Drug Delivery最新文献

Liver cancer is a common malignancy in the world, and its incidence and mortality rate are increasing year by year. The disease has a short course and a high mortality rate, posing a serious threat to humanity and health. The objective of this study is to create novel liver-targeted nanoparticles as a potential treatment for liver cancer. The aptamer (APS613-1) modified redox-sensitive norcantharidin solid lipid nanoparticles (Apt-PEG₂₀₀₀-ss-NCTD-SLNs) were prepared by emulsified ultrasonic dispersion method and characterized. The tumor targeting, antitumor effect and safety of the nanoparticles were investigated and evaluated in vitro and in vivo. The particle size of Apt-PEG₂₀₀₀-ss-NCTD-SLNs was 87.95 ± 3.32 nm, and the encapsulation efficiency was about 80.74 ± 2.36%, which had good biocompatibility. The results of in vitro experiments showed that, compared with unmodified solid lipid nanoparticles (NCTD-SLNs), Apt-PEG_2000-ss-NCTD-SLNs had better targeting for liver tumor cells, and a stronger ability to inhibit cell proliferation and migration, as well as promote cell apoptosis. The in vivo results revealed that Apt-PEG₂₀₀₀-ss-NCTD-SLNs demonstrated good safety and anti-tumor efficacy, and its mechanism was achieved through the inhibition of cell proliferation and induction of apoptosis. The functionalized nanoparticles modified by aptamer APS613-1 can be used for the liver-targeted delivery of antitumor drugs for the treatment of liver cancer, and Apt-PEG₂₀₀₀-ss-NCTD-SLN is a potential drug for the treatment of liver cancer.

Transarterial radioembolization (TARE) is an established treatment method for non-resectable liver tumors. One of the challenges of the approach is the accurate prediction of the microsphere biodistribution in the liver. We propose to use ultrasound contrast microbubbles as holmium microsphere precursors, which allows real-time prediction of the microsphere trajectories and biodistribution using dynamic contrast-enhanced ultrasound (DCE-US). The immediate goal in this in vitro study was to investigate the predictive capabilities of microbubbles as microsphere precursors. The study was conducted in an experimental in vitro model which represents the bifurcating right branch of the hepatic artery. A controlled injection of experimental BR-14 ultrasound contrast microbubbles and non-radioactive holmium-165 microspheres was performed in separate consecutive experiments in an arterial flow phantom. The microbubbles and microspheres were collected separately at the outlets of the phantom and counted using a Coulter counter to determine their distribution over the different outlets. The flow profile, the injection velocity, and the catheter position were monitored during the measurements to ensure stability. The results showed a good correlation between the microbubble and the microsphere distributions (p = 0.0038, r = 0.88) measured at the outlets. Differences in the distributions could be attributed to the characteristics of microbubbles and microspheres alone (e.g. particle size and concentration), since critical parameters were kept stable between the two experiments. The current in vitro study provides confidence that the microsphere biodistribution can be predicted using contrast microbubbles. The comparison provided by this study forms a foundation for the development of a DCE-US guided TARE treatment.

Bacterial diseases are a significant challenge to human and animal health. The current treatment methods still have obvious shortcomings, such as poor targeting, low bioavailability, high side effects and drug resistance. Chitosan, with its outstanding biocompatibility, biodegradability, adhesiveness, antimicrobial properties, and ability to minimize drug side effects while improving bioavailability and therapeutic outcomes, serves as an ideal material for drug delivery systems, presenting a promising strategy for treating bacterial diseases. In this review, we briefly summarize the preparation methods of chitosan-based drug delivery systems and their application in the treatment of bacterial infections. The advantages of preparation of different types of chitosan-based drug delivery systems are discussed, supported by examples demonstrating their ability to improve drug antimicrobial activity, targeting, and bioavailability. Moreover, the current challenges, limitations, and future perspectives in this field were discussed, laying the groundwork for further development of chitosan-based drug delivery systems as high-performance and safe antimicrobial therapeutics.

A clinical need exists for more effective intravitreal (IVT) drug delivery systems (DDS). This study tested the hypothesis that a novel biodegradable, injectable microsphere-hydrogel drug delivery system loaded with aflibercept (aflibercept-DDS) would exhibit long-term safety and biocompatibility in a non-human primate (NHP) model. We generated aflibercept-loaded poly (lactic-co-glycolic acid) microparticles with a modified double emulsion technique then embedded them into a biodegradable, thermo-responsive poly (ethylene glycol)-co-(L-lactic-acid) diacrylate/N-isopropylacrylamide hydrogel. Aflibercept-DDS (50 µL, 15 µg) was injected into the right eye of 23 healthy rhesus macaques. A complete ophthalmic examination, intraocular pressure (IOP), corneal pachymetry, specular microscopy, A-scan biometry, streak retinoscopy, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and electroretinography (ERG) were performed monthly. Globes from 7 NHPs were histologically examined. Aflibercept-DDS was visualized in the vitreous up to 9 months post-IVT injection, slightly impeding fundoscopy in 4 of 23 eyes; no other consistent abnormalities were appreciated during ophthalmic examination. The IOP and total retinal thickness remained normal in all animals over all timepoints. Central corneal thickness, endothelial cell density, axial globe length, and refractive error did not significantly differ from baseline. Scotopic mixed rod-cone implicit times and amplitudes along with photopic cone response implicit times and amplitudes did not significantly differ from control values. No retinal or choroidal vascular abnormalities were detected with FA and normal retinal architecture was preserved using SD-OCT. Intravitreal injection of a biodegradable aflibercept-DDS was safe and well tolerated in NHPs up to 24 months.

As T and NK cell exhaustion is attributed to increased expression of immune checkpoints and decreased production of proliferative cytokines by these cells, immune checkpoint-targeted delivery of proliferative cytokines might induce robust and sustained antitumor immune responses. Here, the expression profile of NKG2A was first found to be narrower than that of PD-1 in tumor-infiltrated immune cells. Moreover, unlike PD-1, NKG2A was predominantly co-expressed with IL-2Rβγ in tumor-infiltrated CD8⁺ T and NK cells, but not in Tregs, suggesting that NKG2A might be an ideal target for delivery of IL-2Rβγ agonists to overcome T and NK exhausting. For NKG2A-targeted delivery of an IL-2Rβγ agonist, a single molecule of de novo designed N215 endowed with Immunoglobin G(IgG)-binding ability was coupled to an antibody against NKG2A (αNKG2A) to produce αNKG2A-N215. NKG2A- and IL-2Rβγ-binding were well preserved in αNKG2A-N215, allowing αNKG2A-N215 to act as both an immune checkpoint inhibitor and a T and NK cell stimulator. Intravenously injected αNKG2A-N215 predominantly induced expansion of tumor-infiltrated CD8⁺ T and NK cells while showing little stimulation of Tregs. Compared with the separate combination using αNKG2A and N215, αNKG2A-N215 exerted a greater antitumor effect in mice bearing MC38 or B16/F1 tumors. 50% of mice bearing MC38 tumors were cured by αNKG2A-N215, and long-term immunological memory against the tumor was induced in these mice. These results indicate that NKG2A is another ideal target for delivery of an IL-2Rβγ agonist, and αNKG2A-N215, with specificities for both NKG2A and IL-2Rβγ, might be developed as a novel agent for immunotherapy.

Cancer poses a major threat to human health, and conventional treatments (such as surgery, radiotherapy (RT), and chemotherapy) are often associated with significant toxic side effects, poor targeting, and drug resistance. In recent years, nanomedicine, an emerging interdisciplinary field, has provided novel strategies for cancer diagnosis and therapy by enabling precise drug delivery and multifunctional integration. Among various nanoplatforms, metal nanoparticles (MNPs) have become a research hotspot due to their unique physicochemical properties, including optical characteristics, catalytic activity, and surface modifiability. This article systematically explores the role of MNPs in cancer therapy. It first outlines their classification and synthesis strategies. Subsequently, it analyzes their innovative applications in tumor diagnosis, RT, chemotherapy, and immunotherapy. A key focus is placed on elucidating how MNPs exploit distinctive features of the tumor microenvironment - such as acidic pH, elevated reactive oxygen species (ROS) levels, and high glutathione (GSH) concentrations - to achieve responsive and targeted drug delivery. Finally, the main challenges currently faced in this field are analyzed. This review aims to provide theoretical guidance and technical references for the rational design and clinical translation of MNPs.

Low solubility restricted transdermal penetration of drugs. We aimed to develop a novel ionic liquid-iontophoresis (IL-IS) technology and assess their efficacy and primary factors in facilitating transdermal drug delivery. Five choline-based ILs with different chain length were synthesized and validated, and the impact of IL and/or IS technology on transdermal penetration of model drugs were investigated. The results indicated that five groups of ILs synthesized in this study exhibited minimal level of toxicity, and the longer the chain of acid ligands of ILs, the greater the cytotoxicity. The longer chain of acid ligand was demonstrated superior solubilizing capabilities compared to the shorter chain. Cinnamic acid-choline-based IL ([Cho] [Cin]) significantly improved permeation of all three model drugs, and permeation quantity was linearly positively associated with the concentration of ILs. The 10 h cumulative permeation of aripiprazole applied with ILs alone was enhanced by about 14-fold when paired with IS, and the penetration was linearly positively associated with the concentration and current strength of the ILs. In vivo results indicated that IL and/or IS technology primarily facilitated drug penetration into the skin, with potential involvement of endocytosis in this process. This study demonstrated that [Cho] [Cin] exhibited a significant enhancement in the transdermal delivery of three sparingly soluble drugs. It further enhanced the transdermal permeation of weak base drug following with the combining IL and IS technology. These findings highlighted that the IL-IS technology holded promise for facilitating the transdermal delivery of sparingly soluble and weak base drugs.

Extracellular vesicles (EVs), particularly small EVs (sEVs), are lipid bilayer vesicles secreted by various cell types and play a key role in intercellular communication. These vesicles are promising tools for cancer immunotherapy owing to their biocompatibility, low immunogenicity, and capacity for targeted drug delivery. In this study, we aimed to assess the potential of engineered antigen-presenting EVs (AP-EVs) to selectively expand and differentiate antigen-specific CD4⁺ T cells. We engineered two types of AP-EVs: AP-EVs-Th1 expressing MHC class II, CD80, and interleukin (IL)-12 on their surface to promote Th1 differentiation, and AP-EVs-Th2 expressing MHC class II, CD80, and IL-4 to induce Th2 differentiation. In vitro experiments demonstrated that AP-EVs successfully induced the antigen-specific proliferation and differentiation of Th1 and Th2 cells, respectively. Notably, in vivo administration of AP-EVs-Th1 significantly enhanced the proliferation and differentiation of tumor antigen-specific Th1 cells, leading to robust anti-tumor effects in a murine melanoma model. These findings highlight the potential of AP-EVs-Th1 for cancer immunotherapy, particularly in augmenting CD4⁺ T cell responses. Furthermore, the versatility and adaptability of EV-based therapies make them beneficial for the development of personalized immunotherapeutic strategies for various cancer types, offering the advantages of targeted immune modulation, ease of use, and reduced risk compared to cell-based therapies.