Weiwei Zhang,Delong Zhang,Xiaoshan Fan,Guangyue Bai,Yuqin Jiang,Zhiguo Hu
Novel dumbbell-shaped amphiphilic copolymers ((PLLA)2–G1–P188–G1–(PLLA)2 and (PDLA)2–G1–P188–G1–(PDLA)2) and linear-shaped amphiphilic copolymers (PLLA–P188–PLLA and PDLA–P188–PDLA) were synthesized by click chemistry and ring opening polymerization (ROP). The stereocomplexes (scPLA)2–G1–P188–G1–(scPLA)2 and scPLA–P188–scPLA were prepared and confirmed by X-ray diffraction (XRD). The stereocomplex interaction between PLLA and PDLA was firstly analyzed using microscale thermophoresis (MST) technology and the dissociation constant (Kd) was obtained as 342 μM. The aggregation behaviors of these stereocomplexes were studied using fluorescence spectroscopy, transmission electron microscopy (TEM) and light scattering (LS). The critical aggregate concentration (CAC) obtained from fluorescence measurements was 0.021 mg mL−1 for (scPLA)2–G1–P188–G1–(scPLA)2 and 0.042 mg mL−1 for scPLA–P188–scPLA. These stereocomplexes can self-associate in aqueous solution into spherical aggregates with a diameter of 181 nm for (scPLA)2–G1–P188–G1–(scPLA)2 and 222 nm for scPLA–P188–scPLA. Furthermore, the biocompatibility of the stereocomplexes was evaluated with a relatively lower cytotoxicity. Finally, DOX was encapsulated into the stereocomplex aggregates to evaluate the drug release ability in phosphate buffer at a pH value of 7.4 or 5.4. The drug loading content and the encapsulation efficiency of the aggregates are 9.8%, 54% for (scPLA)2–G1–P188–G1–(scPLA)2 and 8.2%, 45% for scPLA–P188–scPLA. The release of DOX at pH 5.4 is faster than that at pH 7.4. The pH value has a greater effect on the release rate of DOX from dumbbell-shaped stereocomplex aggregates than that from the linear-shaped ones, which ensures the long blood circulation and the higher DOX-release surrounding the tumor site.
Therapeutic proteins/peptides face severe stability impairment in biotechnology drug delivery systems prepared by the W/O/W solvent evaporation method. Screening of protein stabilizers for poly (D, l -lactide-co-glycolide) (PLGA) nanoparticles can improve the low encapsulation efficiency and undesirable release behavior of proteins caused by PLGA carriers, which is a crucial step to achieve a high proportion of continuous release of encapsulated protein in the target time and give full play to the therapeutic effect. Therefore, model proteins were selected for stability testing to simulate the specific destabilization pathways. Through the comprehensive study of protein conformation, recovery rate, encapsulation rate, and drug release behavior, the effects of additives on the stability of protein were synthetically characterized, and their action links and mechanisms were also further studied. The results showed that different denaturation environments were intertwined during the preparation and release of peptide-loaded NPs, jointly inducing protein denaturation and incomplete release behavior. After optimization with stabilizers, urea and lactose increased the encapsulation efficiency of proteins to more than 95% (P < 0.001). Except for the P188 , all other stabilizers showed great potential for optimizing the release and stability of the encapsulated protein as a whole, increasing the release proportion of protein from 44% to 60 %-75% (P < 0.0001). The improvement of the drug release curve demonstrated the long-term stabilizing effect of the above-mentioned co-solubilizing additives on the therapeutic protein.
Yili Wu,Yujia Zhang,Dong Li,Xiangchun Sheng,Xiaofeng Hu,Meihong Ding,Qunxing Wang,Beihua Xu,Ting Zhang,Yiling He,Senlin Shi
Objective To develop and optimise a VEN nasal thermosensitive in-situ gel for reducing the first-pass effect and enhancing bioavailability.Methods High performance liquid chromatography, central composite design-response surface methodology, the membrane-free erosion and the Franz vertical diffusion cell method were used to clarify the optimised formulation. Pharmacokinetic and pharmacodynamic studies evaluated sustained release and efficacy.Results The optimal formulation (32.87-33.17 °C gelation temp) comprised 12.5% w/v VEN, 20.44% w/v poloxamer 407, 0.74% w/v P188, 5% w/v 2-Hydroxypropyl-β-cyclodextrin, 0.5% w/v hydroxypropyl methyl cellulose, 0.12% w/v potassium sorbate, 10% v/v glycerol, and 90% v/v water; it had a good stability and sustained-release effect of VEN and increased bioavailability and reduced O-desmethylvenlafaxine production. It achieved 90% cumulative release at 15h in vitro, and its intranasal Cmax was higher than oral VEN (p < 0.05) without detectable O-desmethylvenlafaxine. Treatment with VEN thermosensitive in-situ gel in a depressive rat model improved the sucrose preference rate in the sucrose preference test and the total distance of movement in the open field test, also significantly increased the level of 5-hydroxytryptamine and norepinephrine in the hippocampus (p < 0.01).Conclusion This innovative P407/P188-based gel enhances VEN bioavailability and antidepressant efficacy via sustained release and brain targeting, providing critical data for nasal formulation development.
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