Journal of Controlled Release最新文献

High Epidermal growth factor receptor (EGFR) in Cutaneous Squamous Cell Carcinoma (cSCC) is associated with poor prognosis and advanced metastatic stages, severely impeding the efficacy of EGFR-targeting immunotherapy. This is commonly attributed to the combinatory outcomes of hypoxic tumor microenvironment (TME) and immunosuppressive effector cells together. Herein, a novel paradigm of EGFR-targeting oxygen-saturated nanophotosensitizers, designated as CHPFN-O₂, has been specifically tailored to mitigate tumor hypoxia in EGFR-positive cSCC and achieve Cetuximab (CTX)-mediated immunotherapy (CIT). The conjugated CTX in CHPFN-O₂ serves to initiate immune responses by recruiting Fc receptor (FcR)-expressing immune effector cells towards tumor cells, thereby eliciting antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular trogocytosis (ADCT) and antibody-dependent cellular cytotoxicity (ADCC). Besides, CHPFN-O₂ can engender a shift from a tumor-friendly to a tumor-hostile one through improved tumor oxygenation, contributing to oxygen-elevated photodynamic therapy (oxPDT). Notably, the combination of oxPDT and CIT eventually promotes T-cell-mediated antitumor activity and successfully inhibits the growth of EGFR-expressing cSCC with good safety profiles. This comprehensive oxPDT/CIT integration aims not only to enhance therapeutic efficacy against EGFR^high cSCC but also to extend its applicability to other EGFR^high malignancies, thus delineating a new avenue for the highly efficient synergistic treatment of EGFR-expressing malignancies.

Sonoporation-based delivery has great promise for noninvasive drug and gene therapy. After short-term membrane resealing, the long-term function recovery of sonoporated cells affects the efficiency and biosafety of sonoporation-based delivery. It is necessary to identify the key early biological signals that influence cell fate and to develop strategies for manipulating the long-term fates of sonoporated cells. Here, we used a customized experimental platform with a single cavitating microbubble induced by a single ultrasound pulse (frequency: 1.5 MHz, pulse length:13.33 μs, peak negative pressure: ∼0.40 MPa) to elicit single-site reversible sonoporation on a single HeLa cell model. We used a living-cell microscopic imaging system to trace the long-term fates of sonoporated HeLa cells in real-time for 48 h. Fluorescence from intracellular propidium iodide and Fluo-4 was used to evaluate the degree of sonoporation and intracellular calcium fluctuation (ICF), respectively. Changes in cell morphology were used to assess the long-term cell fates (i.e., proliferation, arrest, or death). We found that heterogeneously sonoporated cells had different long-term fates. With increasing degree of sonoporation, the probability of normal (proliferation) and abnormal fates (arrest and death) in sonoporated cells decreased and increased, respectively. We identified ICF as an important early event for triggering different long-term fates. Reversibly sonoporated cells exhibited stronger proliferation and restoration at lower extents of ICF. We then regulated ICF dynamics in sonoporated cells using 2-APB or BAPTA treatment to reduce calcium release from intracellular organelles and enhance intracellular calcium clearance, respectively. This significantly enhanced the proliferation and restoration of sonoporated cells and reduced the occurrence of cell-cycle arrest and death. Finally, we found that the long-term fates of sonoporated cells at multiple sites and neighboring cells were also dependent on the extent of ICF, and that 2-APB significantly enhanced their viability and reduced death. Thus, using a single HeLa cell model, we demonstrated that regulating intracellular calcium can effectively enhance the proliferation and restoration capabilities of sonoporated cells, therefore rescuing the long-term viability of sonoporated cells. These findings add to our understanding of the biophysical process of sonoporation and help design new strategies for improving the efficiency and biosafety of sonoporation-based delivery.

Many chemotherapeutic and molecular targeted drugs have been used to treat brain metastases, e.g., anti-angiogenic vandetanib. However, the blood-brain barrier and brain-specific resistance mechanisms make these systemic therapeutic approaches inefficacious. Brain metastatic cancer cells could mimic neurons to upregulate multiple serpins and secrete them into the extracellular environment to reduce local plasmin production to promote L1CAM-mediated vessel co-option and resist anti-angiogenesis therapy. Here, we developed brain-tumor-seeking and serpin-inhibiting outer membrane vesicles (DE@OMVs) to traverse across the blood-brain barrier, bypass neurons, and specially enter metastatic cancer cells via targeting GRP94 and vimentin. Through specific delivery of dexamethasone and embelin, reduced serpin secretion, restored plasmin production, significant L1CAM inactivation and tumor cell apoptosis were specially found in intracranial metastatic regions, leading to delayed tumor growth and prolonged survival in mice with brain metastases. By combining the brain-tumor-seeking properties with the regulation of the serpin/plasminogen activator/plasmin/L1CAM axis, this study provides a potent and highly-selective systemic therapeutic option for brain metastases.

For the non-invasive treatment of rheumatoid arthritis (RA), a chondroitin sulfate C (CSC)-based dissolving microneedles (cMN) was prepared to deliver human adipose stem cell-derived extracellular vesicles (hASC-EV) into inflamed joints. Owing to their anti-inflammatory function, the hASC-EV-bearing cMN (EV@cMN) significantly suppressed activated fibroblast-like synoviocytes (aFLS) and M1 macrophages (M1), which are responsible for the progression of RA. In addition, EV@cMN facilitated the chondrogenic differentiation of bone marrow-derived stem cells. In mice with collagen-induced arthritis, EV@cMN efficiently delivered both hASC-EV and CSC to inflamed joints. Interestingly, pro-inflammatory cytokines in the inflamed joints were remarkably downregulated by the synergistic effect of CSC and hASC-EV. Consequently, as judged from the overall clinical score and joint swelling, EV@cMN showed an outstanding therapeutic effect, even comparable to the wild-type mice, without significant adverse effects. Overall, EV@cMN might have therapeutic potential for RA by efficiently delivering CSC and hASC-EV into the inflamed joints in a non-invasive manner.

Microcapsules encapsulating payloads are one of the most promising delivery methods. The mechanical properties of microcapsules often determine their application scenarios. For example, microcapsules with low mechanical strength are more widely used in biomedical applications due to their superior biocompatibility, softness, and deformability. In contrast, microcapsules with high mechanical strength are often mixed into the matrix to enhance the material. Therefore, characterizing and regulating the mechanical properties of microcapsules is essential for their design optimization. This paper first outlines four methods for the mechanical characterization of microcapsules: nanoindentation technology, parallel plate compression technology, microcapillary technology, and deformation in flow. Subsequently, the mechanisms of regulating the mechanical properties of microcapsules and the progress of applying microcapsules with different degrees of softness and hardness in food, textile, and pharmaceutical formulations are discussed. These regulation mechanisms primarily include altering size and morphology, introducing sacrificial bonds, and construction of hybrid shells. Finally, we envision the future applications and research directions for microcapsules with tunable mechanical properties.

In this work, we conceived and developed antibody-drug conjugates (ADCs) that could efficiently release the drug after enzymatic cleavage of the linker moiety by tumoral proteases. The antibody-drug linkers we used are the result of a rational optimization of a previously reported PEGylated linker, PUREBRIGHT® MA-P12-PS, which showed excellent drug loading capacities but lacked an inbuilt drug discharge mechanism, thus limiting the potency of the resulting ADCs. To address this limitation, we chose to incorporate a protease-sensitive trigger into the linker to favor the release of a “PEGless” drug inside the tumor cells and, therefore, obtain potent ADCs. Currently, most marketed ADCs are based on the Val-Cit dipeptide followed by a self-immolative spacer for releasing the drug in its unmodified form. Here, we selected two untraditional peptide sequences, a Phe-Gly dipeptide and a Val-Ala-Gly tripeptide and placed one or the other in between the drug on one side (N-terminus) and the rest of the linker, including the PEG moiety, on the other side (C-terminus), without a self-immolative group. We found that both linkers responded to cathepsin B, a reference lysosomal enzyme, and liberated a PEG-free drug catabolite, as desired. We then used the two linkers to generate ADCs based on trastuzumab (a HER2-targeting antibody) and DM1 (a microtubule-targeted cytotoxic agent) with an average drug-to-antibody ratio (DAR) of 4 or 8. The ADCs showed restored cytotoxicity in vitro, which was proportional to the DM1 loading and generally higher for the ADCs bearing Val-Ala-Gly in their structure. In an ovarian cancer mouse model, the DAR 8 ADC based on Val-Ala-Gly behaved better than Kadcyla® (an approved ADC of DAR 3.5 used as control throughout this study), leading to a higher tumor volume reduction and more prolonged median survival.

Taken together, our results depict a successful linker optimization process and encourage the application of the Val-Ala-Gly tripeptide as an alternative to other existing protease-sensitive triggers for ADCs.

Delivering therapeutic agents efficiently to inflamed regions remains an intractable challenge following myocardial ischemia-reperfusion injury (MI/RI) due to the transient nature of the enhanced permeability and retention effect, which disappears after 24 h. Leveraging the inflammation-homing and plasticity properties of circulating monocytes (MN) as hitchhiking carriers and further inducing their polarization into anti-inflammatory phenotype macrophages upon reaching the inflamed sites is beneficial for MI/RI therapy. Herein, DSS/PB@BSP nanoparticles capable of clearing reactive oxygen species and inhibiting inflammation were developed by employing hollow Prussian blue nanoparticles (PB) as carriers to encapsulate betamethasone sodium phosphate (BSP) and further modified with dextran sulfate sodium (DSS), a targeting ligand for the scavenger receptor on MN. This formulation was internalized into MN as living cell drug depots, reprogramming them into anti-inflammation type macrophages to inhibit inflammation. In vitro assessments revealed the successful construction of the nanoparticle. In a murine MI/RI model, circulating MN laden with these nanoparticles significantly enhanced drug delivery and accumulation at the cardiac injury site, exhibiting favorable therapeutic ability and promoting M2-biased differentiation. Our study provides an effective approach with minimally invasion and biosecurity that makes this nanoplatform as a promising candidate for immunotherapy and clinical translation in the treatment of MI/RI.

The microbiota at different sites in the body is closely related to disease. The intake of probiotics is an effective strategy to alleviate diseases and be adjuvant in their treatment. However, probiotics may suffer from harsh environments and colonization resistance, making it difficult to maintain a sufficient number of live probiotics to reach the target sites and exert their original probiotic effects. Encapsulation of probiotics is an effective strategy. Therefore, probiotic delivery systems, as effective methods, have been continuously developed and innovated to ensure that probiotics are effectively delivered to the targeted site. In this review, initially, the design of probiotic delivery systems is reviewed from four aspects: probiotic characteristics, processing technologies, cell-derived wall materials, and interactions between wall materials. Subsequently, the review focuses on the effects of probiotic delivery systems that target four main microbial colonization sites: the oral cavity, skin, intestine, and vagina, as well as disease sites such as tumors. Finally, this review also discusses the safety concerns of probiotic delivery systems in the treatment of disease and the challenges and limitations of implementing this method in clinical studies. It is necessary to conduct more clinical studies to evaluate the effectiveness of different probiotic delivery systems in the treatment of diseases.