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B-cell non-Hodgkin lymphomas (B-NHL) represent the most common type of hematologic malignancies in the Western hemisphere. The therapy of all B-NHL is based on the combination of different genotoxic cytostatics and anti-CD20 monoclonal antibody (mAb) rituximab. Unfortunately, many patients relapse after the mentioned front-line treatment approaches. The therapy of patients with relapsed/refractory (R/R) B-NHL represents an unmet medical need. We designed, developed and tested novel actively targeted hybrid mAb-polymer-drug conjugate (APDC) containing anti-CD20, anti-CD38 or anti-CD19 mAbs. Biocompatible copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) with cytostatic agent doxorubicin attached via stimuli-sensitive hydrazone bond were employed for the mAb grafting. Anti-lymphoma efficacy of the APDC nanotherapeutics was evaluated in vivo on a panel of three patient-derived lymphoma xenografts derived from two patients with R/R B-NHL and one patient with so far untreated B-NHL. In both PDX models derived from patients with R/R B-NHL, the targeting with anti-CD38 antibody daratumumab demonstrated highly improved anti-lymphoma efficacy compared to the targeting with anti-CD20 rituximab, two experimental anti-CD19 antibodies and non-targeted controls. The results represent a proof-of-concept of a new algorithm of personalized anti-tumor therapy based on highly innovative APDC biomaterials.Osteoarthritis (OA) and intervertebral disc degeneration (IVDD) as major cause of chronic low back pain represent the most common degenerative joint pathologies and are leading causes of pain and disability in adults. Articular cartilage (AC) and intervertebral discs are cartilaginous tissues with a similar biochemical composition and pathophysiological aspects of degeneration. Although treatments directed at reversing these conditions are yet to be developed, many promising disease-modifying drug candidates are currently under investigation. Given the localized nature of these chronic diseases, drug delivery systems have the potential to enhance therapeutic outcomes by providing controlled and targeted release of bioactives, minimizing the number of injections needed and increasing drug concentration in the affected areas. This review provides a comprehensive overview of the currently most promising disease-modifying drugs as well as potential drug delivery systems for OA and IVDD therapy.Epidermal growth factor receptor (EGFR), involved in cell proliferation and migration, is overexpressed in ~50% of glioblastomas. Anti-EGFR based strategies using monoclonal antibodies (mAb) such as cetuximab (CTX) have been proposed for central nervous system (CNS) cancer therapy. However, the blood-brain barrier (BBB) drastically restricts their brain penetration which limits their efficacy for the treatment of glioblastomas. Herein, a longitudinal PET imaging study was performed to assess the relevance and the impact of focused ultrasound (FUS)-mediated BBB permeabilization on the brain exposure to the anti-EGFR mAb CTX over time. For this purpose, FUS permeabilization process with microbubbles was applied on intact BBB mouse brain before the injection of 89Zr-labeled CTX for longitudinal imaging monitoring. FUS induced a dramatic increase in mAb penetration to the brain, 2 times higher compared to the intact BBB. The transfer of 89Zr-CTX from blood to the brain was rendered significant by FUS (kuptake = 1.3 ± 0.23 min-1 with FUS versus kuptake = 0 ± 0.006 min-1 without FUS). FUS allowed significant and prolonged exposure to mAb in the brain parenchyma. check details This study confirms the potential of FUS as a target delivery method for mAb in CNS.To date, many clinical trials have been carried out with neoantigen-specific mRNA vaccines, and positive results have been achieved. However, further improvements in the efficiency of the intracellular delivery of mRNA and the production of a stronger immune response are still worth studying. In this study, we used the cholesterol-modified cationic peptide DP7 (VQWRIRVAVIRK), which was developed in our previous study, with a transmembrane structure and immunoadjuvant function to modify DOTAP liposomes to create a common mRNA delivery system. This system was intended to improve the efficiency of the delivery of mRNA encoding individualized neoantigens to dendritic cells (DCs) and enhance the activation of DCs. The system serves dual functions as a carrier and as an immunoadjuvant. As a carrier of mRNA, DP7-C-modified DOTAP liposomes (DOTAP/DP7-C) could transfer mRNA efficiently into different type of DCs in vitro. As an immunoadjuvant, DOTAP/DP7-C liposomes were shown to be more efficacious in stimulating DC maturation, CD103+ DC (contributing to antigen presentation) production and proinflammatory cytokine secretion than DOTAP liposomes both in vitro and in vivo. In animal studies, the subcutaneous administration of DOTAP/DP7-C/LL2 neoantigen-encoding mRNA complexes significantly inhibited the growth of LL2 in situ and the growth of subcutaneous tumors and stimulated the production of antigen-specific lymphocyte reactions, which were superior to the DOTAP/LL2 neoantigen-encoding mRNA complex group. In conclusion, DOTAP/DP7-C liposomes may serve as a potential universal mRNA delivery system, providing a simple method to increase the efficiency of intracellular mRNA delivery and the immunostimulatory activity of DCs.Liposome-supported peritoneal dialysis (LSPD) with transmembrane pH-gradient liposomes was previously shown to enhance ammonia removal in cirrhotic rats and holds promise for the treatment of hyperammonemic crises-associated disorders. The main objective of this work was to conduct the preclinical evaluation of LSPD in terms of pharmacokinetics, ammonia uptake, and toxicology to seek regulatory approval for a first-in-human study. The formulation containing citric acid-loaded liposomes was administered intraperitoneally at two different doses once daily for ten days to healthy minipigs. It was also tested in a domestic pig model of hyperammonemia. The pharmacokinetics of citric acid and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine was linear following intraperitoneal administration of medium and high dose. There was no systemic accumulation following daily doses over ten days. The systemic exposure to phospholipids remained low. Furthermore, the liposome-containing peritoneal fluid contained significantly higher ammonia levels than the liposome-free control, demonstrating efficient ammonia sequestration in the peritoneal space.
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