Make it and break it: Stimuli-responsive Cyclodextrin-based Complex Coacervate Core Micelles

Camilla Facciotti

Research output: Thesisinternal PhD, WU


The treatments of chronic and severe disorders, such as hearth diseases, cancer and diabetes still remain challenging for health care researchers, due to the severe side effects and the limited efficacy. Drugs have often low targeted specificity, non-selective bio-distribution and poor solubility in water, leading to the increase of the drug amount and, thus, also the unwanted side effects. Nanotechnology is emerging as an alternative approach to conventional disease treatments, applicable in early diagnosis, therapy monitoring, drug delivery, and guided surgery. Polymer-based micelles seem promising in nanomedicine, due to their ability of solubilizing poorly water-soluble drugs and to their biocompatibility. Within polymer-based micelles, Complex Coacervate Core Micelles, or C3Ms, are able to encapsulate a wide range of cargoes, such as DNA, RNA, protein, enzymes, etc. The ability of encapsulating several charged cargoes relies on their self-assembly, based on electrostatic interactions between oppositely charged block copolymers. However, the assembly and disassembly mechanism of those micelles, under controlled stimuli in time and space, is still poorly investigated. The aim of this thesis is to develop stimuli-responsive micelles, by introducing host-guest interactions in the core of complex coacervate core micelles.

In chapter 2 we focused on the design of a new class of micelles, called Cyclodextrin-based Complex Coacervate Core Micelles or C4Ms. These micelles represent the propaedeutic milestone for further developments of stimuli-responsive C4Ms. In this chapter, we determined that seven were the minimum number of charges per core-units, required for coacervation and that the micelle stability can be tuned by adding an adamantane guest bislinker, able to combine multiple monomeric core-units into strong polymeric networks.

In chapter 3, we designed redox-responsive C4Ms, called Ad-SS-Ad-based C4Ms, based on the knowledge acquired in chapter 2. Redox is considered an “internal stimulus”, because the response is triggered by intrinsic characteristics of tumor cells. Therefore, designing smart C4Ms, able to disassemble upon high concentration of reducing agent, could be advantageous for future biomedical applications. Upon reducing agent treatment, the disulfide cross-link is cleaved into thiolates, favoring the micellar disassembly. This disassembly is reversible over time, due to the re-oxidation of thiolates to disulfides. The rate of re-assembly was controlled by varying the DTT concentration and the ratio between redox-responsive and non-redox-responsive bislinkers. Preliminary studies showed that Ad-SS-Ad-based C4Ms promote the solubilization of methyl red in water and its release (i.e. to the organic phase) upon micelle dissociation. These results suggested that stimuli-responsive C4Ms could be promising for future drug delivery applications.

In chapter 4, ferrocene-based C4Ms were designed to respond to H2O2 oxidation. H2O2 is a Reactive Oxygen Species (ROS) that originates from aerobic metabolism by-products and therefore is relevant in stress-related biological studies. The key molecule for the oxidant-response property was the ferrocene–modified dipicolinic acid, (Fc-DPA), that, upon oxidation, favors the micellar disassembly. The stability against the oxidant was controlled in three ways: i) by changing monomeric-units into polymeric branched networks, ii) by varying the oxidant concentration and iii) by adding a non-responsive guest.

In chapter 5, we developed light-responsive C4Ms, based on azobenzene-modified dipicolinic acid (Azo-DPA) and αCD-DPA as light-responsive host-guest couple. Light is considered an ideal external stimulus, because time, space, intensity, size sport, etc. can be regulated externally and precisely.

Future studies, based on the combination of different stimuli or “multi-stimuli”, e.g. light and redox, could boost the efficacy of drug delivery systems, increasing time and target specificity and, possibly, decreasing the drug side effects.

Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
  • Velders, Aldrik, Promotor
  • Saggiomo, Vittorio, Co-promotor
Award date16 Dec 2019
Place of PublicationWageningen
Print ISBNs9789463951524
Publication statusPublished - 2019


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