Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Jan 22;13(2):141.
doi: 10.3390/pharmaceutics13020141.

Molecular Modelling Guided Modulation of Molecular Shape and Charge for Design of Smart Self-Assembled Polymeric Drug Transporters

Sousa Javan Nikkhah  1 , Damien Thompson  1
Affiliations
Review

Molecular Modelling Guided Modulation of Molecular Shape and Charge for Design of Smart Self-Assembled Polymeric Drug Transporters

Sousa Javan Nikkhah et al. Pharmaceutics. .

Abstract

Nanomedicine employs molecular materials for prevention and treatment of disease. Recently, smart nanoparticle (NP)-based drug delivery systems were developed for the advanced transport of drug molecules. Rationally engineered organic and inorganic NP platforms hold the promise of improving drug targeting, solubility, prolonged circulation, and tissue penetration. However, despite great progress in the synthesis of NP building blocks, more interdisciplinary research is needed to understand their self-assembly and optimize their performance as smart nanocarriers. Multi-scale modeling and simulations provide a valuable ally to experiment by mapping the potential energy landscape of self-assembly, translocation, and delivery of smart drug-loaded NPs. Here, we highlight key recent advances to illustrate the concepts, methods, and applications of smart polymer-based NP drug delivery. We summarize the key design principles emerging for advanced multifunctional polymer topologies, illustrating how the unusual architecture and chemistry of dendritic polymers, self-assembling polyelectrolytes and cyclic polymers can provide exceptional drug delivery platforms. We provide a roadmap outlining the opportunities and challenges for the effective use of predictive multiscale molecular modeling techniques to accelerate the development of smart polymer-based drug delivery systems.

Keywords: cyclic polymers; dendritic polymers; molecular modeling; polyelectrolytes; self-assembly; smart drug nanocarriers.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic structure of (a) “star burst” dendrimer (of generation 4, G4), (b) hyperbranched polymer, (c) dendrimer multi-arm copolymer, (d) polyelectrolyte (polycation and polyanion) chains, and (e) cyclic polymer.
Figure 2
Figure 2
(a) Triethanolamine (TEA)-core dendrimer (top left), NH3-core dendrimer (top right) in complex with a small fragment of double-helix DNA (highlighted as a magenta ribbon). Mesoscale morphologies of the self-assembled systems between TEA-core dendrimers and DNA (bottom left) and NH3-core and DNA (bottom right) [143]. (b) Evolution of the radius of gyration (Rg) of ssDNA and G4 PAMAM dendrimer at various pH values [144]. (c) Chemical structures of dendrimer and drug molecules in DPD simulation (left), their corresponding simplified beads in the coarse-gained models (middle), and the computed G5-PEG/DOX microspheres (right) [147].
Figure 3
Figure 3
(a) Self-assembly mechanism of the microphase separated small micelle with a spherical-to-cone microphase separation [148] and inset (b) morphological phase diagram of aggregates formed from A42B20 in selective solvents as a function of the interaction parameters. A bead is hydrophobic and B bead is hydrophilic [149].
Figure 4
Figure 4
(a) Schematic of self-assembly of nanoarchitectures from Janus dendrimers and the corresponding structure–concentration phase diagram for amphiphilic dendrimer aqueous solutions [150]. (b) Self-assembled morphologies by various Ca-POSSb-PEGc polymers observed by microscopy (top, with zoom-in on nanoscopic feature in the middle panel) and corresponding DPD modelling images of self-assemblies by the amphiphilic polymers at the initial polymer concentration of 1 mg/mL in aqueous solutions (bottom) [153]. (c) Typical calculated states of the interactions between a lipid bilayer membrane and a PAMAM dendrimer conjugated with ligands. The receptor density of the membrane is fixed at fR = 0.33. The surface tension of the membrane, σ, and the ligand density of the dendrimer, fL, are (top left) σ = 2.09 kBT/rc2 and fL = 0.1, (top right) σ = 0.10 kBT/rc2 and fL = 0.4, (bottom left) σ = −0.65 kBT/rc2 and fL = 0.6, and (bottom right) σ = 1.10 kBT/rc2 and fL = 0.8. Color scheme: lipid head beads (pink), lipid tail beads (cyan), receptor beads (green), charged beads of dendrimer (red), uncharged beads of dendrimer (yellow), and ligand beads (blue) [156].
Figure 5
Figure 5
(a) Computed protein–carrier structures made from poly(styrene sulfonate) (PSS) and polyphosphate (PP), showing PSS5 (top left) and protein-PSS45 (top right) complexes. The polyanion is shown in sticks, the protein is shown in surface representation and colored according to electrostatic potential. The number of bound and unbound repeat units of PP (middle) or PSS (bottom) chains (n is a degree of polymerization) is plotted underneath [191]. (b) Morphological phase diagram of the PE–drug complexes characterized using drug hydrophobicity εd and PE-drug valence ratio Zp:Zd. [192].
Figure 6
Figure 6
(a) Representative computed self-assembled multimeric units of 39 cationic functionalized CD molecules around siRNA [224]. (b) Computed di-oleoyl-glycerolipidyl-β-cyclodextrin–atazanavir (DOCD–ATAZ) (2:1) complex after 100 ns of MD simulation (left) (top and side views) (ATAZ is represented in purple) and (right) average number of contacts between DOCD moieties (lipid chains in orange and the CD moiety in blue) and ATAZ atoms for the MD simulation of 36 DOCD with 18 ATAZ [225]. (c) Coarse-grained models of the β-CD-copolymer (top), computed cross-section views of β-CD-copolymer/gold nanoparticles at 1:3 molar ratio, corresponding density profiles of different layers (middle right) and morphologies of micelles assembled with different building-block topologies (bottom) [226].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Hu C.-M.J., Aryal S., Zhang L. Nanoparticle-Assisted Combination Therapies for Effective Cancer Treatment. Ther. Deliv. 2010;1:323–334. doi: 10.4155/tde.10.13. - DOI - PubMed
    1. Aghabegi Moghanjoughi A., Khoshnevis D., Zarrabi A. A Concise Review on Smart Polymers for Controlled Drug Release. Drug Deliv. Transl. Res. 2016;6:333–340. doi: 10.1007/s13346-015-0274-7. - DOI - PubMed
    1. Pippa N., Demetzos S.P., Demetzos C. Polymer Self-Assembled Nanostructures as Innovative Drug Nanocarrier Platforms. [(accessed on 6 January 2021)]; Available online: https://www.eurekaselect.com/139597/article. - PubMed
    1. Dave S., Shriyan D., Gujjar P. Newer Drug Delivery Systems in Anesthesia. J. Anaesthesiol. Clin. Pharmacol. 2017;33:157–163. doi: 10.4103/joacp.JOACP_63_16. - DOI - PMC - PubMed
    1. Kawasaki E.S., Player A. Nanotechnology, Nanomedicine, and the Development of New, Effective Therapies for Cancer. Nanomed. Nanotechnol. Biol. Med. 2005;1:101–109. doi: 10.1016/j.nano.2005.03.002. - DOI - PubMed

LinkOut - more resources