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Multiscale Modeling of Self-Assembled Polymeric Nanocarriers Responding to Specific Protein Stimuli

English title Multiscale Modeling of Self-Assembled Polymeric Nanocarriers Responding to Specific Protein Stimuli
Applicant Pavan Giovanni Maria
Number 175735
Funding scheme Project funding (Div. I-III)
Research institution Dipartimento Tecnologie Innovative (DTI) Scuola universitaria professionale della Svizzera italiana (SUPSI)
Institution of higher education University of Applied Sciences and Arts of Southern Switzerland - SUPSI
Main discipline Material Sciences
Start/End 01.03.2018 - 28.02.2021
Approved amount 351'100.00
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All Disciplines (2)

Material Sciences
Physical Chemistry

Keywords (14)

responsive material; molecular simulation; stimuli responsive; protein-responsive ; molecular modeling; self-assembly; coarse-graining; enzyme-responsive ; nanoparticle; micelle; vesicle; emulsion; drug delivery; smart nanocarrier

Lay Summary (Italian)

La progettazione di materiali sintetici auto-assemblati, stabili in determinate condizioni, ma che disassemblano in risposta a precisi stimoli proteici (interazione con proteine, scissione enzimatica di legami, ecc.), é interessante per varie applicazioni tecnologiche (rilascio controllato di farmaci, diagnostica, ecc.). Ciò aprirebbe la strada a una nuova classe di materiali che interagiscono attivamente e dinamicamente con gli ambienti biologici in modo simile a virus e altri materiali naturali. Tuttavia, l’estrema complessità di questi sistemi rende difficile comprendere i fattori che controllano le loro proprietà. Al fine di ottenere regole chiare per la loro progettazione è necessario comprendere l'effetto dello stimolo proteico sull'assemblaggio a livello molecolare.
Lay summary


Useremo modelli molecolari e simulazioni computazionali per raggiungere tale obiettivo. Ci concentreremo su assemblaggi polimerici (micelle, particelle, etc.) progettati per rispondere a interazioni specifiche con proteine/recettori o enzimi. Le nostre simulazioni molecolari ci forniranno un punto di vista privilegiato sulla destabilizzazione introdotta dagli stimoli negli assemblaggi. I nostri risultati saranno confrontati con gli esperimenti dei nostri collaboratori, fornendo una caratterizzazione completa di questi materiali proteina-responsivi.

Contesto scientifico e sociale

Materiali sintetici che disassemblano a causa di interazioni specifiche con determinate proteine sono interessanti per varie applicazioni. Poiché molte patologie umane sono caratterizzate da squilibri proteici, questo progetto svilupperà conoscenze fondamentali per lo sviluppo di una nuova generazione di nanocarriers per il trasporto di farmaci, biomateriali per ingegneria tissutale, sensori e materiali avanzati bioinspirati.

Direct link to Lay Summary Last update: 27.02.2018

Responsible applicant and co-applicants


Project partner

Associated projects

Number Title Start Funding scheme
162827 Controlling Water-Soluble Supramolecular Polymers - Toward Rational Design Using Molecular Modeling 01.03.2016 Project funding (Div. I-III)


The incorporation of hydrophobic guests (drugs, etc.) into synthetic nanocarriers is often imperative for their delivery. While different types of polymeric self-assembled systems (e.g., micelles, vesicles, etc.) are commonly used for this purpose, these also suffer of typical drawbacks such as limited guest incorporation, loss of the guests during the delivery (weak self-assembly: off-target release), or guest release issues (too strong self-assembly). The design of macromolecular assemblies that are stable in determined conditions, but disassemble in response to precise protein stimuli (protein binding, enzymes, etc.) is extremely interesting for various technological applications (e.g., drug delivery, diagnostics, imaging, etc.). Since most of the human diseases are characterized by protein imbalances, such intelligent materials would allow safe delivery and release of the guests only once the target tissue/cell is reached, maximizing the efficiency and minimizing the side effects. Amphiphilic polymers, dendrimers, dendrons, etc. are ideal self-assembling candidates for this purpose, as these allow high-control over molecular structure, providing the unique opportunity to study structure-property relationships at the molecular level. However, due to the extreme complexity of the self-assembling systems, the design principles to control the final properties are often unclear. Molecular simulation is a fundamental support in this field. Recently, we have designed a modeling approach to study the responsive self-assembly of amphiphilic dendrons in solution (J. Am. Chem. Soc. 2014, 136, 5385-5399). Focusing on an interesting test case, an assembly of biotin-functionalized dendrons that disassembles and releases the molecular cargo upon specific binding with avidin, our all-atom molecular dynamics simulations provided detailed description of the effect of the specific protein binding on the assembly stability, and a molecular-level rationale to understand the responsive nature of these assemblies. This proposed new directions for further broader investigations.In this project we aim at expanding our modeling approach to study supramolecular assemblies made of various amphiphilic polymeric units (copolymers, dendrimers/dendrons, homopolymers, etc.), designed to respond essentially to two different types of protein stimuli:•Specific binding with precise receptors present on the cell surface: Undestanding the mechanisms controlling binding-induced disassembly is an important step toward the rational design of nanocarriers that efficiently target specific tissues/cells and release the guests at the pathological site in controlled way (outside/inside cells)•Enzymatic cleavage of some key groups in the self-assembling units: We are interested in understanding the effect of the enzyme stimulus on the assembly, and how to control the enzyme-triggered disassembly process (responsiveness) changing the structure of the self-assembling units or the external conditionsWe devised different in silico experiments based on the development of ad hoc atomistic and coarse-grained models to tackle these two points in systematic way. The modeling strategy presented herein will provide a multiscale description of the mechanisms controlling dendron self-assembly and protein-induced disassembly. Our computational work will also benefit from the precious collaboration with the experimental groups of Prof. S. Thayumanavan (University of Massachusetts, Amherst, US) and Prof. Roey J. Amir (Tel Aviv University, IL), leading experts in the field of stimuli-responsive supramolecular polymer structures. The results of this project will remarkably advance the field of responsive materials, and will constitute a first key step toward the rational design of smart nanocarriers.