Controlling Trapping, Release, and Exchange Dynamics of Micellar Core Components

Abstract

Whereas the formation and overall stability of hierarchically organized self-assembled supramolecular structures have been extensively investigated, the mechanistic aspects of subcomponent dynamics are often poorly understood or controlled. Here we show that the dynamics of polyamidoamine (PAMAM) dendrimer based micelles can be manipulated by changes in dendrimer generation, pH, and stoichiometry, as proven by NMR and FRET. For this, dendrimers were functionalized with either fluorescein (donor) or rhodamine (acceptor) and encapsulated into separate micelles. Upon mixing, exchange of dendrimers is revealed by an increase in FRET. While dendrimicelles based on dendrimer generations 4 and 5 show a clear increase in FRET in time, revealing the dynamic exchange of dendrimers between micellar cores, generation 6 based micelles appear to be kinetically trapped systems. Interestingly, generation 6 based dendrimicelles prepared at a pH of 7.8 rather than 7.0 do show exchange dynamics, which can be attributed to about 25% less charge of the dendrimer, corresponding to the charge of a virtual generation 5.5 dendrimer at neutral pH. Changing the pH of dendrimicelle solutions prepared at a pH of 7.8 to 7.0 shows the activated release of dendrimers. High-resolution NMR spectra of the micellar core are obtained from a 1.2 GHz spectrometer with sub-micromolar sensitivity, with DOSY discriminating released dendrimers from dendrimers still present in the micellar core. This study shows that dendrimer generation, charge density, and stoichiometry are important mechanistic factors for controlling the dynamics of complex coacervate core micelles. This knowledge can be used to tune micelles between kinetically trapped and dynamic systems, with tuning of exchange and/or release speeds, to be tailored for applications in, e.g., material science, sensors, or drug delivery.

New insights into protein–polysaccharide complex coacervation: Dynamics, molecular parameters, and applications

“…[ 110 ] For example, take the complex system with only donor and only acceptor as the zero point ( A / D min , 0% FRET), take the donor and acceptor 1:1 as the maximum point ( A / D max , 100% FRET), and use dimensionless parameter α A / D to evaluate the exchange rate at time t ($${\alpha _{A/D}} = \frac{{A/{D_t} - A/{D_{{\mathrm{min}}}}}}{{A/{D_{{\mathrm{max}}}} - A/{D_{{\mathrm{min}}}}}}\;$$). [ 111 ] In some cases, the increase in FRET efficiency depends not only on the exchange rate but also on factors such as initial fluorophore number, fluorophore size, Forster radius, and mixing ratio. [ 112 ]…”

“…[110] For example, take the complex system with only donor and only acceptor as the zero point (A/D min , 0% FRET), take the donor and acceptor 1:1 as the maximum point (A/D max , 100% FRET), and use dimensionless parameter α A/D to evaluate the exchange rate at time t (𝛼 A∕D = A∕D t −A∕D min A∕D max −A∕D min ). [111] In some cases, the increase in FRET efficiency depends not only on the exchange rate but also on factors such as initial fluorophore number, fluorophore size, Forster radius, and mixing ratio. [112] Furthermore, when the donor and acceptor are close to each other, the FRET transfer from donor to acceptor is faster, and the lifetime of the fluorophore becomes shorter.…”

Responsive Supramolecular Polymers for Diagnosis and Treatment

“…In addition, the reversible and highly directional non-covalent interactions of supramolecular polymers make them attractive candidates for their use in regenerative medicine to support, guide, and stimulate regeneration of dysfunctional or even lost tissues [27]. The design of synthetic polymers that mimic the dynamic behavior of natural fibers has recently attracted considerable interest [168,169]. The eukaryotic cytoskeleton is composed of key supramolecular biopolymers, including actin filaments and microtubules, that are important for cell structure and function [51].…”

Research Status of Dendrimer Micelles in Tumor Therapy for Drug Delivery

“…The polydispersity index (PDI) of G5.0 ≈ G10.0 PAMAM dendrimers is less than 1.08, which means that the particle size of each generation of PAMAM dendrimers is very uniform. [23,24] PAMAM has internal cavities and abundant terminal groups on the surface, which can improve the solubility of hydrophobic drugs and show great potential in the delivery of nucleotides. [25] Haensler et al [26] first applied it to gene vectors in 1993, and proposed that G6 PAMAM has the best gene transfection efficiency.…”