by hemoglobin).24 Mechanistic can form multiple structured assemblies, such as secondary/ investigations on several established self-assembled nanosystems tertiary structures and macromolecular complexes. The pop- ff also suggest that positive cooperativity contributes to enhanced ulations and interconversion of di erent assemblies are governed detection sensitivity and specificity in chemical and biological by thermodynamic and kinetic stabilities. 5 fi sensing. Understanding the supramolecular self-assembly Cooperativity is observed in the nal folding step of proteins ff when the side-chains are locked in the native state and water process and associated cooperativity o ers a new paradigm for 28,29 the design and development of nanomaterials in medicine. molecules are squeezed out of the hydrophobic protein core. In this article, we highlight the recent advances in the The Onuchic group used a minimalist model to search for the intermediate states leading to the native structure in parallel with investigation of cooperativity principles underlying the design of 29 self-assembled nanomedicine (Figure 1). The current review desolvation during protein folding. Their results suggested that focuses on the bottom-up chemistry and material science the majority of the structural formation is accomplished before considerations of nanomedicine. Implementation of a top- water is expelled from the hydrophobic core. In another study, the Bustamante group reported that chain topology impacted the down method for nanomedicine development is beyond the 30 scope of the current review. cooperative folding of proteins. They used an optical tweezer method to selectively unfold specific regions of T4 lysozymes 2. CONFORMATION CHANGE-INDUCED and monitored its perturbation on other regions. Results showed COOPERATIVITY IN NATURAL SELF-ASSEMBLED the topological arrangement of the polypeptide chain is critical in determining the folding cooperativity. Data indicated that NANOSTRUCTURES cooperative interactions among protein domains depend not Cooperativity is frequently employed in biology to modulate only on the local interactions between amino acids but also on molecular recognition through sequential binding events, usually the degree of complementary shape and topography of the operated by the conformational changes of the macro- polypeptide chains. 5360 DOI: 10.1021/acs.chemrev.8b00195 Chem. Rev. 2018, 118,
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