INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2023
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IF 5.8
Yiling Liu,Yaqi Ouyang,Liu Yu,Peng Wang,Zhangwen Peng,Hengdeng Liu,Shixin Zhao,Hanwen Wang,Ziheng Zhou,Yang Deng,Yang Liu,Julin Xie
Skin graft rejection is a significant challenge in skin allografts for skin defects, particularly in extensive burn injury patients when autografts are insufficient. Enhancing the survival duration of allogeneic skin grafts can improve the success rate of subsequent autologous skin grafting, thereby promoting the therapeutic efficacy for wound healing. Rapamycin (Rapa), a potent immunosuppressant with favorable efficacy in organ transplantation, is limited by its systemic administration-associated toxicity and side effects. Therefore, addressing the short survival time of allogeneic skin grafts and minimizing the toxicity related to systemic application of immunosuppressive agents is an urgent requirement. Here, we present a topical formulation based on bioadhesive poly (lactic acid)-hyperbranched polyglycerol nanoparticles (BNPs) with surface-modified encapsulation of Rapamycin (Rapa/BNPs), applied for local immunosuppression in a murine model of allogeneic skin grafts. Our Rapa/BNPs significantly prolong nanoparticle retention, reduce infiltration of T lymphocytes and macrophages, decrease the level of pro-inflammatory cytokines and ultimately extend skin allograft survival with little systemic toxicity compared to free Rapa or Rapamycin-loaded non-bioadhesive nanoparticles (Rapa/NNPs) administration. In conclusion, Rapa/BNPs effectively deliver local immunosuppression and demonstrate potential for enhancing skin allograft survival while minimizing localized inflammation, thus potentially increasing patient survival rates for various types of skin defects.
研究领域:
移植学
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药学
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免疫学
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生物医学工程
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高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Jiaxin Dong,Qi Wang,Tingting Gu,Guanxiong Liu,Yuri V. Petrov,Vladimir E. Baulin,Aslan Yu Tsivadze,Dechang Jia,Yu Zhou,Huiping Yuan,Baoqiang Li
Suppression of vascular cell senescence is of great significance in preventing cardiovascular diseases such as hypertension and atherosclerosis. The oxidative stress damage caused by reactive oxygen species (ROS) can lead to cellular senescence. Rapamycin (Rapa) is well known to suppress cell senescence via mammalian target of rapamycin (mTOR) pathway. However, poor water solubility and lack of ROS scavenging ability limit the further development of Rapa. To improve the solubility of Rapa and endow with ROS scavenging ability, Rapa functionalized carbon dots (Rapa-CDs) are target-oriented synthesized via free radical polymerization combination with hydrothermal carbonization. Rapa-CDs improve the solubility of Rapa and show ROS scavenging abilities. The solubility of Rapa-CDs with 9.41 g is improved 3.6 × 10 4 times higher than that of Rapa (2.6 × 10 -4 g). The half maximal inhibitory concentration (IC 50 ) of Rapa-CDs toward hydroxyl radical ( • OH) and 2,2-Diphenyl-1-picrylhydrazyl free radical (DPPH•) are 0.18 and 0.17 mg/mL, respectively. Rapa-CDs show anti-oxidative stress effect in HEVECs (Human Umbilical Vein Endothelial Cells) via reducing ROS levels by 87 %. Rapa-CDs alleviate HUVECs senescence by suppressing mTOR overactivation, attenuate the expression of P53, P 21 and P16. The study demonstrates the target-oriented synthesis of drugs functionalized CDs with anti-senescence via dual-pathway of anti-oxidative stress and mTOR.
研究领域:
药理学
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纳米技术
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心血管疾病
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细胞生物学
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材料科学
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2025
·
IF 5.2
Zhenyang Zhao,Shiyu Yuan,Rui Zhang,Yuxin Hu,Weijia Huang,Qing Ma,Yongjun Wang,Hongzhuo Liu
Corneal alkali burns often result in blindness due to impaired healing processes. The primary contributing factors include inflammatory reactions, corneal neovascularization, and corneal stromal fibrosis following injury. Currently, glucocorticoids are widely employed to alleviate symptoms associated with corneal alkali burns. However, their use is limited to 1–2 weeks post-injury due to the risk of inducing corneal melting, which poses a significant safety concern. Rapamycin, a well-established immunosuppressive agent, exhibits anti-angiogenic and anti-fibrotic properties beneficial for corneal health. Nevertheless, its poor water solubility and ocular barriers limit its bioavailability, as only a minimal amount of the drug can penetrate the eye. To address these limitations, we developed a delivery system utilizing Sodium taurocholate (NaTC) to encapsulate rapamycin prodrugs, thereby enhancing their water solubility and ocular permeability, and consequently improved bioavailability. Our findings demonstrate that this delivery system significantly enhanced rapamycin’s solubility and effectively mitigated post-injury inflammatory responses, corneal neovascularization, and corneal stromal fibrosis. Compared with glucocorticoids, this system offered superior therapeutic efficacy and a longer duration of action. These results provide promising alternatives for treating corneal alkali burns and may also be applicable to other anterior segment diseases.
研究领域:
眼科学
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药物递送
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制药纳米技术
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炎症性疾病
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再生医学
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Acta Biomaterialia
·
2026
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IF 10.4
Yaxin Zheng,Min Su,Shuyao Zhou,Tingting Zhang,Yanqun Wu,Keming Xu,Wenying Zhong
Autophagy plays a dual role in cancer progression, and strategies to drive excessive autophagic flux remain a promising yet challenging therapeutic avenue. Herein, we develop an endoplasmic reticulum (ER)-targeted self-assembling peptide system (P-1-ERT@Rap) that enables localized photodynamic damage and robust ER stress, which synergizes with rapamycin (Rap) for inducing dual autophagy activation in cancer cells. The peptide P-1-ERT co-assembles with Rap into well-dispersed micelles, which exhibit pH-responsive morphological transformation from nanoparticles to nanofibers under acidic conditions, thereby facilitating lysosomal escape and cellular release of therapeutics. Importantly, P-1-ERT selectively accumulates in the ER and generates reactive oxygen species under laser exposure, triggering significant ER stress with upregulation of CHOP proteins. Concurrently, cellular delivery of Rap, an autophagy inducer, further amplifies autophagic flux with increasing LC3B-II/I ratios, ultimately promoting programmed cell death in A375 cells. Notably, the P-1-ERT@Rap system achieves higher tumor accumulation compared to free photosensitizer in vivo . Moreover, intravenous administration of P-1-ERT@Rap alongside laser irradiation significantly inhibits tumor growth in an A375-xenografted mouse model, with minimal systemic toxicity observed. This dual modulation strategy for autophagy regulation effectively enhances photodynamic therapy efficacy, and it offers a promising approach for exploiting organelle specific stress pathways in cancer treatment. Statement of Significance This study presents a endoplasmic reticulum (ER)-targeted self-assembling peptide nanoplatform (P‑1‑ERT@Rap) that integrates organelle-specific photodynamic therapy (PDT) with autophagy modulation for synergistic cancer treatment. The system uniquely exploits pH-responsive morphological transformation from micelles to nanofibers in acidic tumor environments, facilitating lysosomal escape and efficient intracellular delivery. By selectively accumulating in the ER and generating localized reactive oxygen species upon irradiation, it induces severe ER stress and upregulates CHOP, while co-delivered rapamycin further amplifies autophagic flux. This dual activation of autophagy leads to enhanced programmed cell death in melanoma cells, as demonstrated both in vitro and in vivo. Our work provides a pioneering strategy for organelle-precise therapy that leverages dual stress pathways to overcome the limitations of conventional monotherapies. We believe that this new approach has the potential to revolutionize the field of precision oncology, setting a new paradigm for significantly enhancing treatment outcomes across a broad spectrum of tumor types.
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JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS
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2026
·Vol. 114
·期 2
·e70041
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IF 3
Yifan Wu,Chijia Wang,Yu Zhou,Minghao Xu,Jun Zhang,Huiquan Wang,Ruijuan Chen,Guang Han,Jinhai Wang
Improving the patency rate of small-diameter vascular grafts in a pathological environment is the key to achieving their clinical translation and application. The current approach to in vivo implantation evaluations of small-diameter vascular grafts is predominantly based on healthy animal models. However, the majority of patients who undergo vascular transplantation are afflicted with vascular diseases, such as hyperlipidaemia or atherosclerosis. In this study, we constructed an ApoE gene knockout atherosclerotic mouse model and investigated the patency and regenerative performance of small-diameter vascular grafts in a diseased environment. We prepared heparinized Poly (ε-caprolactone) (PCL) vascular grafts (PCL-Hep) using electrospinning technology. By taking advantage of the physical adsorption of heparin, rapamycin (RM) was loaded onto the surface of grafts to obtain PCL-Hep-RM vascular grafts, which exhibited exceptional mechanical properties and drug sustained-release characteristics. Subsequently, the PCL-Hep-RM vascular grafts were implanted into the carotid arteries of atherosclerotic mice. The results demonstrated that PCL-Hep-RM significantly enhanced the patency rate and suppressed intimal hyperplasia in comparison with the PCL control group. This study offers novel concepts and methodologies for addressing challenges such as the low long-term patency rate and luminal stenosis of vascular grafts in a diseased environment, thereby promoting the translational medicine research of small-diameter vascular grafts.
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Food Science & Nutrition
·
2026
·Vol. 14
·期 7
·e72122
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IF 5
Kunlin Chang,Duowen He,Junfeng Dong,Yayu Zhang,Shuxin Deng,Mengyao Zhao,Jiayang Jin,Xiaoguo Ji,Hao Yin,Liming Zhao
Islet cell transplantation (ICT) is an effective treatment for diabetes mellitus, but postoperative islet function recovery and inflammation are closely linked to immunosuppressants. Using multi-omics and fecal microbiota transplantation (FMT) in human microbiota-associated (HMA) mice, this study explored rapamycin-induced gut dysbiosis and its impacts on islet function and inflammation post-ICT. ICT significantly altered the gut microbiota of type 2 diabetes mellitus (T2DM) patients, and FMT from these patients to antibiotic-treated mice recapitulated metabolic disorders in the mice. These disorders included hyperglycemia, hepatic and pancreatic injury, and impaired intestinal barrier. Rapamycin decreased beneficial bacteria ( Akkermansia , Faecalibacterium ) and enriched Desulfovibrio in HMA-T2DM mice. Targeted microbial modulation by chitooligosaccharides (COS) ameliorated rapamycin-induced deficits in insulin and C-peptide secretion, as well as elevated glycated hemoglobin levels. COS also significantly reduced serum inflammatory markers IP-10 and MCP-1, while upregulating colonic barrier proteins ( Muc2 , Occludin ) in HMA-T2DM-ICT mice. COS additionally mitigated postoperative hyperglycemia via the PI3K/AKT/GSK3β/FOXO1 signaling pathway. This study identified COS as a microbiota-targeted adjunctive strategy to improve metabolic recovery and islet function under post-transplant immunosuppression.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2026
·
IF 5.9
Weinan Sun,Qin Wang,Dehui Zhang,Lu Yin,Yuwei Chen,Xinzhou Zhang,Hao Liu,Liping Sun
A folate-targeted Mn 3 O 4 nanoplatform was developed for cisplatin-induced AKI. • The platform combined ROS scavenging with localized rapamycin delivery. • FA modification enhanced tubular cell uptake via an FR-associated mechanism. • RAP@Mn 3 O 4 -FA promoted AMPK/mTOR-associated autophagic flux. • Treatment improved renal function and showed progressive clearance within 120 h. Acute kidney injury (AKI) is a critical clinical syndrome characterized by an abrupt decline in renal function and is associated with substantial morbidity and mortality. Current therapeutic options remain predominantly supportive. Cisplatin-induced AKI, a clinically relevant subtype of AKI, is driven by oxidative stress, mitochondrial dysfunction, inflammatory activation, and tubular epithelial cell injury. Rapamycin, a potent mechanistic target of rapamycin (mTOR) inhibitor, has shown renoprotective potential in preclinical AKI models; however, its therapeutic application is limited by poor renal accumulation, low aqueous solubility, a narrow therapeutic window, and potential systemic toxicity. To address these limitations, a kidney-targeted nanotherapeutic was engineered by loading rapamycin onto ultrasmall manganese oxide (Mn 3 O 4 ) nanoparticles surface-functionalized with folic acid (RAP@Mn 3 O 4 -FA). This nanoplatform integrates the intrinsic ROS-scavenging activity of Mn 3 O 4 with folate receptor (FR)-mediated renal targeting, thereby enhancing intrarenal drug delivery while reducing off-target exposure. In a cisplatin-induced AKI mouse model, RAP@Mn 3 O 4 -FA improved renal function, attenuated histological injury, activated AMPK/mTOR-associated autophagy, and showed a favorable preliminary biosafety profile. These findings suggest that RAP@Mn 3 O 4 -FA is a promising kidney-targeted nanotherapeutic candidate for cisplatin-induced AKI treatment.
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EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2025
·
IF 4.3
Fangming Liang,Yue Wang,Ning Li,YuBo Liu,Yuan Gao,Yinan Song,Zhenzhen Zhao,Yongjun Wang,Hongzhuo Liu
The treatment of posterior uveitis remains challenging due to the need for long-term medication and the limited efficacy of current therapies. In this study, we developed an injectable rapamycin-based nanoparticle formulation designed to extend intraocular residence time and enhance retinal penetration, thereby improving therapeutic outcomes. The nanoparticles were formed via self-assembly of rapamycin conjugated with a hydrophobic alkyl chain, yielding uniformly spherical particles with an average diameter of approximately 90 nm. In vitro experiments confirmed that the formulation exhibited minimal cytotoxicity, potent anti-inflammatory effects, inhibition of endothelial cell migration, and efficient uptake by retinal pigment epithelial (RPE) cells. In vivo imaging demonstrated that the nanoparticles rapidly localized to the RPE layer of the posterior segment following intravitreal injection, in contrast to the free drug. Moreover, experimental autoimmune uveoretinitis (EAU) rats treated with nanoparticles exhibited a substantial alleviation of ocular inflammation and a concomitant reduction in the expression of inflammatory markers, including CD45, CD68, IBA-1, and IL-17.
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Biomaterials Advances
·
2025
·
IF 6
Naiyu Wang,Shiqi Kang,Qi Zeng,Wu Xu,Yuanyuan Zhao,Xudong Shi,Ruijun Li
Limited ability of nerve regeneration and the formation of nerve adhesions result to poor outcomes of peripheral nerve injury (PNI) following surgical nerve repair. Currently, there is no efficient therapy for the improvement of functional recovery after surgical repair. Rapamycin (Rapa) has been found useful for promoting nerve regeneration through removing cellular debris at the early stages after PNI. However, its lower oral bioavailability and significant adverse effects limit its clinical application. In this study, we developed a biocompatible nerve wrap based on biocompatible monomethoxy poly (ethylene gly co l)-poly (lactic- co -glycolic acid) (mPEG-PLGA) for the local delivery of Rapa. The Rapa-mPEG-PLGA nerve wrap exhibited a rough surface and good hydrophilicity with strong mechanical strength. In vitro release studies revealed an initial rapid phase within the first 8 days, followed by a stable release about 10 days. The released Rapa remained its bioactivity to induce autophagy and promote cell migration. In a rat model of sciatic nerve transection and immediate repair, the implantation of Rapa-mPEG-PLGA nerve wrap significantly enhanced axonal regeneration and myelination. Furthermore, the nerve wraps effectively prevented the occurrence of nerve adhesions. Improved functional recovery was observed with Rapa-mPEG-PLGA membrane wrap post-surgery 4 weeks and 8 weeks. In summary, the Rapa-loaded mPEG-PLGA nerve wrap promoted nerve regeneration by releasing Rapa at the early stage after injury, and acted as a physical barrier to reduce nerve adhesions. This local dual-action strategy is a promising candidate for clinical translation in the treatment of PNI following surgical repair.
研究领域:
生物医学工程
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神经科学
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药理学
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生物材料
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再生医学
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Applied Materials Today
·
2021
·
IF 10.041
Renting Jiang,Xin Li,Dun Hu,Min Zhu,Di Zhou,Mengying Yuan,Xin Hu,Shengdan Nie,Jiajia Liu,Haoyue Xiang,Hua Yang,Yi Zhang,Shan Wang
Upregulating the susceptibility of cancer cells to ferroptosis is crucial to upgrade anti-cancer efficiency of ferroptosis drug system. At present, optimizing the sensitizer for ferroptosis with expected mechanism and improved transport via facile nanocarriers still heavily rely on serendipitous discovery and repetitious assignment. Herein, we employ the tannic acid (TA)-templated silicon nanoparticle as nanocore to descend the lysosome-controlled disintegratable Fe 3+ @ [email protected] micelles (REFSM) to identify rapamycin as a ferroptosis sensitizer through autophagy-dependent/independent pathways. The as-prepared REFSM dissociates responding to the acidic condition and enzyme system of lysosomes, permitting Fe 3+ and erastin release to irritate ferroptosis, which is reinforced by released rapamycin via irritating ferritinophagy and lipophagy, and suppressing HIF-1α. The rapamycin-reinforced ferroptosis is demonstrated to be specific to H 2 O 2 -overloaded cancer cells. Moreover, the introduction of rapamycin reduces the positive charge of micelle and improves its distribution in tumors. Both the controllable dissociation and the improved charge of REFSM ensure its anti-cancer efficiency at trace amount of erastin (0.3 mg kg −1 ) and rapamycin (2.2 mg kg −1 ) and minimize the systematic toxicity. This archetypical template provides a versatile platform for rapamycin as sensitizer to enhance ferroptosis by displaying its multiple pharmacological mechanism, controlling its release and improving its distribution in vivo .
研究领域:
药理学
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纳米技术
·
癌症研究
·
细胞生物学
·
材料科学
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高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2019
·
IF 4.213
Zhonghui Xie,Zhenhai Zhang,Huixia Lv
Rapamycin as a novel macrolide immunosuppressive agent has been commonly used in organ transplantation owing to its stronger immunosuppressive effect, non-nephrotoxicity and lower side effect. However its drawbacks of low bioavailability and big individual difference remain to be improved in clinical application. Here rapamycin loaded TPGS-Lecithins-Zein nanoparticles (RTLZ-NPs) with core-shell structure were prepared by the phase separation method. The RTLZ-NPs were approximately 190.3 nm in size, with PDI and zeta potential about 0.256 and −19.71 mV respectively. Drug entrapment and loading achieved were about 86.64 and 25.73% respectively. Meanwhile RTLZ-NPs exhibited favorable enzymolysis resistance abilities in gastrointestinal environments and enhanced uptake in Caco-2 cells. The optimum absorption sites of rapamycin in the intestine were duodenum and jejunum as single-pass intestinal perfusion assay. Upon also considering the results of Caco-2 cell assay, it could be speculated that the transport of rapamycin in vivo involved active transport as well as P-glycoprotein (P-gp) based efflux. Finally, the relative oral bioavailability of RTLZ-NPS was 4.33 fold higher than free rapamycin in SD rat . Altogether the designed nanoparticles can be an efficient oral delivery strategy for rapamycin analogues to prevent the attacks from destructive enzymes, reduce cell efflux, increase cell uptake, and then enhance the oral bioavailability.
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ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Yan Cheng,Airong Cheng,Yanlong Jia,Lin Yang,Yan Ning,Liang Xu,Yazhi Zhong,Zerui Zhuang,Jitian Guan,Xiaolei Zhang,Yan Lin,Teng Zhou,Xiusong Fan,Jianwu Li,Peng Liu,Gen Yan,Renhua Wu
Stroke is the second leading cause of death globally and the most common cause of severe disability. Several barriers need to be addressed more effectively to treat stroke, including efficient delivery of therapeutic agents, rapid release at the infarct site, precise imaging of the infarct site, and drug distribution monitoring. The present study aimed to develop a bio-responsive theranostic nanoplatform with signal-amplifying capability to deliver rapamycin (RAPA) to ischemic brain tissues and visually monitor drug distribution. A pH-sensitive theranostic RAPA-loaded nanoparticle system was designed since ischemic tissues have a low-pH microenvironment compared with normal tissues. The nanoparticles demonstrated good stability and biocompatibility and could efficiently load rapamycin, followed by its rapid release in acidic environments, thereby improving therapeutic accuracy. The nano-drug-delivery system also exhibited acid-enhanced magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging signal properties, enabling accurate multimodal imaging with minimal background noise, thus improving drug tracing and diagnostic accuracy. Finally, in vivo experiments confirmed that the nanoparticles preferentially aggregated in the ischemic hemisphere and exerted a neuroprotective effect in rats with transient middle cerebral artery occlusion (tMCAO). These pH-sensitive multifunctional theranostic nanoparticles could serve as a potential nanoplatform for drug tracing as well as the treatment and even diagnosis of acute ischemic stroke. Moreover, they could be a universal solution to achieve accurate in vivo imaging and treatment of other diseases.
研究领域:
药学
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神经科学
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纳米技术
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医学成像
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药物递送系统
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PubMed
高影响因子
危险品化学品经营许可证（带存储）