Synthesis of semicrystalline nanocapsular structures obtained by Thermally Induced Phase Separation in nanoconfinement

Abstract

Phase separation of a polymer solution exhibits a peculiar behavior when induced in a nanoconfinement. The energetic constraints introduce additional interactions between the polymer segments that reduce the number of available configurations. In our work, this effect is exploited in a one-step strategy called nanoconfined-Thermally Induced Phase Separation (nc-TIPS) to promote the crystallization of polymer chains into nanocapsular structures of controlled size and shell thickness. This is accomplished by performing a quench step of a low-concentrated PLLA-dioxane-water solution included in emulsions of mean droplet size <500 nm acting as nanodomains. The control of nanoconfinement conditions enables not only the production of nanocapsules with a minimum mean particle diameter of 70 nm but also the tunability of shell thickness and its crystallinity degree. The specific properties of the developed nanocapsular architectures have important implications on release mechanism and loading capability of hydrophilic and lipophilic payload compounds.

Figure 1. Size and Shape of PLLA Semicrystalline Nanocapsules by SEM and DLS results.

(a) Scanning Electron Microscope images showing the morphology of nanocapsules obtained by TIPS (PLLA NCs Mean Diameter: 70 nm); (b) Detail of a Particle Size Distribution obtained for experiments conducted at 2000 bar and PLLA concentration of 0.5% wt/v; (c) The effect of polymer concentration on the mean diameter is plotted on the graph; it highlights how by reducing the polymer concentration and -consequently- Droplet Size Distribution, Mean Diameter of nanocapsules also decreases.

Figure 2. Analysis of shell thickness by TEM results.

(a–c) Cryo –TEM and TEM nanocapsules obtained by Thermally Induced Phase Separation in a nanoconfinement by changing the polymer concentration from 0.5 to 1.5% wt/v, respectively, at a constant pressure of 2000 bar; (d) Graph showing the reduction of shell thickness as a function of the NCs mean diameter. A significant decreasing of mean diameter and shell thickness is observed by changing the polymer concentration.

Figure 3. Crystallinity grade analysis by DSC and XRD.

(a) DSC heating curves of PLLA nanocapsules at different polymer concentrations, from the top: 0.1- 0.5- 1- 1.5% wt/v–PLLA Raw; (b) Table reports DSC data in detail and the crystallinity grade, showing how the polymer concentration can influence crystallization phenomena (DSC heating rate: 5 °C/min); (c) XRD patterns at different PLLA concentrations from 0.1% wt/v to 1.5% wt/v; (d) Degree of crystallinity versus PLLA concentration.

Figure 4. Loading capability and release mechanism.

(a–c) STED high-resolution images of randomly dispersed fluorescence of (a) 250 nm, (b) 115 nm and (c) 95 nm. (d) Effect of polymer structure and drug release characteristics. Dye release profile of loaded nanocapsules as a function of size and shell thickness for different % of dye loadings. The graph also confirms the release mechanism typical of micro and nanocapsules.

Figure 5. Schematic representation of thermally induced phase separation (TIPS) of a polymer solution in a nanoconfinement.

(a) Phase morphologies influenced by a nanoconfinement. Phase separation patterns are showed by cooling the nanoconfined system at a quench temperature. In detail, a narrow DSD is obtained by High-Pressure Homogenization with a droplet mean diameter of about 500 nm and a PDI of 0.15 (phase 1). Each droplet containing a polymer solution is cooled below Cloud Point condition. At a certain temperature, phase separation occurs within the droplet and pushes them in a higher energy state similar to a spinodal phase (phase 2). Because of the nanoconfinement, polymer chains have a reduced number of available configurations to reduce their energy, so that a transition to a more orderly structure is preferred. When keeping cooling the system, a further segregation is originated such that the bending of the polymer chains forms one or more nanocapsular structures at low free energy (phase 3). (b,c) Schematic representation of nanocapsules and cross section highlighting crystal lamellae within the shell. (d) Standard polymer segregation and phase diagram displaying spinodal curves, within the coexistence curves and upper critical point. (e) Energy content of the different phase steps to obtain nanocapsules. Starting from a ternary solution in an emulsified system (phase 1), corresponding to a ∆G <0, no heterogeneity appears from the system before point D at a lower T, where signs of liquid-liquid miscibility gap can be detected and nanoconfined nucleation starts showing an increase in ∆G, while the presence of a nanoconfinement drives the polymer solution to a chain alignment at atypical conditions to reduce the free energy (phase 2). When keeping cooling the system, (phase 3) an interconnected system appears to form a nanocapsular structure.