Journal of Controlled Release最新文献

In vitro-in vivo correlation (IVIVC), linking in vitro drug release to in vivo drug release or in vivo drug absorption, has been explored chiefly for oral extended-release dosage forms. Currently, there are no official guidelines on IVIVC development for non-oral drug delivery systems. Recently, many long-acting injectable (LAI) formulations based on poly(lactide-co-glycolide) (PLGA) have been developed to deliver various drugs, ranging from small molecules to peptides and proteins, for up to 6 months. The circumstances involved in the LAI formulations are drastically different from those in oral formulations, which generally deliver drugs for a maximum of 24 h. This article examines 37 IVIVC studies of PLGA microparticle formulations available in the literature. Understanding and establishing an IVIVC of LAI formulations requires more than merely plotting the percentage in vitro drug release against the percentage in vivo absorption. In vivo drug absorption (or release) should be measured to provide a complete pharmacokinetic profile when feasible. Accelerated in vitro release methods need to be respective of the real-time measurements by sharing the same release mechanism. Obtaining meaningful IVIVCs with predictive capability will be highly useful for future regulatory actions and for developing generic and new formulations.

Ionizable lipids are widely recognized as the crucial component of lipid nanoparticles (LNPs). They enable mRNA encapsulation, shield it from enzymatic degradation, facilitate cellular uptake, and foster its cytosolic release for subsequent translation into proteins. In addition, PEGylated lipids are added to stabilize the particles in storage and in vivo. In this study, we investigate the potency of LNPs prepared using commonly adopted ionizable and pegylated lipids in vitro (using HEK293 cells) and in vivo (mouse studies) to consider the impact of structure on potency. LNPs were prepared using a fixed molar ratio of DSPC: Cholesterol: ionizable/cationic lipid: PEG lipid (10:38.5:50:1.5 mol%). All LNP formulations exhibited similar critical quality attributes (CQAs), including particle size <100 nm, low PDI (<0.2), near-neutral zeta potential, and high encapsulation efficiency (>90%). However, the potency of these LNPs, as measured by in vitro mRNA expression and in vivo expression following intramuscular injection in mice varied significantly. LNPs formulated with SM-102 exhibited the highest expression in vitro, whilst in vivo SM-102 and ALC-0315 LNPs showed significantly higher mRNA expression than DLin-MC3-DMA (MC3), DODAP and DOTAP LNPs. We also investigated the effect of PEG lipid choice (ALC-0159, DMG-PEG2k, and DSPE-PEG2k), which did not impact LNP CQAs, nor their clearance from the injection site. However, PEG lipid choice significantly influenced mRNA expression with the incorporation of DSPE-PEG2k reducing expression. This work contributes valuable insights to the evolving landscape of mRNA research, emphasizing that CQAs are a marker of the quality of the LNP production process, but not discriminatory regarding LNP potency. Similarly, standard in vitro studies do not provide insights into in vivo potency. These results further emphasize the intricacies of formulation design and the importance of bridging gaps between experimental outcomes in different settings.

Drug delivery efficiency often affects chemotherapy outcome due to dense collagen barrier in tumor environment. Here, we report a nanoparticle capable of pH and glutathione dual-responsive drug delivery to enhance the efficacy of breast cancer chemotherapy. Maleiminated polyethylene glycol and polylactide block copolymer were synthesized as a core material, doxorubicin was encapsulated into the nanoparticle by self-assembly. Thiocollagenase and maleimide were connected on the nanoparticle surface by click chemistry, and further coated with chondroitin sulfate as a protective layer to form dual-responsive doxorubicin nanoparticle. The results showed that the nanoparticle had the ability to penetrate deep tumor tissue, to target on CD44 of cancer cell, and to release doxorubicin in cancer cell in response to pH and glutathione signals, demonstrating superior anticancer efficacy in breast cancer-bearing mice. In conclusion, the dual-responsive nanoparticle could be used as a drug carrier to enhance drug delivery in breast cancer chemotherapy.

Breast cancer holds the highest incidence rate among women. Doxorubicin (DOX) is a potent frontline drug for the treatment of breast cancer. The anticancer mechanisms of DOX include inducing immunogenic cell death in tumor cells, causing damage to tumor DNA, and generating free radicals. However, its pharmacological efficacy and wide use are restricted by its substantial dose-dependent side effects. We have recently revealed that 1,7-Heptanediol (1,7-Hept) severely impairs the bioenergetics and metabolism of aggressive human cancer cells. In the present work, we prepared liposomes co-loaded with DOX and 1,7-Hept (DOX/1,7-Hept-lipo) and assessed their potential synergistic anti-tumor effects. In vitro studies demonstrated that 4T1 cells (the mouse breast cancer cell) exhibited higher sensitivity to 1,7-Hept and DOX/1,7-Hept-lipo could induce ICD of 4T1 cells. Cell viability was markedly reduced when 4T1 cells were treated with a combination of DOX and 1,7-Hept. In a mouse breast cancer model, the DOX/1,7-Hept-lipo exhibited superior anti-tumor efficacy compared to liposomes loaded with individual drugs, resulting in almost total elimination of the tumors at lower doses of DOX with reduced systemic toxicity. Notably, the number of immune cells significantly increased in the tumor microenvironment, and macrophages were more transformed into the anti-tumor M1 phenotype. Our findings suggest strong synergistic anti-tumor effects of DOX and 1,7-Hept, enhancing the efficacy of tumor immunotherapy and mitigating the toxic side effects of DOX.

Organ-on-a-chip is an advanced system for evaluating drug response in diseases. It simulates the in vivo tumor microenvironment, aiding in the understanding of drug mechanisms and tumor responses. It mimics the structure of the tumor microenvironment and the dynamic conditions within the body. As a result, it holds the potential for applications in precision and personalized medicine. However, there are still limitations in sequential development processes and complex structures, resulting in time-consuming molecular interference during system development. In this study, we developed a channel-assembling tumor microenvironment-on-chip (CATOC) system to overcome these limitations. CATOC was easily segmented into blood vessels and a tumor microenvironment-on-chip, which can be independently developed. The tumor microenvironment-on-chip consists of two independent channels for evaluating drug responses in different types of tumor microenvironments. Each fully developed system was physically interconnected to create a CATOC. Interconnected CATOC was used to validate chemical and targeted anticancer drug responses in different subtypes of the breast tumor microenvironment. We also emphasized the significance of on-chip experiments by observing the drug response of tumor spheroids on CATOC and scaffold-free platforms.