Investigation of morphology and structure of drug-loaded PLA-b-PEO-b-PLA polymeric micelle: A dissipative particle dynamics simulations study.

The dissipative particle dynamics (DPD) simulation was used to study the morphologies and structures of the paclitaxel-loaded PLA-b-PEO-b-PLA polymeric micelle. We focused on the influences of PLA block length, PLA-b-PEO-b-PLA copolymer concentration, paclitaxel drug content on morphologies and structures of the micelle. Our simulations show that: (i) with the PLA block length increase, the self-assemble structure of PLA-b-PEO-b-PLA copolymers with paclitaxel vary between onion-like structure (core-middle layer-shell) to spherical core-shell structure. The PEO shell thins and the size of the PLA core increases. The onionlike structures are comprised of the PEO hydrophilic core, the PLA hydrophobic middle layer, and the PEO hydrophilic shell, the distribution of the paclitaxel drug predominantly occurs within the hydrophobic intermediate layer; (ii) The system forms a spherical core-shell structure when a small amount of the drug is added, and within a certain range, the size of the spherical structure increases as the drug amount increases. When the drug contents (volume fraction) cdrug = 10%, it can be observed that the PLA4-b-PEO19-b-PLA4 spherical structures connect to form rod-shaped structures. With the length of PLA block NPLA = 8, as the paclitaxel drug concentrations cdrug = 4%, PEO has been insufficient to completely encapsulate the PLA and paclitaxel drug beads. To enhance drug loading capacity while maintaining stability of the system in aqueous solution, the optimal composition for loading paclitaxel is PLA4-b-PEO19-b-PLA4; the drug content is not higher than 4%; (iii) The paclitaxel-loaded PLA4-b-PEO19-b-PLA4 micelle undergo the transition from onionlike (core-middle layer-shell) to spherical (core-shell) to rod-shaped and lamellar structure as the PLA4-b-PEO19-b-PLA4 copolymer concentration increases from ccp = 10% to 40%.

Satellite-Type Sulfur Atom Distribution in Trithiocarbonate Bond-Bridged Dimeric Prodrug Nanoassemblies: Achieving Both Stability and Activatability.

Homodimeric prodrug nanoassemblies (HDPNs) hold promise for improving the delivery efficiency of chemo-drugs. However, the key challenge lies in designing rational chemical linkers that can simultaneously ensure the chemical stability, self-assembly stability, and site-specific activation of prodrugs. The "in series" increase in sulfur atoms, such as trisulfide bond, can improve the assembly stability of HDPNs to a certain extent, but limits the chemical stability of prodrugs. Herein, trithiocarbonate bond (─SC(S)S─), with a stable "satellite-type" distribution of sulfur atoms, is developed via the insertion of a central carbon atom in trisulfide bonds. ─SC(S)S─ bond effectively addresses the existing predicament of HDPNs by improving the chemical and self-assembly stability of homodimeric prodrugs while maintaining the on-demand bioactivation. Furthermore, ─SC(S)S─ bond inhibits antioxidant defense system, leading to up-regulation of the cellular ROS and apoptosis of tumor cells. These improvements of ─SC(S)S─ bond endow the HDPNs with in vivo longevity and tumor specificity, ultimately enhancing the therapeutic outcomes. ─SC(S)S─ bond is, therefore, promising for overcoming the bottleneck of HDPNs for efficient oncological therapy.

Amorphous ternary nanoparticle complex of curcumin-chitosan-hypromellose exhibiting built-in solubility enhancement and physical stability of curcumin.

The low aqueous solubility of curcumin (CUR) had greatly limited the clinical efficacy of CUR therapy despite its well-known potent therapeutic activities. Previously, we developed amorphous nanoparticle complex (nanoplex) of CUR and chitosan (CHI) as a solubility enhancement strategy of CUR by electrostatically-driven drug-polyelectrolyte complexation. The CUR-CHI nanoplex, however, (1) lacked a built-in ability to produce prolonged high apparent solubility of CUR in the absence of crystallization-inhibiting agents, and (2) exhibited poor physical stability during long-term storage. For this reason, herein we developed amorphous ternary nanoplex of CUR, CHI, and hypromellose (HPMC) where HPMC functioned as the crystallization inhibitor. The effects of incorporating HPMC on the (1) physical characteristics and (2) preparation efficiency of the CUR-CHI-HPMC nanoplex produced were investigated. Compared to the CUR-CHI nanoplex, the HPMC inclusion led to larger nanoplex (≈300-500 nm) having lower zeta potential (≈1-15 mV) and lower CUR payload (≈40-80%), albeit with higher CUR utilization rates (≈100%) attributed to the CUR interactions with both CHI and HPMC. The CUR-CHI-HPMC nanoplex's physical characteristics could be controlled by varying the HPMC to CHI ratio in the feed. Subsequently, the CUR-CHI-HPMC and CUR-CHI nanoplexes were examined in terms of their (1) storage stability, (2) dissolution characteristics in simulated gastrointestinal fluids, and (3) in vitro solubility enhancement. The results showed that the CUR-CHI-HPMC nanoplex exhibited superior (i) amorphous state stability after twelve-month storage, (ii) dissolution characteristics, and (iii) solubility enhancement in simulated gastrointestinal fluids, with minimal cytotoxicity towards human gastric epithelial cells.