Fluorene methoxycarbonyl-PEG-deferoxamine conjugates "hitchhike" with albumin in situ for iron overload therapy.

Although deferoxamine (DFO) has been approved for the treatment the iron overloaded diseases, its clinical application is impeded by very short circulation time and its relating toxicity. In this work, the fluorene methoxycarbonyl (FMOC) for "albumin hitchhiking" was used to prolong the plasma circulation time of DFO and reduce toxicity. The designed FMOC-PEG-DFO conjugates were found to reversible bind to albumin and gradually release DFO in vivo. Herein, the FMOC-PEG1000-DFO conjugates could increase 30 times the blood circulation time of DFO with the improvement of the iron elimination efficacy. Meanwhile, the conjugates markedly reduced the cytotoxicity of DFO. Taken together, the result demonstrated the FMOC-PEG1000-DFO conjugates could be a potential therapeutic choice for iron-overload-related diseases.

An injectable superior depot of Telratolimod inhibits post-surgical tumor recurrence and distant metastases.

The clinical success of Toll-like receptor (TLR) agonists is based on their capacity to efficiently mobilize both innate and adaptive immunity. However, rapid distribution of TLR agonists into the systemic circulation may result in systemic cytokine storms. Telratolimod (Tel) is a TLR 7/8 agonist whose structure has a hydrophobic long chain that helps to prolong its release. Despite this, the phase I study of Tel showed cytokine release syndromes in 3/35 patients. Herein, we designed an injectable phase transition gel (PGE) that served as a superior drug depot for fatty acid-modified drugs. PGE further minimized the systemic drug exposure of Tel and the possible cytokine storms. In vivo studies demonstrated that Tel@PGE facilitated the recruitment of effector CD8+ T lymphocytes (T cells) and the polarization of myeloid-derived suppressor cells (MDSCs) and immunosuppressive M2-like macrophages to tumoricidal antigen-presenting cells. The reshaping of the tumor microenvironment (TME) by Tel@PGE elicited systematic immune responses to significantly prevent B16F10 or 4T-1 tumor postoperative recurrence and metastasis. Therefore, this platform of Tel is expected to provide a clinically available option for effective postoperative combined therapy. STATEMENT OF SIGNIFICANCE: A series of prodrugs or conjugates containing hydrophobic blocks were designed to achieve sustained release at the injection site by reducing the water solubility. However, this strategy sometimes failed short of expectations. Thus, we constructed a biocompatible and biodegradable injectable phase transition gel (PGE) with superior release properties that can be injected subcutaneously into the surgery site. In the long-lasting treatment, the melanoma and breast cancer immunotherapeutic effect significantly enhanced and the risk of cancer metastasis and relapse was reduced. Crucially, for some immune agonists, a superior release control can significantly reduce adverse effects which was decisive for the availability of the drugs.

Combining Co-Amorphous-Based Spray Drying with Inert Carriers to Achieve Improved Bioavailability and Excellent Downstream Manufacturability.

It is crucial to improve poorly water-soluble orally administered drugs through both preclinical and therapeutic drug discovery. A co-amorphous formulation consisting of two low molecular weight (MW) molecules offers a solubility/dissolubility advantage over its crystalline form by maintaining their amorphous status. Here, we report on a co-amorphous solid dispersion (SD) system that includes inert carriers (lactose monohydrate or microcrystalline cellulose) and co-amorphous sacubitril (SAC)-valsartan (VAL) using the spray drying process. The strong molecular interactions between drugs were the driving force for forming robust co-amorphous SDs. Our system provided the highest solubility with more than ~11.5- and 3.12-times solubility increases when compared with the physical mixtures. Co-amorphous lactose monohydrate (LM) SDs showed better bioavailability of APIs (~356.27.8% and 154.01% for the relative bioavailability of LBQ 657 and valsartan, respectively). Co-amorphous inert carrier SDs possessed an excellent compressibility for the production of a direct compression pharmaceutical product. In conclusion, these brand-new co-amorphous SDs could reduce the number of unit processes to produce a final pharmaceutical product for downstream manufacturability.

Designing orodispersible films containing everolimus for enhanced compliance and bioavailability.

INTRODUCTION: Everolimus (EVR) has been approved for the treatment of various advanced cancers and its indications are increasingly expanding. Therefore, it is crucial for patients who have difficulty in swallowing, such as pediatric and elderly patients, to obtain a convenient formulation. The oral absorption of EVR is limited due to its low solubility in water, intestinal metabolism by CYP3A4 enzyme, P-gp-mediated efflux, and metabolism in the liver. The aim of this study was to develop a novel sublingual orodispersible film loading everolimus for improving patient compliance and enhancing oral bioavailability of EVR. RESEARCH DESIGN AND METHODS: Sublingual orodispersible films loading EVR were prepared by the solvent casting method and evaluated by in vitro and in vivo studies. RESULTS: The properties of films were determined by scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectrometry. The addition of acacia gum appeared to be crucial for protecting the drug from oxidation. Pharmacokinetic studies showed that loading into the sublingual orodispersible films significantly increased the oral bioavailability of EVR. CONCLUSION: The EVR-loaded sublingual orodispersible films are a promising, economical, and convenient approach for delivering EVR efficiently in a solid dosage form.