Journal of Controlled Release最新文献

The retinoid fenretinide (FENR) is a promising compound for preventing breast cancer recurrence but faces challenges due to poor solubility and low bioavailability. This study explores the development of dissolving microneedles (MNs) containing FENR-loaded ethosomes for minimally invasive breast cancer chemoprevention, aiming to enhance local drug distribution. Ethosomes were formulated using ethanol, propylene glycol, soya lecithin, water, and polysorbate 80 micelles. MNs were created from poly(vinyl alcohol) and poly(vinylpyrrolidone) hydrogels by adding polymer powder directly into ethosomes suspensions, reducing manufacturing time and cost. Two methods were used to load ethosomes into high-density moulds: 1) only in the needle area, and 2) in both the needle area and baseplate. Dynamic light scattering confirmed nanostructures in the hydrogels and MNs. Micelle-based ethosomes dissolved MNs in 15 min, compared to 30 min for other MNs. Skin deposition studies showed greater drug deposition (up to 10 μg/patch) and enhanced skin permeation of FENR (up to 40 μg) with Method 2. In-vivo studies in rats demonstrated that oral administration resulted in plasma FENR levels below 10 ng/g in the first three hours, whereas MN administration delayed delivery, reaching a maximum plasma concentration of 52 ng/g at 48 h. Skin deposition of FENR from MNs decreased from 3 μg/g on day 1 to <0.3 μg/g by the last day. This study indicates that MNs are a potential minimally invasive dosage form for delivering FENR, offering a new approach for breast cancer chemoprevention.

Small extracellular vesicles (SEV) have attracted much attention both as mediators of intercellular communication and as drug delivery systems. In addition, recent studies have shown that SEV containing virus components and virus particles are released from virus-infected cells. Oncolytic viruses, which efficiently kill tumor cells by tumor cell-specific replication, have been actively studied as novel anticancer agents in clinical and preclinical studies. However, it remains to be fully elucidated whether SEV released from oncolytic virus-infected cells are involved in the antitumor effects of oncolytic viruses. In this study, we examined the tumor cell killing efficiencies and innate immune responses following treatment with SEV released from oncolytic reovirus-infected tumor cells in vitro and in vivo. Reovirus-infected B16 cells secreted SEV associated with or containing reovirus particles (Reo-SEV) with a diameter of approximately 130 nm and a zeta potential of −17 mV, although death of reovirus-infected B16 cells was not observed. The secreted Reo-SEV also contained interferon (IFN)-β, tumor antigens, and damage-associated molecular patterns (DAMPs), including heat shock proteins (HSPs). Reo-SEV were secreted from the tumor tissues of reovirus-injected mice. Inhibition of the SEV secretion pathway using GW4869, which is a neutral sphingomyelinase inhibitor, resulted in significant reduction in the infectious titers of reovirus in the culture supernatants, suggesting that the cells released progeny virus via the SEV secretion pathway. Reo-SEV more efficiently killed mouse tumor cells and induced innate immune responses in mouse bone marrow-derived dendritic cells than reovirus. Reovirus and Reo-SEV mediated efficient and comparable levels of growth suppression of B16 subcutaneous tumors and induction of tumor infiltration of CD8+ T cells following intravenous administration. These results indicate that Reo-SEV are a promising oncolytic agent and that SEV are an effective delivery vehicle for oncolytic virus.

Corneal neovascularization (CNV) is a major cause of blindness worldwide. However, the recent drug treatment is limited by repeated administration and low drug bioavailability. In this work, SU6668 (an inhibitor of receptor tyrosine kinases) and indocyanine green (ICG) are loaded onto poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and then coated with anti-VEGFR2 single chain antibody (AbVr2 scFv) genetically engineered cell membrane vesicles. The nanomedicine is delivered via eye drops, and the hyperthermia induced by laser irradiation could block the blood vessels. Meanwhile, the photothermal effect can also cause the degradation of nanomaterials and release chemotherapeutic drugs in the blocked area, thereby continuously inhibit the neovascularization. Furthermore, SU6668 could inhibit the expression of heat shock protein 70 (HSP70), promoting the cell death induced by photothermal effect. In conclusion, the combination of photothermal and chemotherapy drugs provides a novel, effective and safe approach for the treatment of CNV.

Predictive performance assays are crucial for the development and approval of nanomedicines and their bioequivalent successors. At present, there are no established compendial methods that provide a reliable standard for comparing and selecting these formulation prototypes, and our understanding of the in vivo release remains still incomplete. Consequently, extensive animal studies, with enhanced analytical resolution for both, released and encapsulated drug, are necessary to assess bioequivalence. This significantly raises the cost and duration of nanomedicine development. This work presents the development of a discriminatory and biopredictive release test method for liposomal prednisolone phosphate. Using model-informed deconvolution, we identified an in vivo target release. The experimental design employed a discrete L-optimal configuration to refine the analytical method and determine the impact of in vitro parameters on the dosage form. A three-point specification evaluated the key phases of in vivo release: early (T-5%), intermediate (T-20%), and late release behavior (T-40%), compared to the in vivo release profile of the reference product, NanoCort®. Various levels of shear responses and the influence of clinically relevant release media compositions were tested. This enabled an assessment of the effect of shear on the release, an essential aspect of their in vivo deformation and release behavior. The type and concentration of proteins in the medium influence liposome release. Fetal bovine serum strongly impacted the discriminatory performance at intermediate shear conditions. The method provided deep insights into the release response of liposomes and offers an interesting workflow for in vitro bioequivalence evaluation.

Self-amplifying RNA (saRNA) is a next-generation RNA platform derived from an alphavirus that enables replication in host cytosol, offering a promising shift from traditional messenger RNA (mRNA) therapies by enabling sustained protein production from minimal dosages. The approval of saRNA-based vaccines, such as the ARCT-154 for COVID-19 in Japan, underscores its potential for diverse therapeutic applications, including vaccine development, cancer immunotherapy, and gene therapy. This study investigates the role of delivery vehicle and administration route on saRNA expression kinetics and reactogenicity. Employing ionizable lipid-based nanoparticles (LNPs) and polymeric nanoparticles, we administered saRNA encoding firefly luciferase to BALB/c mice through six routes (intramuscular (IM), intradermal (ID), intraperitoneal (IP), intranasal (IN), intravenous (IV), and subcutaneous (SC)), and observed persistent saRNA expression over a month. Our findings reveal that while LNPs enable broad route applicability and stability, pABOL (poly (cystamine bisacrylamide-co-4-amino-1-butanol)) formulations significantly amplify protein expression via intramuscular delivery. Notably, the disparity between RNA biodistribution and protein expression highlight the nuanced interplay between administration routes, delivery vehicles, and therapeutic outcomes. Additionally, our research unveiled distinct biodistribution profiles and inflammatory responses contingent upon the chosen delivery formulation and route. This research illuminates the intricate dynamics governing saRNA delivery, biodistribution and reactogenicity, offering essential insights for optimizing therapeutic strategies and advancing the clinical and commercial viability of saRNA technologies.

Although lipid nanoparticles (LNPs) have been FDA-approved for mRNA delivery, there is still much to learn about these fascinating multi-component delivery systems. Here, I discuss the presence of “bleb” structures on LNPs and the co-existence of mRNA-empty LNPs in LNP-mRNA-based formulations. Specifically, I discuss key articles on these structural and compositional heterogeneities, whether these features present negative or positive LNP attributes, and how to deal with them in research and quality control settings. Additionally, I present current approaches and propose novel strategies on how to study and quantify bleb and empty LNP structures. With the conflicting views on these features in the literature and limited systematic studies on their impact on safety and efficacy, I hope this Perspective will support current and bring forward new thinking about these matters. I anticipate that novel studies and insights could emerge from these lines of thinking, which could potentially enhance the development of safe and efficient LNP-based drug products that will either embrace, leverage, or mitigate the presence of blebs and empty LNPs.

Bioorthogonal nanozymes have emerged as a potent tool in biomedicine due to their unique ability to perform enzymatic reactions that do not interfere with native biochemical processes. The integration of stimuli-responsive mechanisms into these nanozymes has further expanded their potential, allowing for controlled activation and targeted delivery. As such, intelligent bioorthogonal nanozymes have received more and more attention in developing therapeutic approaches. This review provides a comprehensive overview of the recent advances in the development and application of stimuli-responsive bioorthogonal nanozymes. By summarizing the design outlines for anchoring bioorthogonal nanozymes with stimuli-responsive capability, this review seeks to offer valuable insights and guidance for the rational design of these remarkable materials. This review highlights the significant progress made in this exciting field with different types of stimuli and the various applications. Additionally, it also examines the current challenges and limitations in the design, synthesis, and application of these systems, and proposes potential solutions and research directions. This review aims to stimulate further research toward the development of more efficient and versatile stimuli-responsive bioorthogonal nanozymes for biomedical applications.

Immunological adjuvants are vaccine components that enhance long-lasting adaptive immune responses to weakly immunogenic antigens. Monophosphoryl lipid A (MPLA) is a potent and safe vaccine adjuvant that initiates an early innate immune response by binding to the Toll-like receptor 4 (TLR4). Importantly, the binding and recognition process is highly dependent on the monomeric state of MPLA. However, current vaccine delivery systems often prioritize improving the loading efficiency of MPLA, while neglecting the need to maintain its monomeric form for optimal immune activation. Here, we introduce a Pickering emulsion-guided MPLA monomeric delivery system (PMMS), which embed MPLA into the oil-water interface to achieve the monomeric loading of MPLA. During interactions with antigen-presenting cells, PMMS functions as a chaperone for MPLA, facilitating efficient recognition by TLR4 regardless of the presence of lipopolysaccharide-binding proteins. At the injection site, PMMS efficiently elicited local immune responses, subsequently promoting the migration of antigen-internalized dendritic cells to the lymph nodes. Within the draining lymph nodes, PMMS enhanced antigen presentation and maturation of dendritic cells. In C57BL/6 mice models, PMMS vaccination provoked potent antigen-specific CD8⁺ T cell-based immune responses. Additionally, PMMS demonstrated strong anti-tumor effects against E.G7-OVA lymphoma. These data indicate that PMMS provides a straightforward and efficient strategy for delivering monomeric MPLA to achieve robust cellular immune responses and effective cancer immunotherapy.

Upon intravascular applications, i.e., cancer treatment, nanoparticles (NPs) are required to deliver through blood circulation, sustain serum protein interactions, before they penetrate the blood vessels and reach targeted sites for payload drug release. For a delivery process as such, it is elusive and difficult to comprehend the morphological change of NP surface and evaluate associated effects on its targeted delivery. Herein, we used silica NPs with different surface modifications to demonstrate the morphological impact of NPs during the application of the NP-blood protein interaction, vascular endothelial cell penetration, subsequent targeted delivery and photodynamic therapy efficacy, and pursue high drug-load NPs with surface designs. Compared to solid and mesoporous NPs, we found the spiky tubular NPs reserved the NPs' antifouling properties (or shedding of “protein corona”), promoted better endothelial penetration and less destruction in vitro and in vivo. Such effects could be attributed to their spiky surface structures, which can limit the NP-protein interaction area and promote the NP-protein steric hindrance. Further in molecular simulations, we determined that the spiky tubular morphological modification on NPs enhanced the interaction free energy and lowered the amino acids number and the subsequent frequency in contacting with VE-cadherin of vascular endothelia. As a result, the spiky tubular NPs demonstrated its advantages in mitigating damages to VE-cadherin stability and endothelial cell integrity. Exploiting such spiky tubular surface modification, we can improve the NP delivery efficiency and prohibit the leakiness of vascular endothelia, helping address challenges faced by tumor migration in nanomedicine applications for cancer therapy.

Recent studies have indicated that the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an ideal therapeutic target for osteoporosis because it affects the differentiation of osteoblasts and osteoclasts. RNA sequencing utilizing multifunctional graphene oxide (GO) nanosheets revealed a correlation between GO nanomaterials and the NLRP3 inflammasome, as well as osteogenic genes in macrophages. This study aimed to construct a bone microenvironment-responsive multifunctional two-dimensional GO coating on the surface of microporous sulfonated polyetheretherketone (SPEEK) via polydopamine modification (SPEEK@PDA-GO). In vitro analysis showed that the SPEEK@PDA-GO implants weakened the STAT3-mediated NLRP3/caspase-1/IL-1β signaling pathway in macrophages and subsequently prevented the formation of an extracellular inflammatory microenvironment, which is crucial for osteoclastogenesis. SPEEK@PDA-GO displayed significantly higher expression of M2 macrophage markers and osteogenic genes, indicating that the multifunctional GO nanosheets could facilitate bone regeneration via their immunomodulatory properties. The ability of SPEEK@PDA-GO to stimulate new bone formation and block bone loss caused by estrogen loss due to ovariectomy was also analyzed. The findings of this study offer valuable information on the possible involvement of the NLRP3 inflammasome in the interaction between the immune system and bone health in patients with osteoporosis.