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Dual pH- and Thermo-responsive Supramolecular Nanoparticles for Drug Delivery

Technology

Guanosine-based small molecules self-assemble under temperature or pH stimuli for controlled encapsulation and release of guest molecules

Background

A large number of drugs, including small molecules and proteins exhibit good in vitro activity but little efficacy in vivo due to poor pharmacokinetics. Drug delivery systems based on nanoparticles (NPs) have become one of the most promising strategies to overcome this obstacle. NPs can encapsulate guest small molecules, or even complex macromolecules, and protect them from the surrounding environments (e.g., physiological conditions).

Despite the advantages of NPs for drug delivery, there are challenges associated with the use of typical NPs. For instance, lipid- and polymer-based NPs improve drug efficacy, but still battle important limitations. Lipid-based nanoparticles (LNPs) tend to be unstable during dilution, thus leading to cargo leakage. And, polymer-based nanoparticles (PNPs) often encounter polydispersity (non-uniform distribution of molecules) issues, hampering the purity and reproducibility required to produce clinical grade materials, especially during scale up synthesis.

Technology Overview

The self-assembly of small molecules enables the development of functional NPs with the advantages of simpler synthesis methodologies over LNPs and PNPs. Beside their ease of synthesis, small molecules can be produced in large scales with the required clinical grade purity and reproducibility, and also enable smart adaptative functions since these can be modified and optimized for specific biomedical applications.

This technology relies on the use of small molecules that self-assemble and disassemble in a controlled manner, building uniform and well-defined NPs that overcome polydispersity concerns. Named supramolecular hacky sacks (SHS) due to their architectural features, these NPs are composed of supramolecular G-quadruplexes (SGQs), formed by the self-assembly of amphiphilic guanosine derivatives via non-covalent interactions in the presence of a salt. These non-polymeric supramolecular structures demonstrate properties and applications comparable to those of polymer-based NPs but using small molecules instead for the development of the stimuli-responsive nanocarrier systems. The guanosine derivatives arrange into octameric SGQs (oSGQ) under neutral pH or hexadecameric SGQs (hSGQ) in acidic pH, producing the SHS mesoglobular gel-like structures. Reaching the Lower Critical Solution Temperature (LCST) is another strategy to modulate the oSGQ structures to obtain the hSGQ hydrogel globules (see Figure 1). A fixing process stabilizes the SHS and the resulting f-SHS (fixed SHS) can tolerate a variety of physical manipulations such as dilutions, pipetting, freeze-drying, and media transfers. The SHS can be used for the encapsulation and controlled release of a variety of therapeutic agents such as small molecules, carbohydrates, proteins, and DNA into biological systems, avoiding the cargo leakage after the fixing process.

Further Details:

  • Betancourt JE, Rivera JM (2008) Hexadecameric Self-Assembled Dendrimers Built from 2′-Deoxyguanosine Derivatives. Org Lett 10:2287–2290. https://doi.org/10.1021/ol800701j PMCID: PMC2654094
  • Betancourt JE, Subramani C, Serrano-Velez JL, et al. (2010) Drug encapsulation within self-assembled microglobules formed by thermoresponsive supramolecules. Chem Commun 46:8537. https://doi.org/10.1039/c0cc04063k PMCID: PMC3021979
  • Negrón LM, Díaz TL, Ortiz-Quiles EO, et al. (2016) Organic Nanoflowers from a Wide Variety of Molecules Templated by a Hierarchical Supramolecular Scaffold. Langmuir 32:2283–2290. https://doi.org/10.1021/acs.langmuir.5b03946 PMCID: PMC4896646
  • Santos S, Ramírez M, Miranda E, et al. (2019) Enhancement of Immune Responses by Guanosine-Based Particles in DNA Plasmid Formulations against Infectious Diseases. J Immunol Res 2019:1–15. https://doi.org/10.1155/2019/3409371 PMCID: PMC6556318

Stage of Development

The Technology Readiness Level (TRL) is estimated at 4.

Benefits

  • Irreversible self-assembly
  • Smart adaptive functions
  • Encapsulation and controlled release of therapeutic agents
    • small molecules
    • carbohydrates
    • proteins
    • nucleic acids
  • Easy to synthesize
  • Fully scalable
  • Maintain stability and integrity under manipulations
    • dilutions
    • pipetting
    • freeze-drying
    • transfers between different media

Applications

  • Drug delivery
  • Gene therapy
  • Vaccine adjuvants
  • Biocatalysts
  • Functional nanotechnology

Opportunity

  • Exclusive and non-exclusive licensing