A dendrimer–hydrophobic interaction synergy improves the stability of polyion complex micelles

Abstract

Polyion complex (PIC) micelles incorporating PEG-dendritic copolymers display an unprecedented stability towards ionic strength that is amplified via hydrophobic interactions. The tridimensional orientation of peripheral hydrophobic linkers between charged groups and the globular/rigid dendritic scaffold maximizes this stabilization compared to PIC micelles from linear polymers. As a result, micelles stable at concentrations higher than 3 M NaCl are obtained, which represents the highest saline concentration attained with PIC micelles. Advantage of this stabilizing dendritic effect has been taken for the design of a robust, pH-sensitive micelle for the controlled intracellular release of the anticancer drug doxorubicin. This micelle displays a slightly higher toxicity, and distinctive mechanisms of cell uptake and intracellular trafficking relative to the free drug. The preparation of mixed PIC micelles by combining differently functionalized PEG-dendritic block copolymers has allowed to fine-tune their stability, paving the way towards the facile modulation of properties like biodegradability, drug loading, or the response to external stimuli.

Tuning the Size of Nanoassembles: A Hierarchical Transfer of Information from Dendrimers to Polyion Complexes

“…PIC revealed high stability over time and temperature (dialysis in 10 mM PB pH 7.4, 150 mM NaCl for 24 h at 25 °C, followed by 24 h at 37 °C), even for dendrimers as small as 2G2 with only 18 terminal amines (Figures 2 and S3-S6, Table S1); exceeding the stability of PIC from linear polymers of much higher DP as previously reported. 18,19 Larger dendrimers afforded smaller PIC, an effect associated to their higher rigidity and multivalency, in accordance with our hypothesis of a hierarchical transfer of information. No PIC was obtained from PEG 5k -PGA 25 .…”

“…27 Since such a size tuning has not been unveiled so far in dendritic PIC micelles 28 , 29 , 30 and vesicles 31 , we decided to thoroughly explore the scope of a dendrimer to PIC hierarchical transfer of information using a combinatorial approach comprising a large PIC library from six GATG amino-dendrimers (18- With this aim, two new families of symmetrical GATG dendrimers, namely 2[Gn] and 3[Gn], were designed from di-and trifunctionalized cores (Figure 1). Following a divergent growth sequence involving an amide coupling with the GATG repeating unit (EDC, HOBt, 93-96%) and azide reduction (Ph 3 P, 90-100%), four dendrimer generations were synthesized in excellent yields with up to 243 terminal azide/amino groups: 2G1 (6 terminal groups), 3G1 (9), 2G2 (18), 3G2 (27), 2G3 (54), 3G3 (81), 2G4 (162), 3G4 (243). The high solubility of these dendrimers facilitates their preparation at high G and purification in large scale (MPLC in just 10 min, ultrafiltration is also possible for G3 and G4), the bottlenecks in the synthesis of dendrimers.…”

Nanoplatforms for Targeted Stimuli-Responsive Drug Delivery: A Review of Platform Materials and Stimuli-Responsive Release and Targeting Mechanisms

“…These methods can lead to increased micelle size, which is unfavorable for the extension of circulation half-life and the utilization of enhanced permeability and retention effect (see Section 2.6.1 below) for tumor targeting. Unstable micelles are formed if the hydrophilic block is too short [ 31 ]. More commonly used methods for increasing micelle stability are to incorporate covalent crosslinking and increasing the number and strength of intermolecular interaction (such as optimized topology, π-π interaction, and host–guest complexation) in the core or shell of micelles [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

On Complex Coacervate Core Micelles: Structure-Function Perspectives

“…This has motivated the development of novel carrier systems aiming to encapsulate and deliver small molecular drugs to specific target sites, whilst minimizing adverse side effects. C3Ms have been utilized to load a variety of water-soluble, inorganic, and molecular therapeutics bearing multiple charged groups, charged drugs [ 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 ], metal complexes [ 138 , 139 , 140 ], and photosensitizers [ 141 , 142 , 143 , 144 ]. An overview of small therapeutics encapsulated in C3Ms is given in Table 1C.…”