Drug Delivery最新文献

The present study aimed to prepare and optimize lamotrigine-loaded bovine serum albumin nanoparticles (LAM-NP) using the Quality by Design (QbD) approach and to investigate both the in vitro and ex vivo effects of different cross-linking agents glutaraldehyde (GLUT), glucose (GLUC) and 1-(3-dimethylaminutesopropyl)-3-ethylcarbodiimide hydrochloride (EDC) on intranasal applicability. Cross-linked LAM-NP from EDC (NP-EDC-1) showed the lowest Z-average value (163.7 ± 1.9 nm) and drug encapsulation efficacy (EE%) of 97.31 ± 0.17%. The drug release of GLUC cross-linked LAM-NP (NP-GLUC-9), glutaraldehyde cross-linked LAM-NP (NP-GLUT-2), and NP-EDC-1 at blood circulation conditions was higher than the initial LAM. The results of the blood-brain barrier parallel artificial membrane permeability assay (BBB-PAMPA) showed an increase in the permeability of LAM through the BBB with NP-GLUC-9 and an increase in flux with all selected formulations. The ex vivo study showed that LAM diffusion from the selected formulations through the human nasal mucosa was higher than in case of initial LAM. The cytotoxicity study indicated that BSA-NP reduced LAM toxicity, and GLUC 9 mM and EDC 1 mg could be alternative cross-linking agents to avoid GLUT 2% v/v toxicity. Furthermore, permeability through Caco-2 cells showed that nasal epithelial transport/absorption of LAM was improved by using BSA-NPs. The use of BSA-NP may be a promising approach to enhance the solubility, permeability through BBB and decrease the frequency of dosing and adverse effects of LAM.

Anagrelide (ANA) is a phosphodiesterase 3A (PDE3A) inhibitor, commonly prescribed for essential thrombocythemia. It also functions as a molecular glue, inducing complex formation between PDE3A and Schlafen 12. This association either triggers apoptosis or inhibits proliferation in tumor cells, supporting its use in cancer therapy. Conventionally administered orally, ANA undergoes rapid metabolism and elimination, resulting in a short drug exposure time at the site of action. Here, we explored the pharmacokinetic profile of a subcutaneously (SC) injected ANA formulation in Sprague-Dawley rats by quantifying plasma ANA and metabolite concentrations using liquid-chromatography-tandem mass spectrometry. We further evaluated the in vivo tumor regression efficacy of orally and SC administered ANA in a patient-derived gastrointestinal stromal xenograft mouse model - UZLX-GIST2B - characterized by a KIT exon 9 driver mutation. The SC ANA exhibited extended-release plasma concentration-time profiles compared to intravenous and oral administrations. After a single administration in rats, plasma concentrations of ANA were detected up to 56 days later, and ANA metabolites up to 30 days later. The SC formulation also significantly reduced tumor volumes and demonstrated dose-dependent histological responses, nearly eradicating tumor tissue in 11 days with the highest dose. These findings suggest that the SC slow-release formulation maintains stable drug concentrations during treatment, potentially improving therapeutic efficacy at the target site.

Cannabidiol (CBD) is recognized for its therapeutic properties in various conditions. However, CBD's limited water solubility and sensitivity to environmental stresses hinder its efficacy and bioavailability. Encapsulation in drug delivery systems, particularly liposomes, offers a promising solution. This study aims to prepare CBD-containing liposomes using commercially used lipids distearoyl phosphatidylcholine (DSPC) and dipalmitoyl phosphatidylcholine (DPPC), and 1,2 distearoyl-sn-glycero-3 phosphoethanolamine-N-[carbonyl-amino(polyethylene glycol)-4300] (ammonium salt) (DSPE-PEG) and to perform in vitro studies - cell viability and CBD release. Liposomes were synthesized using thin-film hydration method, and characterized by Fourier-transform infrared (FT-IR) spectroscopy, dynamic light scattering (DLS), and scanning transmission electron microscopy (STEM). DLS analysis revealed that CBD incorporation reduced liposome size by 23-53%, depending on the liposomes. Encapsulation efficiency followed the order: DPPC CBD (63%) < DSPC CBD (74%) < DSPC DPPC CBD (81%) < DSPC DSPE-PEG CBD (87%). CBD release profiles indicated that DPPC CBD liposomes released the highest CBD amount initially, while DSPC DSPE-PEG CBD exhibited sustained release, achieving 79% release over 504 h. In vitro cell viability tests showed that blank liposomes were non-cytotoxic. However, CBD-loaded liposomes significantly reduced cell viability for defined type of CBD containing liposomes. The inclusion of DSPE-PEG improved encapsulation efficiency and liposome stability, making DSPC DSPE-PEG CBD liposomes more suitable for long-term CBD release. Compared to other studies, encapsulation of CBD in liposomes enhances its bioavailability, allowing lower concentrations of CBD to be directly delivered to cells, resulting in observable changes in cell viability.

Biopolymers, such as collagens, elastin, silk fibroin, spider silk, fibrin, keratin, and resilin have gained significant interest for their potential biomedical applications due to their biocompatibility, biodegradability, and mechanical properties. This review focuses on the design and integration of biomimetic peptides into these biopolymer platforms to control the release of bioactive molecules, thereby enhancing their functionality for drug delivery, tissue engineering, and regenerative medicine. Elastin-like polypeptides (ELPs) and silk fibroin repeats, for example, demonstrate how engineered peptides can mimic natural protein domains to modulate material properties and drug release profiles. Recombinant spider silk proteins, fibrin-binding peptides, collagen-mimetic peptides, and keratin-derived structures similarly illustrate the ability to engineer precise interactions and to design controlled release systems. Additionally, the use of resilin-like peptides showcases the potential for creating highly elastic and resilient biomaterials. This review highlights current achievements and future perspectives in the field, emphasizing the potential of biomimetic peptides to transform biopolymer-based biomedical applications.

Recent studies on head and neck squamous cell carcinoma (HNSCC) tumorigenesis have revealed several dysregulated molecular pathways. The phosphatidylinositol-3-kinase (PI3K) signaling pathway is frequently activated in HNSCC, making it an attractive target for therapies. PHT-427 is a dual inhibitor of PI3K and the mammalian target of AKT/PDK1. This study evaluates the anticancer efficacy of the inhibitor PHT-427 loaded into polymeric nanoparticles (NP) based on α-TOS (NP-427) administered by intratumoral injection into a hypopharyngeal squamous cell carcinoma (FaDu cells) heterotopic xenograft mouse model. The nanocarrier system, based on block copolymers of N-vinylpyrrolidone (VP) and a methacrylic derivative of α-TOS (MTOS), was synthesized, and PHT-427 was loaded into the delivery system. First, we evaluated the effect of NP-427 on tumor growth by measuring tumor volume, mouse weight, survival, and the development of tumor ulceration and necrosis. In addition, we measured PI3KCA/AKT/PDK1 gene expression, PI3KCA/AKT/PDK1 protein levels, Epidermal Growth Factor Receptor (EGFR), and angiogenesis in the tumor tissue. PHT-427 encapsulation increased drug efficacy and safety, as demonstrated by decreased tumor volume, reduced PI3K/AKT/PDK1 pathway expression, and improved antitumor activity and necrosis induction in the mouse xenograft model. EGFR and angiogenesis marker (Factor VIII) expression were significantly lower in the NP-427 group compared to other experimental groups. Administration of encapsulated PHT-427 at the tumor sites proves promising for HNSCC therapy.

Extracellular vesicles (EVs) are an experimental class of drug carriers. Alternative sources of EVs are currently being explored to overcome limitations related to their manufacturing from mesenchymal stem cells. In this work, Citrus limon-derived EVs were tested as carriers for the widely used chemotherapeutic drug - doxorubicin (DOX). Capillary electrophoresis (CE) and nanoplasmonic sensing (NPS) were developed for the quality control of DOX-EV preparations. It was found that the CE method enables simultaneous detection of free and incorporated DOX and allows assessing the stability of the preparations and the drug leakage. NPS, on the other hand, demonstrated that DOX is accumulated in the interfacial region of the carrier. The activity of DOX-loaded EVs was tested on HeLa (cervical cancer cells) and HEK293T (human embryonic kidney cells) cell lines. It was found that DOX incorporation into plant-derived EVs virtually does not affect the drug's cytotoxicity to HeLa cells but significantly decreases DOX activity against HEK293T cell line.

Celastrol (Cel) is a potential anticancer therapeutic candidate, but its limited practical applicability is due to its low solubility, poor tumor selectivity, and cytotoxicity. Clinically, ginsenoside Rg3 (RG3) is typically combined with chemotherapy to enhance antitumor effects and reduce side effects. Herein, we developed novel pH-sensitive prodrug nanoparticles (NPs) containing RG3 and Cel for the synergistic treatment of pancreatic cancer (PC). Amphiphilic prodrug, a PEGylated chitosan oligosaccharide coupled with RG3 via Schiff base bond, was self-assembled with hydrophobic Cel into NPs with drug loadings of 2.12% (Cel) and 1.63% (RG3). NPs exhibited a suitable particle size of 124.01 nm, zeta potential of -39.89 mV and good physical stability. In addition, NPs also showed a controlled drug release when the Schiff base bonds were hydrolyzed in the acidic environment. In Pan02 tumor-bearing mice, NPs exhibited a high accumulation in tumor tissues and prolonged blood circulation time. Furthermore, NPs could more effectively inhibit tumor growth and reduce systemic toxicity, compared with the free Cel, RG3, prodrug, and Cel + RG3. The results indicated that the NPs could provide a safe and promising nanoplatform for PC therapy.

Intradiscal drug delivery is a promising strategy for treating intervertebral disk degeneration (IVDD). Local degenerative processes and intrinsically low fluid exchange are likely to influence drug retention. Understanding their connection will enable the optimization of IVDD therapeutics. Release and retention of an inactive hydrophilic fluorine-19 labeled peptide (¹⁹F-P) as model for regenerative peptides was studied in a whole IVD culture model by measuring the ¹⁹F-NMR (nuclear magnetic resonance) signal in culture media and IVD tissue extracts. In another set-up, noninvasive near-infrared imaging was used to visualize IR-780, as hydrophobic small molecular drug model, retention upon injection into healthy and degenerative caudal IVDs in a rat model of disk degeneration. Furthermore, IR-780-loaded degradable polyester amide microspheres (PEAM) were injected into healthy and needle pricked degenerative IVDs, subcutaneously, and in knee joints with and without surgically-induced osteoarthritis (OA). Most ¹⁹F-P was released from the IVD after 7 days. IR-780 signal intensity declined over a 14-week period after bolus injection, without a difference between healthy and degenerative disks. IR-780 signal declined faster in the skin and knee joints compared to the IVDs. IR-780 delivery by PEAMs enhanced disk retention beyond 16 weeks. Moreover, in degenerated IVDs the IR-780 signal was higher over time than in healthy IVDs while no difference between OA and healthy joints was noted. We conclude that the clearance of peptides and hydrophobic small molecules from the IVD is relatively fast. These results illustrate that development of controlled release formulations should take into account the target anatomical location and local (patho)biology.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Beside early detection, early diagnosis, and early surgery, it is urgent to try new strategies for the treatment of HCC. Triptolide (TPL) has been employed to treat HCC. However, its clinical applications were restricted by the narrow therapeutic window, severe toxicity, and poor water-solubility. In this study, we developed cancer cell membrane-camouflaged biomimetic PLGA nanoparticles loading TPL (TPL@mPLGA) with the homologous targeting property for the treatment of HCC. The TPL@mPLGA was successfully prepared with particle size of 195.5 ± 7.5 nm and zeta potential at -21.5 ± 0.2 mV with good stability. The drug loading (DL) of TPL@mPLGA was 2.94%. After Huh-7 cell membrane coating, the natural Huh-7 cell membrane proteins were found to be retained on TPL@mPLGA, thus endowing the TPL@mPLGA with enhanced accumulation at tumor site, and better anti-tumor activity in vitro and in vivo when compared with TPL or TPL@PLGA. The TPL@mPLGA showed enhanced anti-tumor effects and reduced toxicity of TPL, which could be adopted for the treatment of HCC.