Search

Intrauterine adhesion (IUA) is characterized by endometrial stromal replaced with fibrous tissue during the trauma or operation induced injury. Current clinic IUA management mainly involves surgical removal of the connective tissues and physical separation and often results in reoccurrence. It is of clinic interest to directly address the issue via facilitating the endometrial repair and thereby inhibiting the formation of re-adhesion. To this end, we designed a nanocomposite aloe/poloxamer hydrogel for β-estradiol (E2) intrauterine delivery to exert multi-therapeutic effects and promote endometrial regeneration for IUA treatment. Nanoparticulate decellularized uterus (uECMNPs) was prepared to encapsulate E2 (E2@uECMNPs), which improved the solubility and prolonged cargo release. Then, E2@uECMNPs were further embedded into the thermosensitive aloe-poloxamer hydrogel (E2@uECMNPs/AP). Multiple components from E2@uECMNPs/AP system could collectively promote proliferation and inhibit apoptosis of endometrial stromal cells. E2@uECMNPs/AP significantly increased morphological recovery and decreased uterine fibrosis rate compared with IUA rats in other groups in vivo. Additionally, the levels of Ki67, cytokeratin, and estrogen receptor β were all up-regulated, along with the decreased expression of TGF-β1 and TNF-α in the uterus from rats receiving E2@uECMNPs/AP therapy. Taken together, in situ administration of E2@uECMNPs/AP hydrogel could effectively promote endometrial regeneration and prevent the re-adhesion., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Intrauterine adhesions (IUA) frequently occur after infectious or mechanical injury to the endometrium, which may lead to infertility and/or pregnancy complications. There are few effective treatments due to the complex function of endometrium and shortage of native materials. 17β-estradiol (E 2 ) is commonly used as an ancillary treatment in IUA patients, but it is limited by its poor solubility in aqueous solutions and low concentrations at the injured sites. In this research, a mini-endometrial curette was used to injure the rat's endometrium to form an IUA model. 17β-estradiol was encapsulated into the micelles of heparin-poloxamer and a thermosensitive hydrogel (E 2 -HP hydrogel) was formed. This sustained releasing system was applied to restore the structure and function of the injured uterus. E 2 -HP hydrogel was constructed and relevant characteristics including gelation temperature and micromorphology were evaluated. Sustained release of 17β-estradiol from HP hydrogel was performed both in vitro and in vivo. Ultrasonography measurement and pathologic characteristics on the IUA rats were performed to evaluate the therapeutic effect of E 2 -HP hydrogel. Endoplasmic reticulum (ER) stress-related apoptosis was analyzed to explore the possible mechanisms in IUA recovery. E 2 -HP hydrogel showed a prolonged release of E 2 at the targeting region and more effective endometrium regeneration in IUA rats. Significant improvements in both gland numbers and fibrosis area were observed in the E 2 -HP hydrogel group. We also demonstrated that E 2 -HP hydrogel in the recovery of IUA was closely related to the suppression of ER stress signals via the activation of downstream signals, PI3K/Akt and ERK1/2. HP hydrogel might be an effective approach to deliver E 2 into the injured endometrium. Therapeutic strategies targeting ER stress using E 2 -HP hydrogel might be a promising solution for the treatment of women with intrauterine adhesions., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Although intranasal delivery bypasses the blood-brain barrier (BBB), the anatomical location of the olfactory mucosa and respiratory airflow interference lead to less brain-targeted drug delivery. In addition to intranasal delivery, evidence indicates that facial intradermal injection might be a novel strategy for bypassing the BBB via the trigeminal nerve (TN). The hypothesis was verified by pharmacokinetic evaluation, nasal injury, lymphatic vessels inhibition and immunohistochemistry. Intradermal injection into the rat mystacial pad (i.d.) elevated the brain sub-areas and trigeminal Evans Blue (EB) concentrations, C max and AUC (0-t) . I.d. also increased them in brain sub-areas beyond those of intranasal (i.n.) and intravenous injection (i.v.), especially the pons varolii and the medulla oblongata (sub-areas associated with TN). I.d. injection increased the brain drug targeting efficiency, brain direct transport percentage and brain bioavailability of EB while i.n. injection altered them slightly. Trigeminal transection and nasal injury reduced trigeminal EB with i.d. administration. Trigeminal perineurium, epineurium, perivascular spaces, neurons and Schwann cells were involved in the EB brain-targeted delivery. The lymphatic system mediated EB diffusion from the mystacial pad to the nasal mucosa and the brain. Thus, facial intradermal injection might be a promising strategy for brain-targeting delivery, bypassing the BBB via the trigeminal substructures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Either cardiovascular or peripheral vascular diseases have become the major cause of morbidity and mortality worldwide. Recently, growth factors therapeutics, whatever administrated in form of exogenous growth factors or their relevant genes have been discovered to be an effective strategy for the prevention and therapy of vascular diseases, because of their promoting angiogenesis. Besides, as an alternative, stem cell-based therapy has been also developed in view of their paracrine-mediated effect or ability of differentiation toward angiogenesis-related cells under assistance of growth factors. Despite of being specific and potent, no matter growth factors or stem cells-based therapy, their full clinical transformation is limited from bench to bedside. In this review, the potential choices of therapeutic modes based on types of different growth factors or stem cells were firstly summarized for vascular diseases. The confronted various challenges such as lack of non-invasive delivery method, the physiochemical challenge, the short half-life time, and poor cell survival, were carefully analyzed for these therapeutic modes. Various strategies to overcome these limitations are put forward from the perspective of drug delivery. The expertised design of a suitable delivery form will undoubtedly provide valuable insight into their clinical application in the regenerative medicine., (Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Because of the short half-life, either systemic or local administration of bFGF shows significant drawbacks to spinal injury. In this study, an acellular spinal cord scaffold (ASC) was encapsulated in a thermo-sensitive hydrogel to overcome these limitations. The ASC was firstly prepared from the spinal cord of healthy rats and characterized by scanning electronic microscopy and immunohistochemical staining. bFGF could specifically complex with the ASC scaffold via electrostatic or receptor-mediated interactions. The bFGF-ASC complex was further encapsulated into a heparin modified poloxamer (HP) solution to prepare atemperature-sensitive hydrogel (bFGF-ASC-HP). bFGF release from the ASC-HP hydrogel was more slower than that from the bFGF-ASC complex alone. An in vitro cell survival study showed that the bFGF-ASC-HP hydrogel could more effectively promote the proliferation of PC12 cells than a bFGF solution, with an approximate 50% increase in the cell survival rate within 24 h (P < 0.05). Compared with the bFGF solution, bFGF-ASC-HP hydrogel displayed enhanced inhibition of glial scars and obviously improved the functional recovery of the SCI model rat through regeneration of nerve axons and the differentiation of the neural stem cells. In summary, an ASC-HP hydrogel might be a promising carrier to deliver bFGF to an injured spinal cord.

Diabetic wounds are challenging to heal due to complex pathogenic abnormalities. Routine treatment with acid fibroblast growth factor (aFGF) is widely used for diabetic wounds but hardly offers a satisfying outcome due to its instability. Despite the emergence of various nanoparticle-based protein delivery approaches, it remains challenging to engineer a versatile delivery system capable of enhancing protein stability without the need for complex preparation. Herein, a polyphenol-driven facile assembly of nanosized coacervates (AE-NPs) composed of aFGF and Epigallocatechin-3-gallate (EGCG) was constructed and applied in the healing of diabetic wounds. First, the binding patterns of EGCG and aFGF were predicted by molecular docking analysis. Then, the characterizations demonstrated that AE-NPs displayed higher stability in hostile conditions than free aFGF by enhancing the binding activity of aFGF to cell surface receptors. Meanwhile, the AE-NPs also had a powerful ability to scavenge reactive oxygen species (ROS) and promote angiogenesis, which significantly accelerated full-thickness excisional wound healing in diabetic mice. Besides, the AE-NPs suppressed the early scar formation by improving collagen remodeling and the mechanism was associated with the TGF-β/Smad signaling pathway. Conclusively, AE-NPs might be a potential and facile strategy for stabilizing protein drugs and achieving the scar-free healing of diabetic wounds. Diabetic chronic wound is among the serious complications of diabetes that eventually cause the amputation of limbs. Herein, a polyphenol-driven facile assembly of nanosized coacervates (AE-NPs) composed of aFGF and EGCG was constructed. The EGCG not only acted as a carrier but also possessed a therapeutic effect of ROS scavenging. The AE-NPs enhanced the binding activity of aFGF to cell surface receptors on the cell surface, which improved the stability of aFGF in hostile conditions. Moreover, AE-NPs significantly accelerated wound healing and improved collagen remodeling by regulating the TGF-β/Smad signaling pathway. Our results bring new insights into the field of polyphenol-containing nanoparticles, showing their potential as drug delivery systems of macromolecules to treat diabetic wounds. [Display omitted] [ABSTRACT FROM AUTHOR]

Silk was easily dyed in traditional textile industry because of its strong affinity to many colorants. Herein, the biocompatible silk fibroin was firstly extracted from Bombyx mori silkworm cocoons. And SF nanoparticles (SFNPs) were prepared for dyeing indocyanine green (ICG) and construct a therapeutic nano-platform (ICG-SFNPs) for photo-thermal therapy of glioblastoma. ICG was easily encapsulated into SFNPs with a very high encapsulation efficiency reaching to 97.7 ± 1.1%. ICG-SFNPs exhibited a spherical morphology with a mean particle size of 209.4 ± 1.4 nm and a negative zeta potential of −31.9 mV, exhibiting a good stability in physiological medium. Moreover, ICG-SFNPs showed a slow release profile of ICG in vitro, and only 24.51 ± 2.27% of the encapsulated ICG was released even at 72 h. Meanwhile, ICG-SFNPs exhibited a more stable photo-thermal effect than free ICG after exposure to near-infrared irradiation. The temperature of ICG-SFNPs rapidly increased by 33.9 °C within 10 min and maintained for a longer time. ICG-SFNPs were also easily internalized with C6 tumor cells in vitro, and a strong red fluorescence of ICG was observed in cytoplasm for cellular imaging. In vivo imaging showed that ICG-SFNPs were effectively accumulated inside tumor site of C6 glioma-bearing Xenograft nude mice through vein injection. Moreover, the temperature of tumor site was rapidly rising up to kill tumor cells after local NIR irradiation. After treatment, its growth was completely suppressed with the relative tumor volume of 0.55 ± 033 while free ICG of 33.72 ± 1.90. Overall, ICG-SFNPs may be an effective therapeutic means for intraoperative phototherapy and imaging. [ABSTRACT FROM AUTHOR]

Intratumoral drug delivery (IT) is an inherently appealing approach for concentrating toxic chemotherapies at the site of action. However, for most chemotherapies, poor tumor penetration and short retention at the administration site limit their anti-tumor effects. In this work, we describe permeable nanoparticles (NPs) prepared with a novel amphiphilic polymer, RRR-α-tocopheryl succinate-grafted-ε-polylysine conjugate (VES-g-ε-PLL). The nanoparticles (NPs) of VES-g-ε-PLL exhibited an ultra-small hydrodynamic diameter (20.8 nm) and positive zeta potential (20.6 mV), which facilitate strong glioma spheroid penetration ability in vitro. Additionally, the hydrophobic model drug docetaxel (DTX) could be effectively encapsulated in the nanoparticles with 3.99% drug loading and 73.37% encapsulation efficiency. To prolong the retention time of DTX-loaded nanoparticles (DTX-NPs) in the tumor, intact decellularized brain extracellular matrix (dBECM) derived from healthy rats was used as a drug depot to adsorb the ultra-small DTX-NPs. The intact DTX-NPs-adsorbing dBECM scaffold was further homogenized into an injectable DTX-NPs-dBECM suspension for intratumoral administration. The DTX-NPs-dBECM suspension exhibited slower DTX release than naked DTX-NPs without compromising the tumor penetration ability of DTX-NPs. An antitumor study showed that the DTX-NPs-dBECM suspension exhibited more powerful in vitro inhibition of tumor spheroid growth than free DTX solution or DTX-NPs. Due to strong tumor penetration ability and prolonged retention, DTX-NPs-dBECM led to complete suppression of glioma growth in vivo at 28 days after treatment. The therapeutic mechanism was due to enhanced proliferation inhibition and apoptosis of tumor cells and angiogenesis inhibition of glioma after treatment with DTX-NPs-dBECM. Finally, the safety of DTX-NPs-dBECM at the therapeutic dose was demonstrated via pathological HE assay from heart, liver, spleen, lung and kidney tissues. In conclusion, permeable nanoparticle-absorbing dBECM is a potential carrier for intratumoral delivery of common chemotherapeutics. [ABSTRACT FROM AUTHOR]

A poor percutaneous penetration capability for most topical anti-inflammatory drugs is one of the main causes compromising their therapeutic effects on psoriatic skin. Even though curcumin has shown a remarkable efficacy in the treatment of psoriasis, its effective penetration through the stratum corneum is still a major challenge during transdermal delivery. The aim of our study was to design skin-permeating nanoparticles (NPs) to facilitate delivery of curcumin to the deeper layers of the skin. A novel amphiphilic polymer, RRR-α-tocopheryl succinate-grafted-ε-polylysine conjugate (VES-g-ε-PLL) was synthesized and self-assembled into polymeric nanoparticles. The nanoparticles of VES-g-ε-PLL exhibiting an ultra-small hydrodynamic diameter (24.4 nm) and a positive Zeta potential (19.6 mV) provided a strong skin-penetrating ability in vivo. Moreover, curcumin could effectively be encapsulated in the polymeric nanoparticles with a drug loading capacity of 3.49% and an encapsulating efficiency of 78.45%. In order to prolong the retention time of the ultra-small curcumin-loaded nanoparticles (CUR-NPs) in the skin, silk fibroin was used as a hydrogel-based matrix to further facilitate topical delivery of the model drug. In vitro studies showed that CUR-NPs incorporated in silk fibroin hydrogel (CUR-NPs-gel) exhibited a slower release profile of curcumin than the plain CUR-gel, without compromising the skin penetration ability of CUR-NPs. In vivo studies on miquimod-induced psoriatic mice showed that CUR-NPs-gel exhibited a higher therapeutic effect than CUR-NPs as the former demonstrated a more powerful skin-permeating capability and a more effective anti-keratinization process. CUR-NPs-gel was therefore able to inhibit the expression of inflammatory cytokines (TNF-α, NF-κB and IL-6) to a greater extent. In conclusion, the permeable nanoparticle-gel system may be a potential carrier for the topical delivery of lipophilic anti-psoriatic drugs. [ABSTRACT FROM AUTHOR]