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Small · 2024 · IF 13

Microneedle Patch for Transdermal Sequential Delivery of KGF-2 and aFGF to Enhance Burn Wound Therapy

Huacheng He,Wen Huang,Shihui Zhang,Jie Li,Jian Zhang,Bingxin Li,Jie Xu,Yuting Luo,Huiling Shi,Yue Li,Jian Xiao,Odinaka Cassandra Ezekiel,Xiaokun Li,Jiang Wu

Severe burn wounds usually destroy key cells’ functions of the skin resulting in delayed re-epithelization and wound regeneration. Promoting key cells’ activities is crucial for burn wound repair. It is well known that keratinocyte growth factor-2 (KGF-2) participates in the proliferation and morphogenesis of epithelial cells while acidic fibroblast growth factor (aFGF) is a key mediator for fibroblast and endothelial cell growth and differentiation. However, thick eschar and the harsh environment of a burn wound often decrease the delivery efficiency of fibroblast growth factor (FGF) to the wound site. Therefore, herein a novel microneedle patch for sequential transdermal delivery of KGF-2 and aFGF is fabricated to enhance burn wound therapy. aFGF is first loaded in the nanoparticle (NP aFGF ) and then encapsulated NP aFGF with KGF-2 in the microneedle patch (KGF-2/NP aFGF @MN). The result shows that KGF-2/NP aFGF @MN can successfully get across the eschar and sequentially release KGF-2 and aFGF. Additional data demonstrated that KGF-2/NP aFGF @MN achieved a quicker wound closure rate with reduced necrotic tissues, faster re-epithelialization, enhanced collagen deposition, and increased neo-vascularization. Further evidence suggests that improved wound healing is regulated by significantly elevated expressions of hypoxia-inducible factor-1 alpha (HIF-1ɑ) and heat shock protein 90 (Hsp90) in burn wounds. All these data proved that KGF-2/NP aFGF @MN is an effective treatment for wound healing of burns.

研究领域: 生物医学工程 · 药剂学 · 组织修复与再生
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES · 2025 · IF 8.5

Calcium carbonate hollow microspheres encapsulated cellulose nanofiber/sodium alginate hydrogels as a sequential delivery system

Wenqian Bai,Haiying Chen,Junyao Li,Wenrong Cai,Yong Kong,Xiaoming Zuo

By using folic acid (FA) as the template, calcium carbonate hollow microspheres (CaCO 3 HMs) are prepared through the Ostwald ripening process, which can be utilized for the loading of doxorubicin hydrochloride (DOX). The DOX loaded CaCO 3 HMs (CaCO 3 /DOX) are co-encapsulated with ibuprofen (IBU) in the cellulose nanofiber (CNF)/sodium alginate (SA) hydrogels cross-linked by Ca 2+ . The loading efficiency of DOX in the CaCO 3 HMs is 95.7 %, and the loading efficiency of IBU in the hydrogels is 97.0 %. In the weakly alkaline environment (pH ~7.4) that is characteristic of intestinal fluids of human body, the CNF/SA hydrogels are swollen and the encapsulated IBU is first released for pain control, and the release rate of IBU can reach 57.8 %. In the weakly acidic environment (pH ~6.5) that is characteristic of colonic fluids of human body, the CaCO 3 HMs are decomposed to release the loaded DOX with a release rate of 50.1 %, which can be used for the treatment of colorectal cancer. The results of release kinetics indicate that the delivery of IBU is governed by first-order model and DOX by zero-order model. The developed sequential delivery system (SDS) can not only enable the release of DOX in colon of human body, but also simultaneously relieve the pain of patients during the chemotherapy of colon cancer.

研究领域: 生物材料学 · 药物递送系统 · 肿瘤治疗学
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ANALYTICAL CHEMISTRY · 2019 · IF 6.35

Sequential Delivery and Cascade Targeting of Peptide Therapeutics for Triplexed Synergistic Therapy with Real-Time Monitoring Shuttled by Magnetic Gold Nanostars

Rong Wu,Qianhao Min,Jingjing Guo,Tingting Zheng,Liping Jiang,Jun-Jie Zhu

Due to the outstanding synergistic effects and low-toxicity, combination therapy exhibits more considerable potential in antitumor activity than monotherapy. Herein, a core–shell magnetic gold nanostar (Fe3O4@GNS, MGNS)-based system for codelivery of a mitochondrial targeting amphipathic tail-anchoring peptide (ATAP) and a membrane-associated cytokine (tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) was constructed. The magnetic core can facilitate delivery of the drug vehicle by external magnetic field, which results in accurate accumulation and enhances tumor cellular uptake for preliminary targeting. TRAIL and ATAP could sequentially target and be released toward the plasma membrane and mitochondria, initiating the extrinsic and intrinsic apoptosis pathways, respectively. The gold shell of MGNS can cause local tumor hyperthermia due to broad-band plasmon resonances in the near-infrared region, which can act as a complement with the peptide drug to further enhance apoptosis. Both in vitro and in vivo experiments revealed that rationally integrating extrinsic apoptosis, intrinsic apoptosis and hyperthermia for triplexed synergistic therapy, enabled the smart drug vehicle with pinpoint peptide drug delivery capabilities, and minimized side effects, enhancing the antitumor efficiency.

CAS / MDL: 9002-98-6
研究领域: 纳米技术 · 药学 · 癌症研究 · 生物医学工程 · 诊疗学
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ACS Applied Materials & Interfaces · 2020 · IF 8.758

Multilayer Injectable Hydrogel System Sequentially Delivers Bioactive Substances for Each Wound Healing Stage

Zhijie Ma,Wei Song,Yaohua He,Haiyan Li

Wound healing is a dynamic and complex process that contains several sequential phases. However, most of the current drug delivery systems were designed to treat only one certain phase of wound repair, ignoring the fact that every stage plays critical roles in the wound healing process and those critical stages coordinately work to ensure optimal tissue regeneration. Therefore, a delivery system that can precisely meet the requirements of each wound healing stage is desired to enhance tissue regeneration. In this study, an injectable sodium alginate/bioglass (SA/BG) composite hydrogel was used to carry SA microparticles containing a conditioned medium (CM) of cells (SACM). Inside the SACM microparticles, poly(lactic-co-glycolic acid) (PLGA) microspheres containing pirfenidone (PFD) were encapsulated (PLGAPFD). This multilayer injectable hydrogel system (SA/BG-SACM-PLGAPFD) was designed to sequentially deliver bioactive molecules for meeting the bioactivity requirement and timeline of each wound healing stage. First, SA/BG hydrogels could rapidly release BG ionic products in the first 1–3 days to regulate the inflammatory response of the host and initiate the subsequent tissue regeneration. Then, SACM hydrogel microparticles could release CM of RAW 264.7 cells stimulated with BG ionic products in 2–7 days to facilitate the formation of the vascularized granulation tissue. Finally, PLGAPFD microspheres released PFD in 8–20 days to prevent the fibrosis and scar formation in the regenerated skin. Thus, this SA/BG-SACM-PLGAPFD delivery system could restrain host inflammation, accelerate wound healing, and inhibit the fibrosis formation in a diabetic mouse skin damage model, enhancing skin regeneration. As the bioactive components in each layer of the system can be adjusted according to the requirements of different tissue regeneration, this three-layered injectable biomaterial system has a wide application potential in the regenerative medicine field.

CAS / MDL: 9002-89-5
研究领域: 药学 · 材料科学 · 再生医学 · 生物医学工程
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ADVANCED FUNCTIONAL MATERIALS · 2023 · IF 19

“Kupffer Cell Teleportation” Strategy for Liver Fibrosis Alleviation Based on Hybrid Polymer- Bimetallic Sequential Delivery System

Zitong Qiu,Valentin A. Milichko,Yue Zhou,Huaqing Jing,Qiang Lu,Haobo Wang,Bei Kang,Xinxing Wang,Nan Li

Although direct hepatic stellate cell (HSC) inhibition is considered a promising strategy for alleviating liver fibrosis, traditional therapies struggle with off-target effects due to limited penetration of liver sinusoidal endothelial cell barriers. This study reports on the development of a “Kupffer cell (KC) teleportation” strategy to treat liver fibrosis by fabricating a hybrid polymer-bimetallic sequential delivery system, CF@BPPM (baicalin prodrug polymer [BP]/mannose derivative polymer [PM] encapsulated copper [Cu]-iron [Fe] ultrasmall nanoparticles [CFs]). The nanosystems exhibit KCs targeting and acidic response sequential release properties by a hybrid polymer, which first releases CFs in lysosome after being internalized by KCs through a PM targeting effect. The exposed CFs efficiently scavenge reactive oxygen species in KCs and subsequently degrade Cu 2+ / Fe 2+ to upregulate the heme oxygenase expression for suppressing interleukin 1β, interleukin 6, tumor necrosis factor-alpha, and platelet-derived growth factors. Second, baicalin, released from BP in lysosome, further inhibits transforming growth factor beta secretion. These results suggest that CF@BPPM inhibits the inclusive cytokine secretion of KCs, which play a vital conductive role in liver fibrosis progression. Subsequently, CF@BPPM achieves protection against HSCs activation, migration, and collagen production, enriching anti-liver fibrosis therapeutic methods by exploiting messaging between KCs and HSCs.

研究领域: 药理学 · 纳米技术 · 肝病学 · 药物递送系统
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES · 2024 · IF 7.7

Mussel inspired sequential protein delivery based on self-healing injectable nanocomposite hydrogel

Xiao Shuai Han,Peng Cheng Li,Heng Tao Song,Yong Mei Chen,Jian Hui Li,Yang Yang,Hao Peng Li,Hideyuki Miyatake,Yoshihiro Ito

Polysaccharide based self-healing and injectable hydrogels with reversible characteristics have widespread potential in protein drug delivery. However, it is a challenge to design the dynamic hydrogel for sequential release of protein drugs. Herein, we developed a novel mussel inspired sequential protein delivery dynamic polysaccharide hydrogel. The nanocomposite hydrogel can be fabricated through doping polydopamine nanoparticles (PDA NPs) into reversible covalent bond (imine bonds) crosslinked polymer networks of oxidized hyaluronic acid (OHA) and carboxymethyl chitosan (CEC), named PDA NPs@OHA-l-CEC. Besides multiple capabilities (i.e., injection, self-healing, and biodegradability), the nanocomposite hydrogel can achieve sustained and sequential protein delivery of vascular endothelial growth factor (VEGF) and bovine serum albumin (BSA). PDA NPs doped in hydrogel matrix serve dual roles, acting as secondary protein release structures and form dynamic non-covalent interactions (i.e., hydrogen bonds) with polysaccharides. Moreover, by adjusting the oxidation degree of OHA, the hydrogels with different crosslinking density could control overall protein release rate. Analysis of different release kinetic models revealed that Fickian diffusion drove rapid VEGF release, while the slower BSA release followed a Super Case II transport mechanism. The novel biocompatible system achieved sequential release of protein drugs has potentials in multi-stage synergistic drug deliver based on dynamic hydrogel.

CAS / MDL: 9012-76-4
研究领域: 生物医学工程 · 药物递送系统 · 材料科学 · 药学
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BIOMATERIALS · 2018 · IF 8.806

Time-responsive osteogenic niche of stem cells: A sequentially triggered, dual-peptide loaded, alginate hybrid system for promoting cell activity and osteo-differentiation

Zuyuan Luo,Siqi Zhang,Jijia Pan,Rui Shi,Hao Liu,Yalin Lyu,Xiao Han,Yan Li,Yue Yang,Zhixiu Xu,Yi Sui,En Luo,Yuanyuan Zhang,Shicheng Wei

The efficacy of stem cell-based bone tissue engineering has been hampered by cell death and limited fate control. A smart cell culture system with the capability of sequentially delivering multiple factors in specific growth stages, like the mechanism of the natural extracellular matrix modulating tissue formation, is attractive for enhancing cell activity and controlling cell fate. Here, a bone forming peptide-1 (BFP-1)-laden mesoporous silica nanoparticles ( [email protected] ) incorporated adhesion peptide, containing the arginine-glycine-aspartic acid (RGD) domain, modified alginate hydrogel (RA) system ( [email protected] ) was developed to promote the activity and stimulate osteo-differentiation of human mesenchymal stem cells (hMSCs) in sequence. The survivability and proliferation of hMSCs were enhanced in the adhesion peptide modified hydrogel. Next, BFP-1 released from [email protected] induced hMSCs osteo-differentiation after the proliferation stage. Moreover, BFP-1 near the cells was self-captured by the additional cell-peptide cross-linked networks formed by the ligands (RGD) binding to receptors on the cell surface, leading to long-term sustained osteo-stimulation of hMSCs. The results suggest that independent and sequential stimulation in proliferation and osteo-differentiation stages could synergistically enhance the survivability, expansion, and osteogenesis of hMSCs, as compared to stimulating alone or simultaneously. Overall, this study provided a new and valid strategy for stem cell expansion and osteo-differentiation in 2D or 3D culture systems, possessing potential applications in 3D bio-printing and tissue regeneration .

研究领域: 组织工程 · 干细胞生物学 · 生物医用材料 · 再生医学
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