Since many drugs cannot be delivered efficiently due to various obstacles such as low aqueous solubility and short half-life, designing a delivery system that makes the therapeutic agents show their highest possible healing process capacity is imperative, writes Ciara O'Sullivan.

Despite conventional drug delivery systems' functionalities going relatively beyond those limitations, they have not succeeded in delivering many drugs (Hu et al. 2010).

Smart nanoparticle-based drug delivery systems

However, the recent development of modern approaches for smart nanoparticle-based drug delivery systems for the advanced transport of drug molecules provides a platform to modify drug molecules solubility, half-life, biocompatibility, and release properties (Kawasaki and Player 2005).

Smart nanoparticle (NP) drug carriers reduce drug dosage frequency and the side effects experienced with traditional drug delivery systems by applying drugs to specific and targeted sites.

Due to scientists' significant interest in delivering therapeutic, targeting, multidrug treatments and diagnostic agents together in a single system, this novel class of drug carriers as multifunctional platforms has been applied (Madaan et al. 2014). Smart nanostructured systems can be categorised into two main groups:

  1. Organic nano-carriers: mainly consists of polymer micelles, liposomes, dendrimers, glycopeptides, and assembly of proteins (Svenson and Tomalia 2012).
  2. Inorganic nano-carriers: includes carbon-based nanomaterials, gold nanoparticles, silver nanoparticles, silica-based nanomaterials, and quantum dots (Sahu 2013).

While changing their compositions, shape, dimension, and surface properties give the chance to tune their physicochemical characteristics (Hu et al. 2010).

Understanding how smart NPs form and perform becomes crucial for the future development of safe and efficient delivery. Typically, the nano-carriers performance process happens in the scale of picoseconds and nanometers, which rarely can be detected but by very few experimental techniques.

Therefore, there is a lack of knowledge about the interactions and processes in smart drug nano-carriers performance. Hence, molecular simulation becomes an alternative to experiment. They could provide information to better understand the general nature of smart NPs formation and interactions (Hu et al. 2010)  


The results of the coarse-grained dissipative particle dynamics (DPD) simulations are tabulated, where the red and green beads signify the solvophilic blocks, the yellow are the solvophobic blocks, unless stated otherwise. 

The results obtained indicate the architecture, degree of branching and ratio of solvophobic/solvophilic influence the self-assembled morphology.

The more branched the architectures, the higher the possibility of a cylindrical micelle. For example, the dendron and dendrimer architectures both self-assembled to a cylindrical micelle. While the more linear structures like the dendritic linear hybrid self-assembles to a spherical micelle.

Also, when the system's solvophobicity was increased for the block dendrimers, the number of solvophobic cores increased.

Influence self-assembly process

Therefore, the chemical properties and architecture of the copolymer chains influence the self-assembly process.

From a thermodynamic point of view, the copolymer self-assembly process is driven by entropy and enthalpy contributions of the system's free energy.

During the self-assembly process, the entire system evolution is in a path of reaching a free energy minimum and the thermodynamically equilibrated structure. There are two types of entropy and enthalpy affecting the whole micellisation process:

  1. The polymer chains' entropy is losing due to putting them in the confined micelle space, which is not favourable for the polymer chains.
  2. The entropy gaining comes from the solvent molecules getting more freedom by leaving the space between polymer chains at initial configuration and placed outside the micelle, which is a favourable entropy contribution in the micellisation process.

Also, in the system, the enthalpy is favourable for aggregation due to its effect on:

  1. Reducing the surface tension between solvent and solvophobic blocks due to solvophilic blocks shielding effect and reducing the free energy of micellisation.
  2. Reducing free energy by making a volume of material due to like-like interactions between polymer blocks chains.

In all the studied systems, copolymer aggregates are observed, which illustrates, despite the large confinement that the chains had to experience by placing in/on the micelles that resulted in significant entropy loss for the chains, the favourable contributions of enthalpy and the second term of entropy were controlling the micellisation.

The results obtained from the simulations align with what was expected in literature; most of the simulations produced a spherical or cylindrical micelle. While the dendritic polymers used in the modelling are only general structures, they can be fine-tuned and adapted to real-life polymers to predict self-assembly.

Spherical micelles, especially multicore or multicompartment, are highly sought after for drug-delivery devices, particularly for multidrug delivery purposes. The rate at which drug release occurs depends on several factors, including:

  1. The polymer architecture: The more complex/rigid and longer chain is in the micelle, the higher the possibility of chain entanglement formation in the micelle. This would significantly reduce the drug release rate.
  2. Interaction between the drug and micelle: This is crucial as enough of the drug needs to be encapsulated by the micelle to provide enough half-life time for optimum drug performance.
  3. Morphology of the micelle: The placement of the drug depends on the morphology of the micelle.

All of these factors are dependent on each other. They can either positively or negatively affect the release process, which in principle depends on the drug molecular structure, chemistry, and drug administration routes.

Multicore and multicompartment micelles

Multicore and multicompartment micelles are very promising in drug delivery, as mono/multi drugs can be encapsulated or entrapped in all the cores in the micelle without interruption on the performance of each other.

Due to the more complex structure of the multicore/multicompartment micelle, the encapsulated drug cannot be fast released and affect healthy cells after injection. In this way, releasing would be more efficient, with fewer side effects.

The cylindrical multicore/multicompartment micelle can be used for enhanced heavy oil recovery (EOR). The cylindrical micelle can be injected into a solution to form worm-like micellar surfactants; these are highly flexible. The micellar solution has a high surface activity and viscoelasticity; these attributes make cylindrical micelles attractive in practical applications of EOR. 

The novel aspect of this research is that using coarse-grained simulations, a category of copolymers that can form these promising multicore/multicompartment micelles are introduced. This predictive research study can make guidelines for experimental research for production of multicore/multicompartment polymeric-based micelles.


To conclude, it is observed that dendritic polymers with two block types self-assemble to multicore aggregate, hetero-functional dendrimer self-assembles to a multicompartment aggregate, dendrons are capable to self-assemble to multicore aggregate with a hexagonal pattern.

Computational modelling at a coarse-grained level employing DPD is highly effective at predicting the self-assembled model, and with fine-tuning this process, the desired micelle can be formed.

Further work

To make comprehensive guidelines for multicore/multicompartment formation from dendritic copolymers, there are still different effective parameters that should be studied in the future, such as: 

  1. The effect of charge or functional groups in the polymer molecule.
  2. The effect of chain rigidity.
  3. The effect of chains chemical heterogeneity.

Additionally, studying the effect of combining different dendritic architectures on the self-assembly and making 2D morphology phase diagrams to show the combined impact of system parameters on the self-assembly are two other important aspects of this project that are exciting for future research. 


1.) Agarwal, V., Bajpai, M., Sharma, A. (2018) "Patented and Approval Scenario of Nanopharmaceuticals with Relevancy to Biomedical Application, Manufacturing Procedure and Safety Aspects," Recent Patents on Drug Delivery & Formulation, 12(1), 40–52

2.) Hu, C.M.J., Aryal, S., Zhang, L. (2010) "Nanoparticle-assisted combination therapies for effective cancer treatment," Therapeutic Delivery, available:

3.) Kawasaki, E.S., Player, A. (2005) "Nanotechnology, nanomedicine, and the development of new, effective therapies for cancer," Nanomedicine: Nanotechnology, Biology, and Medicine, available:

4.) Madaan, K., Kumar, S., Poonia, N., Lather, V., Pandita, D. (2014) "Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues," Journal of Pharmacy and Bioallied Sciences, 6(3), 139–150, available: /pmc/articles/PMC4097927/.

5.) Svenson, S., Tomalia, D.A. (2012) "Dendrimers in biomedical applications-reflections on the field," Advanced Drug Delivery Reviews.

Author: Ciara O'Sullivan (University of Limerick, Chemical and Biochemical Engineering). Supervisors: Dr Matthias Vandichel, Dr Sousa Javannikhah