Drug Delivery最新文献

PEGylation technology, that is grafting of poly(ethylene glycol)(PEG) to biologics, vaccines and nanopharmaceuticals, has become a cornerstone of modern medicines with over thirty products used in the clinic. PEGylation of therapeutic proteins, nucleic acids and nanopharmaceuticals improves their stability, pharmacokinetic and biodistribution. While PEGylated medicines are safe in the majority of patients, there are growing concerns about the emergence of anti-PEG antibodies and their impact on the therapeutic efficacy of PEGylated medicines as well as broader immune responses, particularly in complement activation and hypersensitivity reactions. These concerns are beginning to scrutinize the future viability of PEGylation technology in medicine design. Here, we outline these concerns, encourage more efforts into looking for comprehensive scientific evidence on the role of anti-PEG antibodies in hypersensitivity reactions, discuss alternatives to PEG and propose strategies for moving PEGylation technology forward.

Mango seed kernel extract (MSKE) and its phytochemical compositions were investigated for their anticancer activities and synergistic effects with doxorubicin (DOX) against hepatocellular carcinoma (HCC) in both 2D and 3D culture models. Molecular docking studies were conducted to elucidate the mechanisms of DOX, MSKE, and major phytochemical components against overexpressed HCC-related proteins. Co-delivery of DOX and MSKE demonstrated significant synergistic anticancer activity in both models. A sequential nanotheranostic platform (SNP), consisting of MSKE encapsulated aminated hollow mesoporous silica nanoparticles capped with graphene quantum dots (GQD-MSKE-NH₂HMSNs) and DOX encapsulated HMSNs (DOX-HMSNs), was synthesized for HCC treatment. GQD conjugation allowed real-time cellular tracking and photothermal therapy (PTT). The SNP exhibited particle sizes of 96.12 ± 5.12 nm for GQD-MSKE-NH₂HMSNs and 94.99 ± 6.30 nm for DOX-HMSNs, both with positive surface charges. Encapsulation efficiency (%EE) and loading capacity (%LC) of GQD-MSKE-NH₂HMSNs were 95.50 ± 0.20% and 46.72 ± 1.14%, respectively, while DOX-HMSNs achieved 96.42 ± 2.48 %EE and 29.0 ± 0.70 %LC. GQD-MSKE-NH₂HMSNs provided PTT and disrupted the tumor microenvironment, collagen type 1, thereby enhancing the penetration of GQD-MSKE-NH₂HMSNs in 3D-HCC spheroids. In parallel, DOX-HMSNs exhibited a pH-responsive drug release behavior, allowing controlled DOX delivery in the acidic tumor area. Therefore, the SNP demonstrated significantly higher anticancer efficacy than the combination of MSKE and DOX at equivalent concentrations and provided the synergistic effect of the triple combination therapy (herbal adjuvant, PTT and chemotherapy) against HCC.

Drug delivery to ocular posterior segment remains difficult due to the challenges imposed by dynamic and static ocular barriers, lesion point targeting, and off-target effect. In this study, a novel approach is demonstrated for non-invasive drug delivery to the ocular posterior segments using lactose-modified azocalix[4] arene (LacAC4A) as a supramolecular ocular drug delivery platform. LacAC4A contains azo groups and is covalently modified by lactose groups, which confers active targeting to the retina, and induces a hypoxic response. The immunomodulator methotrexate (MTX), which is commonly used in ophthalmology to treat immune system diseases such as uveitis, was also selected as a guest to prepare MTX@LacAC4A. The prepared LacAC4A and MTX@LacAC4A systems were characterized, then the internalization mechanisms and hypoxia response abilities were determined through flow cytometry and fluorescence imaging, respectively. Besides, the delivery route and efficiency were verified, and the safety profile of MTX@LacAC4A was evaluated in multiple dimensions. Importantly, it was found that the prepared MTX@LacAC4A exhibits good biocompatibility, can effectively reach the posterior segment, and demonstrates potential ophthalmic applications. These findings lay the grounds for the future development of non-invasive ocular posterior segment disease treatments based on the advanced use of LacAC4A as a drug delivery platform.

Diabetic retinopathy (DR), which affects over millions of individuals globally, is the leading cause of permanent visual loss. Current therapies, including as intravitreal anti-vascular endothelial growth factor (VEGF) medications and laser photocoagulation, are limited by frequent dosing and side effects. Liposomes, with their ability to encapsulate hydrophilic and hydrophobic medications, offer tailored delivery, prolonged release, and low systemic toxicity. This study looks at advances in liposomal formulations that address DR's multifactorial etiology, including as anti-angiogenic, anti-inflammatory, and antioxidant processes. We assess new preparation methods (e.g. supercritical CO₂, microfluidics) and clinical considerations, including stability and cost-effectiveness. To address the heterogeneity of DR, future endeavors will prioritize combinatorial medications and customized therapy.

Pulmonary infection is a serious public health challenge with high morbidity and mortality. The employment of antibiotics is the first-line treatment for pulmonary infections, while other novel anti-infection agents, such as antimicrobial peptides, have also been developed due to the emergence of drug resistance. Recently, inhalable nanoparticle-based delivery systems have garnered significant attention for the delivery of anti-infection agents, which possess great advantages like high lung accumulations and precise delivery performances. However, the respiratory physiological structure, mucus and biofilm have been considered as the barriers that nanoparticle drug delivery systems facing, which compromise the therapeutic effects. In this integrative review, recent advances in the inhalable nanoparticle-based delivery system were introduced. In addition, we focused on the biological characteristics of these barriers and discussed effective strategies to overcome the obstacles, including precise deposition in the lower respiratory tract infection site, effective penetration of mucus and breaking of the biofilm barrier. To sum up, this review aimed to deepen the understanding of the fate of anti-infective nanoformulations in pulmonary delivery and find effective strategies to address the barriers, thus providing new insights for the development of pulmonary delivery systems against pulmonary infections.

The dysregulation of blood-brain barrier (BBB) activates pathological mechanisms such as neuroinflammation after traumatic brain injury (TBI), and glymphatic system dysfunction accelerates toxic waste accumulation after TBI. It is essential to find an effective way to inhibit inflammation and repair BBB and glymphatic system after TBI; however, effective and lasting drug therapy remains challenging because BBB severely prevents drugs from being delivered to central nervous system. Transferrin receptors (TfRs) are mainly expressed on brain capillary endothelial cells. Here, we report a TfR-targeted nanomedicine for TBI treatment by penetrating BBB and delivering fluvoxamine (Flv). The TfR-targeted polypeptide liposome loaded with Flv (TPL-Flv) implements cell targeting ability on human umbilical vein endothelial cells (HUVECs) in vitro detected by flow cytometry, and drug safety was proved through cell viability analysis and blood routine and biochemistry analysis. Afterwards, we established a controlled cortical impact model to explore TPL-Flv administration effects on TBI mice. We confirmed that TPL-Flv could stimulate CXCR4/SDF-1 signaling pathway, activate Treg cells, and inhibit inflammation after TBI. TPL-Flv treatment also alleviated BBB disruption and restored aquaporin-4 (AQP4) polarization, as well as reversed glymphatic dysfunction. Furthermore, TPL-Flv accomplished remarkable improvement of motor and cognitive functions. These findings demonstrate that TPL-Flv can effectively cross BBB and achieve drug delivery to cerebral tissue, validating its potential to improve therapeutic outcomes for TBI.

Delivery of antigenic peptides to antigen presenting cells (APCs) such as dendritic cells (DCs) using monoclonal antibodies (mAbs) is an attractive approach to evoke antigen-specific T cell activation and improve drug efficacy. Peptide linkage to mAbs has previously been achieved through genetic fusion, chemical conjugation, nano-engineered platforms and high affinity peptides. In this study, we have developed a flexible antibody-peptide linking technology using oppositely charged coiled coil domains to non-covalently link peptides to mAbs. The technology comprises (1) an anti-CD40 mAb connected with negatively charged E domains and (2) an immunogenic OVA peptide (SIINFEKL) from ovalbumin used as a model antigenic peptide fused with positively charged K domains. Combining these constructs leads to the formation of complexes that can be targeted to CD40 expressed on cells. Proof of concept antibody constructs connected with E domains generated from transient expressions exhibited good manufacturability, binding, and stability attributes comparable to a control mAb. Also, optimal repeat lengths for coiled-coil oligomerization domains were identified in these studies. Binding kinetics studies showed that connecting E domains to mAbs do not impede Fc gamma and neonatal receptor interactions. Additionally, formation of stable complexes capable of binding CD40 expressing cells was demonstrated in vitro. In vivo functionality evaluations showed that treatment of human CD40 transgenic mice with complexes elicited expansion of OVA peptide-specific CD8+ T cells and potent antitumor effects superior to peptide monotherapies. Overall, these findings demonstrate that the technology has great potential for application as an in vivo tool for antigenic peptide delivery.

Obesity has emerged as a global public health crisis in the 21st century, with its prevalence continuing to rise worldwide. Beyond its well-established links to metabolic diseases (diabetes, hypertension, dyslipidemia, and cardiovascular disease), obesity correlates significantly with oncological and musculoskeletal morbidity. Researchers have discovered that converting energy-storing white adipose tissue (WAT) into energy-expending thermogenic fat through external stimuli or browning agents-a process termed 'white fat browning'-has become a novel therapeutic strategy for obesity and its complications. This transformation is mediated by the activation of key factors such as uncoupling protein 1 (UCP1), which promotes thermogenesis and energy expenditure in adipocytes, thereby reducing fat accumulation. Studies have shown that certain pharmacological agents (e.g. β3-adrenergic receptor agonists) or natural compounds (e.g. resveratrol, capsaicin) can effectively induce white fat browning. However, systemic administration of these agents may cause off-target effects, such as cardiovascular overstimulation or metabolic disturbances, significantly limiting their clinical application. To address this challenge, adipose tissue-targeted drug delivery systems have been developed. These systems utilize either the unique microenvironment of adipose tissue (e.g. specific receptor expression) or nanocarrier technologies (e.g. polymeric nanoparticles) to precisely deliver browning agents to target fat depots. This review summarizes recent advances in targeted delivery vectors for obesity treatment via white fat browning, while also discussing challenges in nanomaterial design, targeting strategy optimization, and clinical translation.

Inflammatory bowel disease (IBD) comprises chronic autoimmune disorders with significant morbidity, highlighting the need for advanced, noninvasive, targeted therapies. Protein-based nanoparticle drug delivery systems (PNP-DDSs) have emerged as promising platforms to overcome limitations of conventional IBD therapies by improving drug stability and bioavailability while enabling colon-specific delivery. This review systematically classifies PNP-DDSs derived from natural proteins (albumin, gelatin, silk fibroin, and plant-derived proteins) and discusses their design principles along with strategies for intestinal targeting, including particle size and surface charge modulation, stimuli-responsive release (triggered by pH, reactive oxygen species, or enzymes), and active targeting. It highlights recent preclinical advances with oral PNP-DDSs delivering curcumin, resveratrol, 5-aminosalicylic acid, quercetin, and other anti-inflammatory agents, which demonstrate the therapeutic potential of these nanoplatforms in IBD models. Despite promising preclinical outcomes, clinical translation of PNP-DDSs remains challenging due to patient heterogeneity, manufacturing scale-up difficulties, and safety concerns. Future progress will require interdisciplinary innovation and optimization of multi‑stimuli-responsive designs for precise and safe clinical application of PNP-DDSs in IBD management.

Topical therapy with imiquimod in a cream [5% w/w imiquimod cream (Aldara™)] for the treatment of nodular basal cell carcinoma (BCC) currently results in low cure rates, attributed to low imiquimod permeation. Herein we have developed novel microneedle array patches (MAPs), to maximize imiquimod intradermal delivery and retention in the skin, with potential as an efficacious treatment for BCC. Enhanced delivery of imiquimod in pig skin and ex vivo BCC tissue was found with the obelisk poly N-acryloylmorpholine (pNAM) MAPs as compared to the 5% w/w imiquimod cream and MAPS manufactured from a commercially available polymer (PVPVA). Additionally, the increased retention in ex vivo BCC tissue was found with the obelisk pNAM MAPs as compared to the 5% w/w imiquimod cream. In addition, detailed characterization of single needles and mechanistic studies of MAPs in tissue using mass spectrometry imaging confirmed the imiquimod homogeneity in the needles. Most importantly, the in vivo tumor efficacy study showed that pNAM obelisk MAPs could deliver imiquimod into the tumor, retarding tumor growth. This study suggests that the drug loaded obelisk pNAM MAPs manufactured here may be of clinical utility for localized intradermal delivery of imiquimod.