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Background: Alveolar Bone loss occurs frequently during the first six months after tooth extraction. Various studies have proposed different methods to reduce as much as possible the atrophy of the alveolar ridge after tooth extraction. Filling the socket with biomaterials after extraction can reduce the resorption of the alveolar ridge. We compared the height of the alveolar process at the mesial and distal aspects of the extraction site and the resorption rate was calculated after the application of HA/β-TCP or synthetic co-polymer polyglycolic - polylactic acid PLGA mixed with blood to prevent socket resorption immediately and after tooth extraction., Methods: The study was conducted on 24 extraction sockets of impacted mandibular third molars bilaterally, vertically, and completely covered, with a thin bony layer. HA/β-TCP was inserted into 12 of the dental sockets immediately after extraction, and the synthetic polymer PLGA was inserted into 12 of the dental sockets. All sockets were covered completely with a full-thickness envelope flap. Follow-up was performed for one year after extraction, using radiographs and stents for the vertical alveolar ridge measurements., Results: The mean resorption rate in the HA/β-TCP and PLGA groups was ± 1.23 mm and ± 0.1 mm, respectively. A minimal alveolar bone height reduction of HA/β-TCP was observed after 9 months, the reduction showed a slight decrease to 0.93 mm, while this rate was 0.04 mm after 9 months in the PLGA group. Moreover, the bone height was maintained after three months, indicating a good HA/β-TCP graft performance in preserving alveolar bone (1.04 mm) while this rate was (0.04 mm) for PLGA., Conclusion: The PLGA graft demonstrated adequate safety and efficacy in dental socket preservation following tooth extraction. However, HA/β-TCP causes greater resorption at augmented sites than PLGA, which clinicians should consider during treatment planning., (© 2024. The Author(s).)

Objectives: Oxidative stress is one of the carcinogenic mechanisms underlying the development of glioblastoma multiforme (GBM), a highly aggressive brain tumor type associated with poor prognosis. Curcumin is known to be an efficient antioxidant, anti-inflammatory, and anticancer compound. However, its poor solubility in water, inappropriate pharmacokinetics, and low bioavailability limit its use as an antitumor drug. We prepared PLGA-based curcumin nanoparticles changed with folic acid and chitosan (curcumin-PLGA-CS-FA) and evaluated its effects on GBM tumor cells' redox status., Methods: The nanoprecipitation method was used to synthesize CU nanoparticles (CU-NPs). The size, morphology, and stability were characterized by DLS, SEM, and zeta potential analysis, respectively. The CU-NPs' toxic properties were studied by MTT assay and measuring the intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) concentrations. The study was completed by measuring the gene expression levels and activity of superoxide dismutase, catalase, glutaredoxin, and thioredoxin antioxidant enzymes., Results: The size, polydispersity index, and zeta potential of CU-NPs were 77.27 nm, 0.29, and -22.45 mV, respectively. The encapsulation efficiency was approximately 98%. Intracellular ROS and MDA levels decreased after CU-NP treatment. Meanwhile, the CU-NPs increased gene expression and activity of superoxide dismutase, catalase, glutaredoxin, and thioredoxin antioxidant enzymes., Conclusion: CU-NPs might be effective in the prevention and treatment of glioblastoma cancer by modulating the antioxidant-oxidant balance., (© 2023 John Wiley & Sons Ltd.)

Breast carcinoma is a molecularly diverse illness, and it is among the most prominent and often reported malignancies in female across the globe. Surgical intervention, chemotherapy, immunotherapy, gene therapy, and endocrine treatment are among the currently viable treatment options for the carcinoma of breast. Chemotherapy is among the most prevalent cancer management strategy. Doxorubicin (DOX) widely employed as a cytostatic medication for the treatment of a variety of malignancies. Despite its widespread acceptance and excellent efficacy against an extensive line up of neoplasia, it has a variety of shortcomings that limit its therapeutic potential in the previously mentioned indications. Employment of nanoparticulate systems has come up as a unique chemo medication delivery strategy and are being considerably explored for the amelioration of breast carcinoma. Polylactic-co-glycolic acid (PLGA)-based nano systems are being utilized in a number of areas within the medical research and medication delivery constitutes one of the primary functions for PLGA given their inherent physiochemical attributes, including their aqueous solubility, biocompatibility, biodegradability, versatility in formulation, and limited toxicity. Herein along with the different application of PLGA-based nano formulations in cancer therapy, the present review intends to describe the various research investigations that have been conducted to enumerate the effectiveness of DOX-encapsulated PLGA nanoparticles (DOX-PLGA NPs) as a feasible treatment option for breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Lung cancer is often diagnosed at an advanced stage where tumors are usually inoperable and first-line therapies are inefficient and have off-targeted adverse effects, resulting in poor patient survival. Here, we report the development of an inhalable poly lactic-co-glycolic acid polymer-based nanoparticle (PLGA-NP) formulation with a biomimetic Infasurf® lung surfactant (LS) coating, for localized and sustained lung cancer drug delivery. The nanoparticles (188 ± 7 nm) were stable in phosphate buffered saline, serum and Gamble's solution (simulated lung fluid), and demonstrated cytocompatibility up to 1000 μg/mL concentration and dose-dependent uptake by lung cancer cells. The LS coating significantly decreased nanoparticle (NP) uptake by NR8383 alveolar macrophages in vitro compared to uncoated NPs. The coating, however, did not impair NP uptake by A549 lung adenocarcinoma cells. The anti-cancer drug gemcitabine hydrochloride encapsulated in the PLGA core was released in a sustained manner while the paclitaxel loaded in the LS shell demonstrated a rapid or burst release profile over 21 days. The drug-loaded NPs significantly decreased cancer cell survival and colony formation in vitro compared to free drugs and single drug-loaded NPs. In vivo studies confirmed greater retention of LS-coated NPs in the lungs of C57BL/6 WT mice compared to uncoated NPs, at 24 h and 72 h following intranasal administration. The overall results confirm that LS coating is a unique strategy for cloaking polymeric NPs to potentially prevent their rapid lung clearance and facilitate prolonged pulmonary drug delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is an inflammatory disease accompanied by synovial joint inflammation, and IL-36 plays an important role in this process. Local application of IL-36 receptor antagonist (IL-36Ra) can effectively control the inflammatory response, thereby protecting cartilage and slowing down the development of OA. However, its application is limited by the fact that it is rapidly metabolized locally. We designed and prepared a temperature-sensitive poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA) hydrogel (IL-36Ra@Gel) system carrying IL-36Ra and evaluated its basic physicochemical characteristics. The drug release curve of IL-36Ra@Gel indicated that this system could slowly release the drug over a longer period. Furthermore, degradation experiments showed that it could be largely degraded from the body within 1 month. The biocompatibility-related results showed that it had no significant effect on cell proliferation compared to the control group. In addition, the expression of MMP-13 and ADAMTS-5 was lower in IL-36Ra@Gel-treated chondrocytes than in the control group, and the opposite results appeared in aggrecan and collagen X. After 8 weeks of treatment with IL-36Ra@Gel by joint cavity injection, HE and Safranin O/Fast green staining showed that the degree of cartilage tissue destruction in the IL-36Ra@Gel-treated group was less than those in other groups. Meanwhile, the joints of mice in the IL-36Ra@Gel group had the most intact cartilage surface, the smallest thickness of cartilage erosion, and the lowest OARSI and Mankins score among all groups. Consequently, the combination of IL-36Ra and PLGA-PLEG-PLGA temperature-sensitive hydrogels can greatly improve the therapeutic effect and prolong the drug duration time, thus effectively delaying the progression of degenerative changes in OA, providing a new feasible nonsurgical treatment for OA.

The main development process of periodontitis involves periodontal pathogenic bacteria as the initiating factor causing the onset of destructive inflammation, which in turn stimulates the destruction of periodontal tissue. It is difficult to achieve the eradication of periodontitis due to the complex interaction among antibacterial, anti-inflammatory, and bone restoration. Herein, we propose an antibacterial-anti-inflammatory-bone restoration procedural treatment strategy with minocycline (MIN) for the efficient treatment of periodontitis. In brief, MIN was prepared into PLGA microspheres with tunable release behavior using different species of PLGA, respectively. The optimally selected PLGA microspheres (LA:GA with 50:50, 10 kDa, and carboxyl group) had a drug loading of 16.91%, an in vitro release of approximately 30 days, which also had a particle size of approximately 11.8 µm with a smooth appearance and a rounded morphology. The DSC and XRD results showed that the MIN was completely encapsulated in the microspheres as an amorphous state. Cytotoxicity tests demonstrated the safety and biocompatibility of the microspheres (cell viabilities at a concentration of 1-200 μg/mL were greater than 97%), and in vitro bacterial inhibition tests showed that the selected microspheres could achieve effective bacterial inhibition at the initial stage after administration. The favorable anti-inflammatory (low TNF-α and IL-10 levels) and bone restoration effects (BV/TV: 71.8869%; BMD: 0.9782 g/cm 3 ; TB.Th: 0.1366 mm; Tb.N: 6.9318 mm -1 ; Tb.Sp: 0.0735 mm) were achieved in a SD rat periodontitis model after administering once a week for four weeks. The MIN-loaded PLGA microspheres were proved to be an efficient and safe treatment for periodontitis by procedural antibacterial, anti-inflammatory, and bone restoration., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Gentamicin is used to treat brucellosis, an infectious disease caused by the Brucella species but the drug faces several issues such as low efficacy, instability, low solubility, and toxicity. It also has a very short half-life, therefore, requiring frequent dosing. Consequently, several other antibiotics are also being used for the treatment of brucellosis as a single dose as well as in combination with other antibiotics but none of these therapies are satisfactory. Nanoparticles in particular polymer-based ones utilizing polymers that are biodegradable and biocompatible for instance PLGA are a method of choice to overcome such drug delivery issues and enable potential targeted delivery. The current study focuses on the evaluation of the structural and dynamical properties of a drug-polymer system consisting of gentamicin drug and PLGA polymer nanoparticles in the water representing a targeted drug delivery system for the treatment of brucellosis. For this purpose, all-atom molecular dynamics simulations were carried out on the drug-polymer systems in the absence and presence of the surfactant bis(2-Ethylhexyl) sulfosuccinate (AOT) to determine the structural and dynamical properties as well as the effect of the surfactant on these properties. We also investigated systems in which the polymer constituents were in the form of monomeric units toward decoupling the primary interactions of the monomer units and polymer effects. The simulation results explain the nature of the interactions between the drug and the polymer as well as transport properties in terms of drug diffusion coefficients, which characterize the molecular behavior of gentamicin-polymer nanoparticles for use in brucellosis., Competing Interests: Declaration of Competing Interest There are no conflicts to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is a major cause of death amongst tuberculosis patients. Nanomedicine avoids some limitations of conventional drug treatment and increases therapeutic efficacy against bacterial infections. However, the effect of anti-TB drug nanoparticle (NP) compounds in anti-TB regimens against MDR-TB remains unclear., Objective: The objective of this article is to prepare levofloxacin, linezolid, ethambutol, prothionamide, and pyrazinamide encapsulated NPs and to evaluate their therapeutic efficacy against MDR-TB in macrophages., Methods: Drug-loaded PLGA NPs were prepared by the multiple emulsion method. The colocalization, intracellular release, and anti-TB activity of these NPs were investigated on cultured macrophages. The immune phenotype of the macrophages, including their mitochondrial membrane potential, reactive oxygen species (ROS), and nitric oxide (NO) production, was evaluated following treatment with NPs or free drug compounds., Results: All drug-loaded PLGA NPs were spherical in shape, 150 to 210 nm in size, and showed 14.22% to 43.51% encapsulation efficiencies and long-duration release. Drug-loaded PLGA NPs were mainly distributed in the cytoplasm of macrophages, showed high cellular compatibility, and maintained their concentration for at least 13 days. Compared with the free drug compounds, the number of colonies after exposure to PLGA NP compounds was significantly less. The enhanced antibacterial activity of the NP compounds may be due to the enhanced levels of ROS and NO and the increased early apoptosis stress within M. tuberculosis-infected macrophages additionally., Conclusion: The application of PLGA NP compounds not only enhances drug efficacy but also induces innate bactericidal events in macrophages, confirming this as a promising approach for MDR-TB therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Currently, the only practical way to treat type 1 and advanced insulin-dependent type 2 diabetes mellitus (T1/2DM) is the frequent subcutaneous injection of insulin, which is significantly different physiologically from endogenous insulin secretion from pancreatic islets and can lead to hyperinsulinemia, pain, and infection in patients with poor compliance. Hence, oral insulin delivery has been actively pursued to revolutionize the treatment of insulin-dependent diabetes. In this review, we provide an overview of recent progress in developing poly(lactic co-glycolic acid) (PLGA) nanoparticles (NPs) for oral insulin delivery. Different strategies for insulin-loaded PLGA NPs to achieve normoglycemic effects are discussed. Finally, challenges and future perspectives of PLGA NPs for oral insulin delivery are put forward., Competing Interests: Declaration of interests No competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Statins, especially simvastatin promote bone formation by stimulating the activity of osteoblasts and suppressing osteoclast activity via the BMP-Smad signaling pathway. Statins present the liver first-pass metabolism. This study attempts to fabricate and evaluate simvastatin functionalized hydroxyapatite encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles (HSIM-PLGA NPs) administered subcutaneously with sustained release properties for effective management of osteoporosis., Methods: Simvastatin functionalized hydroxyapatite (HSIM) was prepared by stirring and validated by docking studies, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). Further, HSIM-loaded PLGA nanoparticles (HSIM-PLGA NPs) were developed via the solvent emulsification method. The nanoparticles were evaluated for zeta potential, particle size, entrapment efficiency, stability studies, and in vitro drug release studies. in vitro binding affinity of nanoparticles for hydroxyapatite was also measured. Bone morphology and its effect on bone mineral density were examined by using a glucocorticoid-induced osteoporosis rat model., Results: The optimized nanoparticles were found to be amorphous and showed no drug-polymer interaction. The particle size of formulated nanoparticles varied from 196.8 ± 2.27nm to 524.8 ± 5.49 nm and the entrapment efficiency of nanoparticles varied from 41.9 ± 3.44% to 70.8 ± 4.46%, respectively. The nanoparticles showed sustained release behaviour (75% in 24 hr) of the drug followed by non-fickian drug release. The nanoparticles exhibited high binding affinity to bone cell receptors, increasing bone mineral density. A significant difference in calcium and phosphorous levels was observed in disease and treatment rats. Porous bone and significant improvement in porosity were observed in osteoporotic rats and treated rats, respectively ( P < 0.05)., Conclusion: Bone-targeting nanoparticles incorporating functionalized simvastatin can target bone. Thus, in order to distribute simvastatin subcutaneously for the treatment of osteoporosis, the developed nanoparticles may act as a promising approach., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Glioblastoma multiforme (GBM) is the most malignant type of brain tumor and has an extremely poor prognosis. Current treatment protocols lack favorable outcomes, and alternative treatments with superior efficacy are needed. In this study, we demonstrate that loading paclitaxel (PTX) in a polymeric, nanoparticulate delivery system is capable of improving its brain accumulation and therapeutic activity. We independently incorporated two different positively charged surface modifiers, poly(amidoamine) (PAMAM) and poly(ethylenimine) (PEI), onto poly(lactic- co -glycolic acid) (PLGA)-polyethylene glycol (PEG), PLGA-PEG, nanoparticles (NPs) using a modified nanoprecipitation technique that assures the formation of nanosized particles while exposing the positively charged polymer on the surface. The prepared NPs underwent comprehensive analyses of their size, charge, in vitro permeability against a BBB cell line, and in vivo biodistribution. Our results demonstrated the successful fabrication of positively charged NPs using PAMAM or PEI. Importantly, significant improvement in brain accumulation (in vivo) was associated with NPs containing PAMAM compared to unmodified NPs or NPs containing PEI. Finally, the efficacy of PAMAM-modified NPs loaded with PTX was evaluated with orthotopic human GBM xenografts in a mouse model, and the data demonstrated improved survival and equivalent safety compared to soluble PTX. Our data substantiate the importance of surface chemistry on the magnitude of NP accumulation in the brain and pave the way for further in vivo evaluation of chemotherapeutic drugs against GBM that have previously been overlooked because of their limited ability to cross the BBB.

Objective: To verrify the anti-tumor efficacy and toxicity between juglone (Jug) and Jug-loaded PLGA nanoparticles (Jug-PLGA-NPs)., Methods: Jug-PLGA-NPs were prepared by ultrasonic emulsification. The anti-tumor activity of Jug (2, 3, 4 µg/mL) and Jug-PLGA-NPs (Jug: 2, 3, 4 µg/mL) in vitro was measured by MTT assay and cell apoptosis analysis. The distribution, anti-tumor effect and biological safety in vivo was evaluated on A375 nude mice., Results: With the advantage of good penetration and targeting properties, Jug-PLGA-NPs significantly inhibited proliferation and migration of melanoma cells both in vitro and in vivo (P<0.05 or P<0.01) with acceptable biocompatibility., Conclusions: Jug can inhibit the growth of melanoma but is highly toxic. With the advantage of sustained release, tumor targeting, anti-tumor activity and acceptable biological safety, Jug-PLGA-NPs provide a new pharmaceutical form for future application of Jug., (© 2021. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Temporomandibular-joint osteoarthritis (TMJOA) management is a major challenge. Minimally invasive therapies (based mainly on injections) have been developed to increase local efficacy and limit adverse systemic effects. However, the requirement for repeat injections due to a short duration of action and expensive healthcare costs have pushed researchers to develop, via tissue engineering, drug-delivery systems (DDSs). In this literature systematic review, we aim to provide an overview of studies that tested DDSs on a TMJOA model., Material and Methods: We searched on PubMed for articles published from November 1965 to March 2021 on DDSs using a TMJOA model. We highlighted the different DDSs and the active molecule employed. Route of drug administration, model type, test duration, and efficacy duration were assessed. To evaluate the quality of each study, a protocol bias was tested using QUADAS-2™., Results: Of the 10 studies that were full text-screened, four used a poly(lactic-co-glycolic acid)-based delivery system. The other DDSs employed chitosan-based hydrogels, microneedles patches, nanostructured lipid carriers, or poloxamer micelles. Hyaluronic acid, nonsteroidal anti-inflammatory drugs, and analgesics were used as active molecules in five studies. The main way to administer DDSs was intra-articular injection and the most used model was the rat., Discussion: Various DDSs and active molecules have been studied on a TMJOA model that could aid TMJOA management. Further works using longer test durations are necessary to validate these advances., Competing Interests: Declarations of Competing Interest None, (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Nanotechnology has shown a revolution in cancer treatments, including breast cancers. However, there remain some challenges and translational hurdles. Surgery, radiotherapy, and chemotherapy are the primary treatment methods for breast cancer, although drug combinations showed promising results in preclinical studies. Herein we report the development of a smart drug delivery system (DDS) to efficiently treat breast cancer by pyroptosis-starvation-chemotherapeutic combination. Cancer-starvation agent glucose oxidase was chemically attached to synthesized iron oxide nanoparticles which were entrapped inside poly(lactic- co -glycolic acid) along with apoptosis-associated speck-like protein containing a caspase recruitment domain plasmid and paclitaxel (PTX). An emulsion solvent evaporation method was used to prepare the DDS. The surface of the DDS was modified with chitosan to which aptamer was attached to achieve site-specific targeting. Hence, the prepared DDS could be targeted to a tumor site by both external magnet and aptamer to obtain an enhanced accumulation of drugs at the tumor site. The final size of the aptamer-decorated DDS was less than 200 nm, and the encapsulation efficiency of PTX was 76.5 ± 2.5%. Drug release from the developed DDS was much higher at pH 5.5 than at pH 7.4, ensuring the pH sensitivity of the DDS. Due to efficient dual targeting of the DDS, in vitro viability of 4T1 cells was reduced to 12.1 ± 1.6%, whereas the nontargeted group and free PTX group could reduce the viability of cells to 29.2 ± 2.4 and 46.2 ± 1.6%, respectively. Our DDS showed a synergistic effect in vitro and no severe side effects in vivo. This DDS has strong potential to treat various cancers.

One can enhance the therapeutic index of anti-cancer drugs using albumin as a tumor homing agent for targeted cancer therapy. Herein, we sought to load lapatinib (LAPA) into small albumin-coated biopolymeric (poly-lactic co-glycolic acid (PLGA)) nanoparticles (APL NPs) by an emulsification method to improve the anti-tumor efficacy of lapatinib. The prepared APL NPs exhibited a small spherical core with an average diameter of 120.5 ± 10.2 nm with a narrow particle size distribution, high drug loading capacity (LC of 9.65 ± 1.53 %), good entrapment efficiency (EE of 75.55 ± 3.25 %), enhanced colloidal stability and a pH-responsive controlled drug release profile. Their cell-uptake and cancer cell growth inhibition were significantly higher compared to free LAPA and uncoated PLGA-LAPA (UPL) NPs, most likely because aggressive breast tumor cells over-express albumin receptors and utilize albumin as nutrient source for their growth. In addition, APL NPs possessed enhanced tumor accumulation and prolonged blood residence time compared to free LAPA and UPL NPs, allowing for potent tumor growth inhibition while exhibiting excellent biosafety. In short, the current study exploited a new and simple strategy to concurrently improve the safety and efficacy of LAPA for breast cancer treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Spinal cord injury (SCI) is characterized by mechanical injury or trauma to the spinal cord. Currently, SCI treatment requires extremely high doses of neuroprotective agents, which in turn, causes several adverse effects. To overcome these limitations, the present study focuses on delivery of a low but effective dose of a naturally occurring antioxidant, α-tocopherol (α-TP). Calcium alginate nanoparticles (CA-NP) and poly D,L-lactic-co-glycolic acid nanoparticles (PLGA-NP) prepared by ionotropic gelation and solvent evaporation technique had particle size of 21.9 ± 11.19 and 152.4 ± 10.6 nm, respectively. Surface morphology, surface charge, as well as particle size distribution of both nanoparticles were evaluated. Entrapment of α-TP into CA-NP and PLGA-NP quantified by UPLC showed entrapment efficiency of 4.00 ± 1.63% and 76.6 ± 11.4%, respectively. In vitro cytotoxicity profiles on human astrocyte-spinal cord (HA-sp) showed that blank CA-NP at high concentrations reduced the cell viability whereas blank PLGA-NP showed relatively safer cytotoxic profiles. In addition, PLGA nanoparticles encapsulated with α-TP (α-TP-PLGA-NP) in comparison to α-TP alone at high concentrations were less toxic. Pretreatment of HA-sp cells with α-TP-PLGA-NP showed two-fold higher anti-oxidative protection as compared to α-TP alone, when oxidative stress was induced by H 2 O 2 . In conclusion, CA-NP were found to be unsuitable for treatment of SCI due to their cytotoxicity. Comparatively, α-TP-PLGA-NP were safer and showed high degree of protection against oxidative stress than α-TP alone., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Zoledronic acid (ZA), a third-generation bisphosphonate, has been extensively used to treat osteoporosis and cancer bone metastasis and demonstrated to suppress proliferation of varied cancer cells and selectively kill tumor-associated microphages (TAMs). However, the clinical applications of ZA in extraskeletal tumor treatment are largely restricted due to its rapid renal clearance and binding to bones. In this study, to promote intracellular delivery of ZA for amplified antitumor efficacy, tumor acidity-responsive polymeric nanoparticles with high ZA payload ( ca. 12.3 wt%) and low premature ZA leakage were designed. As a pivotal material for surface coating, the acidity-sensitive and amphiphilic methoxy poly(ethylene glycol) (mPEG)-benzoic imine-octadecane (C18) (mPEG- b -C18) was synthesized by conjugation of mPEG-CHO with 1-octadecylamine upon Schiff base reaction. Through tailor-made co-assembly of the hydrophobic poly(lactic- co -glycolic acid) (PLGA), amphiphilic tocopheryl polyethylene glycol succinate (TPGS) and mPEG- b -C18 to encapsulate ionic complexes composed of ZA molecules and branched poly(ethylenimine) (PEI) segments, the attained therapeutic polymeric nanoparticles, characterized to have a hydrophobic PLGA/ZA/PEI-constituted core covered with mPEG- b -C18 and TPGS, were able to not only detach mPEG shielding upon acidity-triggered hydrolysis of benzoic imine bonds but also expose surface positive charges of protonated PEI segments. The in vitro cellular uptake and cytotoxicity studies demonstrated that the internalization of acidity-sensitive ZA-encapsulated nanoparticles by TRAMP-C1 mouse prostate cancer cells and murine macrophages RAW 264.7 was considerably promoted upon acidity-elicited PEG detachment and surface charge conversion, thus remarkably boosting intracellular ZA delivery and anticancer potency. Compared to PEG non-detachable ZA-loaded nanoparticles with poor tumor deposition and antitumor effect, the PEG-detachable ZA-carrying nanoparticles markedly accumulated in TRAMP-C1 solid tumors in vivo and inhibited tumor growth, thereby increasing the survival rate of the treated mice. The collective data suggest the great promise of tumor acidity-sensitive ZA-carrying hybrid nanoparticles in the treatment of extraskeletal solid tumors.

Targeted drug delivery has become attention in chemotherapy during the last decade. The principle of chemotherapy seeks maximum effect to the desired site and the minimum impact to other undesired sites of action. The nanoparticulated drug delivery system progressed a lot in this aspect in the last twenty years. Plant-derived natural products and their semisynthetic analogues boosted chemotherapy through their excellent mechanistic approach to killing cancer cells. Keeping in mind the available molecular targets in colorectal carcinoma (CRC), in this article, we proposed a peptide conjugated novel polymeric nanoparticle to deliver garcinol against colorectal carcinoma. Integrin binding peptide iRGD, sequence c(CRGDKGPDC), has been selected as a targeting moiety, as most CRC overexpress integrins. We encapsulated garcinol in biodegradable polymeric nanoparticle (PLGA)-conjugated with iRGD peptide on the particles' surface, and analyzed its (iRGD-GAR-NP's) in vitro and in vivo antineoplastic potential against CRC in a comparative way with gracinol (GAR) and garcinol-loaded PLGA nanoparticles (GAR-NP). In vitro cellular studies on human CRC cell lines, HCT116 and HT-29, revealed the superior cytotoxic potential of iRGD-GAR-NP over GAR and GAR-NP. The IC 50 value on HCT116 cells was reduced by 2.3 times compared to GAR upon the application of iRGD-GAR-NP. At equivalent doses, iRGD-GAR-NP induced higher apoptosis in HCT116 cells and caused blockage of cell cycle at G0/G1 phase of the same. iRGD-GAR-NP increased the apoptotic population of HCT116 cells by 2.5 times compared to GAR. In vivo biodistribution study uncoiled the ability of GAR-NP and iRGD-GAR-NP to accumulate in the colons of dimethyl hydrazine-induced CRC-bearing Sprague-Dawely (SD) rats. In vivo antitumor efficacy study demonstrated the better effect of iRGD-GAR-NP to reduce CRC tumor progression in experimental animals. The survival rate of animals was also increased by 166% in the case of iRGD-GAR-NP compared to CRC-bearing animals received no treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Diabetic cardiomyopathy (DCM) mainly results from development of coronary microcirculatory dysfunction (CMD). Polysaccharide sulfate (PSS), as one heparin drug, has a variety of biological activities. This study examined the efficacy of a new type of PSS-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles (PSS-NPs) on DCM, in finding a theoretical basis for CMD treatment. After establishment of DCM model, the animals were administrated with PSS, PSS-NPs, normal saline or poly(ethylene glycol)1 (PEG1) through intraperitoneal injection. 8 weeks after injection of streptozotocin (STZ), heart function of rats was assessed by echocardiography. The rat tissues were collected and detected by histological analysis. Quantitative reverse transcription PCR (RT-qPCR) and Western blot analyses determined the levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and pro-inflammatory factors. PSS-NPs had a good protective effect on cardiac insufficiency in rats. Administration of PSS-NPs prolonged survival state, and enhanced cardiac function, thereby alleviating the symptoms, and inducing formation of micro vessels. Importantly, it improved the symptoms of DCM patients and their quality of life. Moreover, pro-inflammatory factor levels decreased upon the treatment, accompanied with inactivation of NF- κ B signaling pathways, thereby improving DCM. This study demonstrated that the PSS-NPs significantly relieved DCM and restored cardiac function in rats through NF- κ B signaling pathways, providing a theoretical basis for development of PSS-NPs, and new treatment ideas for CMD of DCM.

Combating triple-negative breast cancer (TNBC) is one of the greatest challenges in cancer therapy. This is primarily due to the difficulties in developing drug delivery systems that can effectively target cancer sites. In this study, we demonstrated a proof-of-principle concept using modified surfaces of poly(lactic-co-glycolic acid) nanoparticles linked with a riboflavin analogue (PLGA-CSRf) to obtain a dual-functional material. PLGA-CSRf nanoparticles were able to function as a drug delivery ligand and a photodynamic therapy agent for TNBC cells (MDA-MB-231). Biocompatibility of novel PLGA-CSRf nanoparticles was evaluated with both breast cancer and normal breast (MCF-10A) cells. In vitro studies revealed a six-fold increase in the cellular uptake of PLGA-CSRf nanoparticles in cancer cells compared with normal cells. The results demonstrate the ability of riboflavin (Rf) to enhance the delivery of PLGA nanoparticles to TNBC cells. The viability of TNBC cells was decreased following treatment with doxorubicin-encapsulated PLGA-CSRf nanoparticles in combination with UV irradiation, due to the photosensitizing property of Rf on the surface of the nanoparticles. This work demonstrated the ability of PLGA-CSRf to function both as an effective drug delivery carrier and as a therapeutic entity, with the potential to enhance photodynamic effects in the highly aggressive TNBC model., (© 2021 American Society for Photobiology.)

Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. Here we develop a CaCO 3 -assisted double emulsion method to encapsulate lipoxidase and hemin with poly(lactic-co-glycolic acid) (PLGA) to enhance RFA. We show the HLCaP nanoreactors (NRs) with pH-dependent catalytic capacity can continuously produce cytotoxic lipid radicals via the lipid peroxidation chain reaction using cancer cell debris as the fuel. Upon being fixed inside the residual tumors post RFA, HLCaP NRs exhibit a suppression effect on residual tumors in mice and rabbits by triggering ferroptosis. Moreover, treatment with HLCaP NRs post RFA can prime antitumor immunity to effectively suppress the growth of both residual and metastatic tumors, also in combination with immune checkpoint blockade. This work highlights that tumor-debris-fueled nanoreactors can benefit RFA by inhibiting tumor recurrence and preventing tumor metastasis., (© 2021. The Author(s).)

Introduction: The experiment was undertaken to estimate the effect of BMSC seeding in different scaffold incorporation with HBO on the repair of a seawater-immersed bone defect. And future compared n-HA/PLGA with β-TCP/PLGA as a scaffold in treatment effect of the seawater-immersed bone defect., Methods: Sixty New Zealand White rabbits with standard seawater defect in radius were randomly divided into group A (implant with nothing), group B (implanted with autogenous bone), group C (implanted with n-HA/PLGA/BMSCs), and group D (implanted with β-TCP/PLGA/BMSCs). After the implant, each rabbit receives HBO treatment at 2.4 ATA 100% oxygen for 120 min/day for 2 weeks. Radiograph, histological, and biomechanical examinations were used to analyze osteogenesis., Result: X-ray analysis shows that n-HA/PLGA/BMSCs and β-TCP/PLGA/BMSCs could accelerate the new bone formation, and the new bone formation in group C was larger than that in group D or group A and close to group B (P < 0.05). After 12 weeks, in group A, the defect without scaffold shows a loose connect tissue filled in the areas. The medullary canal in group B was recanalized. Defects in groups C and D show a larger number of woven bone formation. The new woven bone formation in defect areas in group C was larger than that in group D. The mechanical examination revealed ultimate strength at 12 weeks was group D > group C > group B > group A (P < 0.05)., Conclusion: Scaffolds of n-HA/PLGA and β-TCP/PLGA incorporation with HBO and BMSCs were effective to treat seawater-immersed bone defect, and n-HA/PLGA was more excellent than β-TCP/PLGA.

Hemangiomas, also called infantile hemangiomas (IH), are the most common congenital benign vascular tumors in infants and young children. At present, there are many treatment methods for proliferative hemangiomas, which have different effects and lack predictability. Propranolol has gradually replaced glucocorticoids as the first-line treatment for infants and young children with hemangiomas. However, premature discontinuation is prone to relapse, and the efficacy and safety of medication need to be further studied and determined. The exact pathogenesis of hemangiomas is still unclear. Therefore, in this study, poly(lactic-co-glycolic acid) (PLGA) nanoparticles were used as drug delivery carriers, propranolol was encapsulated, and PLGA-propranolol (PLGA-PP) nanodelivery preparations were prepared and targeted. Anisotropy and pharmacokinetics were preliminary studied. At the same time, after the treatment of HemECs cells with PLGA-PP in gradient concentration in vitro , CCK-8 method was used to detect the cell proliferation, and Anyixin-V/PI double staining method was used to detect the apoptosis rate of cells. The effect of PLGA-PP nano-delivery vector on hemangioma was studied by western blot method to detect the expression level of Id-1 protein in HemECs. The results showed that after PLGA-PP treated HemECs for 24 h, PLGA-PP significantly inhibited HeECs proliferation and promoted their apoptosis, and the intracellular Id-1 protein expression was also reduced. Therefore, this study believes that the mechanism of PLGA-PP nano-targeted delivery preparations in the treatment of hemangiomas is achieved by down-regulating the Id-1 gene, thereby inhibiting the colonization of HemECs and promoting its apoptosis effect.

Our exploration of multimodal nanoprobes aims to combine photoacoustic (PA) imaging, 19 F magnetic resonance (MR), and fluorescence (FL) imaging, which offers complementary advantages such as high spatial resolution, unlimited penetration, and high sensitivity to enable more refined images for accurate tumor diagnoses. In this research, perfluorocarbons (PFCs) and indocyanine green (ICG) are encapsulated by poly(lactic- co -glycolic acid) (PLGA) for intravital 19 F MR/FL/PA tri-modal imaging-guided photothermal therapy. Then, it is coated with an A549 cancer cell membrane (AM) to fabricate versatile theranostic nanoprobes (AM-PP@ICGNPs). After systemic administration, FLI reveals time-dependent tumor homing of NPs with high sensitivity, 19 F MRI provides tumor localization of NPs without background signal interference, and PAI illustrates the detailed distribution of NPs inside the tumor with high spatial resolution. What is more, AM-PP@ICGNPs accumulated in the tumor area exhibit a prominent photothermal effect (48.4 °C) under near infrared (NIR) laser irradiation and realize an enhanced antitumor response in vivo. These benefits, in combination with the excellent biocompatibility, make AM-PP@ICGNPs a potential theranostic nanoagent for accurate tumor localization and ultimately achieve superior cancer therapy.

Triple-negative breast cancer (TNBC) is an immune-enriched subset of breast cancer that has recently demonstrated clinical responsiveness to combinatorial immunotherapy. However, the lack of targeted interventions against hormone receptors or HER2 continues to limit treatment options for these patients. To begin expanding available interventions for patients with metastatic TNBC, we previously reported a therapeutic vaccine regimen that significantly reduced spontaneous lung metastases in a preclinical TNBC model. This heterologous vaccine approach "primed" mice with tumor lysate antigens encapsulated within poly(lactic- co -glycolic) acid microparticles (PLGA MPs), and then "boosted" mice with tumor lysates plus adjuvant. The use of the PLGA MP prime as monotherapy demonstrated no efficacy, suggesting that improving this component of our therapy would achieve greater vaccine efficacy. Here, we functionally improved the PLGA MP prime by coating microparticles with biotinylated streptavidin-conjugated using 1-ethyl-3-(3-dimethylaminoproplyl) carbodiimide/ N -hydroxysuccinimide (EDC/Sulfo-NHS) linkers. This modification enhanced the immunostimulatory potential of our PLGA MPs, as evidenced by increased phagocytosis, maturation, and stimulatory ligand expression by antigen-presenting cells (APCs). Therapeutic prime/boost vaccination of TNBC-bearing mice with surfaced-coated PLGA MPs significantly reduced spontaneous lung metastases by an average of 56% relative to mice primed with unmodified PLGA MPs, and a significant 88% average reduction in spontaneous lung metastases relative to untreated control mice. These findings illustrate that relatively common biotin-streptavidin conjugation formulations can positively affect microparticle-based vaccine immunogenicity resulting in enhanced therapeutic efficacy against established preclinical mammary tumors.

Poly (lactic-co-glycolic acid)-graft-pullulan (PPLGA) based self-organized nanoparticles hold immense potential for synergistic thermo-chemotherapy of tumor. Herein, the biocompatible and biodegradable PPLGA were synthesized by a novel microwave-assisted solution polymerization. The polymers showed thermo-responsive properties, which was attributed to the change of polymer-water hydrogen bonding in controlling the macromolecular contraction, chain collapse as a result of changes in micro-rigidity of core. The curcumin loaded PPLGA nanoparticles (CUR-PPLGA-N), with impressively high drug loading (10.85 ± 0.27 %), exhibited temperature dependence in drug release kinetics. The results of both MTT and antitumor efficiency elucidated that the CUR-PPLGA-N under high temperature facilitated on-demand drug release from the nano-assembly and had a synergistic therapeutic effect for cancer. Thus the developed thermo-responsive PPLGA addressed concerns related to the low drug loading and inefficient drug release at target sites, and might be considered as a powerful nanoplatform for synergistic thermo-chemotherapy of tumor., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cisplatin (CDDP) is a potent chemotherapeutic drug, but its severe side-effects often prohibit its use. Combined treatment with CDDP plus Farnesol (FAR) and their co-encapsulated nano form were investigated in in vitro to examine if synergistic cytotoxicity of this combination could reduce unwanted side-effects of CDDP chemotherapy and potentiate CDDP anticancer activity against hepatocellular carcinoma (HCC) cells. After finding combination therapy of CDDP and FAR successfully combat HCC we formulated co-encapsulation of CDDP and FAR within poly(lactic-co-glycolic acid) copolymer (NCDDPFAR) by following the standardized solvent displacement method. NCDDPFAR treatment caused faster drug mobility, sustained particle release, site-specific action and higher percentage of apoptotic death compared with single drug treatment even at relatively low concentrations. Co-encapsulation of two drugs exhibited additive effects against HCC; FAR reduced CDDP-induced glutathione level by increasing expression of CYP2E1 while CDDP directly interacted with DNA; FAR up-regulated the expression of TopII, thereby promoting DNA breaks and escaping DNA repair machinery. Expression pattern of apoptotic genes like p53, Bax, cytochrome c and caspase-3 suggested that NCDDPFAR induced HCC cell death through mitochondrial intrinsic pathway. Administration of NCDDPFAR had better ability of drug carriage and enhanced anticancer potentials against HCC cells.

Our study is aimed at evaluating the effects of pretreatment with Poly(lactic-co-glycolic) acid nanoparticle loaded with resveratrol (RSV PLGA NPs) compared to conventional resveratrol (RSV) on isoproterenol (ISO) induced myocardial infarction (MI) in rats. Sixty rats were randomly divided into six groups of 10 rats each. RSV and RSV PLGA NPs were given by gavage in two different doses (50 mg/kg body weight [BW] and 100 mg/kg BW) for 3 weeks. RSV and RSV PLGA NPs were given for 2 weeks starting 1 week before ISO administration. The blood samples were taken 24 hr after the last dose of ISO. The antioxidant, anti-inflammatory, and cardioprotective effects were evaluated in all groups. Only 100 mg/kg dose of RSV and both doses of RSV PLGA NPs offered a cardioprotective effect by preventing cardiac troponin T (cTnT) levels, lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) activities leakage from cardiomyocytes, with the best result for RSV PLGA NPs. All the oxidative stress parameters were significantly improved after RSV PLGA NPs compared to RSV pretreatment. RSV PLGA NPs were more efficient than RSV in limiting the increase in inflammatory cytokine expressions such as tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and NF-kappaB (NF-kB) expression. In addition, RSV PLGA NPs significantly upregulated eNOS expression and downregulated iNOS expression. RSV PLGA NPs better prevented myocardial necrosis and reduced interstitial edema and neutrophil infiltration than RSV, on histopathological examination. Therefore, improving the bioactivity of RSV by nanotechnology may help limit cardiac injury after myocardial infarction., (© 2020 International Union of Biochemistry and Molecular Biology.)

The objectives of the present research work were systematic development of novel in situ gel formulation containing nanoparticles for localised delivery of moxifloxacin against bacterial periodontitis. PLGA nanoparticles were prepared and optimised in a systematic manner. Factor screening was performed with the help of half-factorial design to identify the influential factors, while response surface optimisation of the nanoparticles was conducted using central composite design. The optimum nanoparticle formulation was chosen on the basis of lower particle size, higher drug entrapment and controlled drug release characteristics up to 1 week time period, while the optimum in situ gel was selected on the basis of faster gelling and higher viscosity and gel strength properties for improved retention in the periodontium. In vivo histopathological studies and in vivo gamma scintigraphy studies revealed the extended release, superior efficacy and enhanced retention of nanoparticle-loaded in situ gelling system. Results obtained from in vivo histopathological studies after 1 week treatment with in situ gel formulation containing nanoparticles of moxifloxacin were found to be better than with 3 weeks treatment of marketed gel formulation. Overall, the studies ratify successful development of an effective site-specific drug delivery system with enhanced biopharmaceutical attributes for the periodontitis treatment.

Background: The purpose of this study was to evaluate the biomechanical and histologic properties of rotator cuff repairs using a vented anchor attached to a bioresorbable interpositional scaffold composed of aligned PLGA (poly(l-lactide-co-glycoside)) microfibers in an animal model compared to standard anchors in an ovine model., Methods: Fifty-six (n = 56) skeletally mature sheep were randomly assigned to a repair of an acute infraspinatus tendon detachment using a innovative anchor-PLGA scaffold device (Treatment) or a similar anchor without the scaffold (Control). Animals were humanely euthanized at 7 and 12 weeks post repair. Histologic and biomechanical properties of the repairs were evaluated and compared., Results: The Treatment group had a significantly higher fibroblast count at 7 weeks compared to the Control group. The tendon bone repair distance, percentage perpendicular fibers, new bone formation at the tendon-bone interface, and collagen type III deposition was significantly greater for the Treatment group compared with the Control group at 12 weeks (P ≤ .05). A positive correlation was identified in the Treatment group between increased failure loads at 12 weeks and the following parameters: tendon-bone integration, new bone formation, and collagen type III. No statistically significant differences in biomechanical properties were identified between Treatment and Control Groups (P > .05)., Conclusions: Use of a vented anchor attached to a bioresorbable interpositional scaffold composed of aligned PLGA microfibers improves the histologic properties of rotator cuff repairs in a sheep model. Improved histology was correlated with improved final construct strength at the 12-week time point., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Developing new strategies to reduce the output power of microwave (MW) ablation while keeping anti-tumor effect are highly desirable for the simultaneous achievement of effective tumor killing and avoidance of complications. We find that mild MW irradiation can significantly increase intracellular Ca 2+ concentration in the presence of doxorubicin hydrochloride (DOX) and thus induce massive tumor cell apoptosis. Herein, we designed a synergistic nanoplatform that not only amplifies the intracellular Ca 2+ concentration and induce cell death under mild MW irradiation but also avoids the side effect of thermal ablation and chemotherapy., Results: The as-made NaCl-DOX@PLGA nanoplatform selectively elevates the temperature of tumor tissue distributed with nanoparticles under low-output MW, which further prompts the release of DOX from the PLGA nanoparticles and tumor cellular uptake of DOX. More importantly, its synergistic effect not only combines thermal ablation and chemotherapy, but also obviously increases the intracellular Ca 2+ concentration. Changes of Ca 2+ broke the homeostasis of tumor cells, decreased the mitochondrial inner membrane potential and finally induced the cascade of apoptosis under nonlethal temperature. As such, the NaCl-DOX@PLGA efficiently suppressed the tumor cell progression in vivo and in vitro under mild MW irradiation for the triple synergic effect., Conclusions: This work provides a biocompatible and biodegradable nanoplatform with triple functions to realize the effective tumor killing in unlethal temperature. Those findings provide reliable solution to solve the bottleneck problem bothering clinics about the balance of thermal efficiency and normal tissue protection.

Tissue engineering is a promising approach to repair osteochondral defects, yet successful reconstruction of different layers in an integrated graft, especially the interface remains challenging. The multiphasic, functionally integrated tissue engineering graft described herein mimics the entire osteochondral tissue in terms of structure and composition at the cartilage, bone and cartilage-bone interface layer to repair osteochondral defects. In this manuscript, we report the fabrication of a multiphasic graft via bonding of a cartilaginous hydrogel and a sintered poly(lactic-co-glycolic acid) microsphere scaffold by an endogenous fibrotic cartilaginous extracellular matrix. We demonstrated that culturing chondrocytes within the alginate hydrogel conjugated to the poly(lactic-co-glycolic acid) scaffold allows for (i) gradient transition and integration from the cartilage layer to the subchondral bone layer as assessed by scanning electron microscopy, histology and biochemistry, and (ii) superior tissue repair efficacy in a rabbit knee defect model. Industrialization of the graft remains an unsolved challenge as after decellularization the tissue repair efficacy of the graft decreased. Taken together, the multiphasic osteochondral graft repaired the osteochondral defects successfully and has the potential to be applied clinically as an implant in orthopaedic surgery.

Objective: To investigate whether poly (lactic-co-glycolic acid) (PLGA) as protein delivery vehicles that encapsulate CC chemokine receptor 5 antibody (anti-CCR5) has more suppressive function on macrophages than single anti-CCR5 in mouse endometriosis model. Methods: The PLGA/anti-CCR5 nanoparticles were synthesized. The cumulative release of anti-CCR5 from PLGA/anti-CCR5 nanoparticles was evaluated. The mouse endometriosis model was established and divided into control group, anti-CCR5 group and PLGA/anti-CCR5 group. Meanwhile, ectopic endometrial cells (EEC) and macrophages isolated from peritoneal fluid were cultured in vitro. Flow cytometry was used to detect the proportion of macrophages in the peritoneal fluid of each group. The secretion of interleukin 10 (IL-10) and transforming growth factor β (TGF-β) in each group were determined by ELISA. The proliferation and infiltration of EEC were detected by 5-bromodeoxyuridine proliferation kit and matrigel invasion kit. Results: The PLGA/anti-CCR5 nanoparticles were successfully synthesized. The mouse endometriosis model was established and the EEC and macrophages were cultured. Compared with the anti-CCR5 without nanoparticles, the bioconjugate PLGA/anti-CCR5 nanoparticles could control the release of anti-CCR5 from day 3 to day 24. The proportion of macrophages in PLGA/anti-CCR5 group were gradually reduced compared with those in anti-CCR5 group ( P< 0.01), the ratios of day 7 [(4.5±1.5)%] and day 3 [(6.3±0.6)%], day 14 [(2.6±0.7)%] and day 7 were significantly different ( P< 0.01 and P< 0.05). PLGA/anti-CCR5 reduced IL-10 and TGF-β levels relative to anti-CCR5 ( P< 0.01),and decreased gradually on day 3, day 7, and day 14 ( P< 0.01). Anti-IL-10+anti-TGF-β could reduce the proliferation [(70.8±7.6)%] and invasion ability [(50.2±9.1)%] of EEC ( P< 0.05). Conclusions: In mouse endometriosis model, PLGA/anti-CCR5 may inhibit the proliferation and invasion of EEC by inhibiting the secretion of IL-10 and TGF-β by macrophages, suggesting that it provide a new idea for the treatment of clinical endometriosis.

In breast cancer chemophotothermal therapy, it is a great challenge for the development of multifunctional nanoagents for precision targeting and the effective treatment of tumors, especially for metastasis. Herein, we successfully design and synthesize a multifunctional black phosphorus (BP)-based nanoagent, BP/DTX@PLGA, to address this challenge. In this composite nanoagent, BP quantum dots (BPQDs) are loaded into poly(lactic- co -glycolic acid) (PLGA) with additional conjugation of a chemotherapeutic agent, docetaxel (DTX). The in vivo distribution results demonstrate that BP/DTX@PLGA shows striking tropism for targeting both primary tumors and lung metastatic tumors. Moreover, BP/DTX@PLGA exhibits outstanding controllable chemophotothermal combinatory therapeutics, which dramatically improves the efficacy of photothermal tumor ablation when combined with near-light irradiation. Mechanistically, accelerated DTX release from the nanocomplex upon heating and thermal treatment per se synergistically incurs apoptosis-dependent cell death, resulting in the elimination of lung metastasis. Meanwhile, in vitro and in vivo results further confirm that BP/DTX@PLGA possesses good biocompatibility. This study provides a promising BP-based multimodal nanoagent to constrain cancer metastasis.

Surgery of the chest wall is potentially required to cover large defects after  removal of malignant tumours. Usually, inert and non-degradable Gore-Tex serves to replace the missing tissue. However, novel biodegradable materials combined with stem cells are available that stimulate the healing. Based on poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles (PLGA/aCaP) and pure PLGA, a dual layer biodegradable hybrid nanocomposite was generated. Mouse adipose-derived stem cells were cultered on electrospun disks (ASCs of C57BL/6), and biomechanical tests were performed. The cell-seeded scaffolds were engrafted in C57BL/LY5.1 mice to serve as a chest wall substitute. Cell invasion into the bi-layered material, extent of CD45 + cells, inflammatory response, neo-vascularization and ECM composition were determined at 1 and 2 months post-surgery, respectively. The bi-layered hybrid nanocomposite was stable after a 2-week in vitro culture, in contrast to PLGA/aCaP without a PLGA layer. There was a complete biointegration and good vascularization in vivo. The presence of ASCs attracted more CD45 + cells (hematopoietic origin) compared to cell-free scaffolds. Inflammatory reaction was similar for both groups (±ASCs) at 8 weeks. A bi-layered hybrid nanocomposite fabricated of electrospun PLGA/aCaP and a reinforcing layer of pristine PLGA is an ideal scaffold for chest wall reconstruction. It is stable and allows a proper host tissue integration. If ASCs are seeded, they attract more CD45 + cells, supporting the regeneration process.

Pseudomonas aeruginosa is the major infectious agent of concern for cystic fibrosis (CF) patients. Therefore, it is necessary to develop appropriate strategies for preventing colonization by this bacterium and/or neutralizing virulence factors. In this study, we formulated the encapsulation of exotoxin A into PLGA nanoparticles. The biological activities of the nanovaccine candidate were also characterized. Based on the results, ETA-PLGA can act as a suitable immunogen to stimulate the humoral and cellular immune response. The antibodies raised against ETA-PLGA significantly decreased bacterial titer in the spleens of the immunized mice after challenge with PAO1 strain, compared to the control groups. The encapsulation of PLGA into ETA led to a significantly higher production of INF-γ, TNF-α, IL-4, and IL-17A cytokine responses compared to the ETA group. ETA-PLGA enhanced IgG responses in immunized mice compared to ETA antigen. We concluded that encapsulation of Pseudomonas aeruginosa ETA to PLGA nanoparticles can increase its functional activity by decreasing the bacterial dissemination.

Background: MicroRNA-145 (miR-145) reportedly alters the phenotype of vascular smooth muscle cells (VSMCs) from a proliferative to a contractile state. So far, viral or plasmid vectors have been experimentally used to transduce microRNAs into VSMCs. We hypothesized that a simple ex vivo microRNA delivery system using miR-145-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA NPs) could control the VSMC phenotype and prevent intimal hyperplasia., Methods: Jugular vein grafts of male Japanese white rabbits were soaked in phosphate-buffered saline, control microRNA (cont-miR)-loaded PLGA NP solution or miR-145-loaded PLGA NP solution for 30 minutes (n = 8 for each). Vein grafts were implanted in the ipsilateral carotid artery and assessed 2 weeks after the implantation., Results: Quantitative polymerase chain reaction analysis showed significantly higher miR-145 expression in the miR-145-treated group. The neointimal area was significantly smaller in the miR-145-treated group (phosphate-buffered saline-treated vs cont-miR-treated vs miR-145-treated group; 1.63 ± 0.52 mm 2 vs 1.67 ± 0.49 mm 2 vs 0.88 ± 0.34 mm 2 , respectively; P < .01 for the miR-145-treated vs the cont-miR-treated group). In the miR-145-treated group, Ki-67-positive cells were significantly fewer, indicating lower VSMC proliferation. An inflammation-related molecule, CD40 expression was significantly reduced by miR-145-loaded PLGA NP treatment., Conclusions: Local and sustained release of miR-145 by PLGA NPs attenuated intimal hyperplasia in the rabbit model by maintaining VSMCs in a contractile state. This simple ex vivo miR-145 delivery system would be promising toward broader clinical application., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Secreted aspartyl proteinases (Saps), are gene products that have been shown to directly contribute to Candida albicans pathogenicity. Despite the clear difficulties of systemic C. albicans infections control, Antimicrobial peptides (AMPs) are regarded as one of the most promising alternatives in this regard. Recently, drug-loaded electrospun nanofibers have attracted a great deal of attention. In this study we have established the nanofibrous scaffold of new synthetic peptide/Poly (Vinyl Alcohol)/Poly l-Lactic Acid on expression of Secretory aspartyl proteinases 4 to 6 genes of C. albicans in comparison with free peptide. We designed new synthetic Antimicrobial peptide (AMPs) used bioinformatics tools to predict structure and stabilities. The electrospinning method was used to produce the polymeric nanofibers. Scanning Electron Microscopy (SEM) was used to measure the nanofibers diameters and morphology. To analyze the expression of SAP4, SAP5 and SAP6 genes, RNA was extracted from clinical isolates of C. albicans before and after treatment with subinhibitory concentrations of new synthetic peptide on nanofibrous scaffold of new synthetic peptide/PVA/PLLA and then the cDNA was synthesized and used for Real-time PCR assay. Scanning electron microscopy (SEM) images showed that the morphology, the diameter, are affected from peptide. Reletive quantitative Real-time PCR results revealed that the mRNA levels of SAP4, SAP5 and SAP6 genes significantly decreased after treatment with nanofibrous scaffold of new synthetic peptide/PVA/PLLA (P < .05). Electrospun nanofibrous of new Synthetic Peptide/PVA/PLLA is effective in downregulating of expression SAP4, SAP5 and SAP6 genes of C. albicans strains., (Copyright © 2019. Published by Elsevier B.V.)

Candida albicans is a human opportunistic pathogen that causes superficial and life-threatening infections. An important reason for the failure of current antifungal drugs is related to biofilm formation, mostly associated with implanted medical devices. The present study investigated the synergistic antifungal efficacy of low-frequency and low-intensity ultrasound combined with amphotericin B (AmB)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (AmB-NPs) against C. albicans biofilms. AmB-NPs were prepared by a double-emulsion method and demonstrated lower toxicity than free AmB. We then established biofilms and treated them with ultrasound and AmB-NPs separately or jointly in vitro and in vivo The results demonstrated that the activity, biomass, and proteinase and phospholipase activities of biofilms were decreased significantly after the combination treatment of AmB-NPs with 42 kHz of ultrasound irradiation at an intensity of 0.30 W/cm 2 for 15 min compared with the controls, with AmB alone, or with ultrasound treatment alone ( P  < 0.01). The morphology of the biofilms was altered remarkably after joint treatment based on confocal laser scanning microscopy (CLSM), especially in regard to reduced thickness and loosened structure. Furthermore, the same synergistic effects were found in a subcutaneous catheter biofilm rat model. The number of CFU from the catheter exhibited a significant reduction after joint treatment with AmB-NP and ultrasound for seven continuous days, and CLSM and scanning electron microscopy (SEM) images revealed that the biofilm on the catheter surface was substantially eliminated. This method may provide a new noninvasive, safe, and effective therapy for C. albicans biofilm infection., (Copyright © 2019 American Society for Microbiology.)

Combination therapy is a common clinical practice in the management of malignancies. Synergistic therapeutic outcomes are achieved only when tumor cells are exposed to drugs in an optimal ratio and sequence; therefore, carriers coencapsulating multiple drugs are widely pursued for their coordinated delivery. However, it is challenging to coload drugs with different physicochemical properties in a single carrier with specific ratios. It is not even beneficial to load them in one carrier if they need to be released at different times. We propose to load drugs into chemically compatible carriers separately, equalize different carriers by a simple, rapid, and versatile camouflage technique based on natural polyphenol tannic acid (TA), and administer them in desirable ratios and sequences. To demonstrate this potential, different nanoparticles (NPs) with different charges and material basis, such as polymeric (carboxyl-terminated or amine-terminated cationic polystyrene NPs or poly(lactic- co-glycolic acid (PLGA) NPs), inorganic (mesoporous silica NPs (MSNs)), and liposomal NPs, are camouflaged with TA layers and further modified with folate-conjugated polyethylene glycol to aid in the delivery to tumors. The camouflaged NPs show similar physicochemical properties and interactions with KB cells despite the difference in core platforms, and their mixtures interact with common cell targets in a ratiometric manner. In KB-tumor-bearing mice, the camouflaged PLGA NPs and MSNs show near-perfect colocalization in tumors. These results support that TA helps equalize different NPs with high versatility and enables their ratiometric delivery to common targets. This approach can relieve technical challenges in ratiometric codelivery or sequential delivery of therapeutic agents with distinct physicochemical properties.

Bone defect repair is a challenging clinical problem in musculoskeletal system, especially in orthopaedic disorders such as steroid associated osteonecrosis (SAON). Magnesium (Mg) as a biodegradable metal with properly mechanical properties has been investigating for a long history. In this study, Mg powder, poly (lactide-co-glycolide) (PLGA), β-tricalcium phosphate (β-TCP) were the elements to formulate a novel porous PLGA/TCP/Mg (PTM) scaffolds using low temperature rapid prototyping (LT-RP) technology. The physical characterization of PTM scaffold and Mg ions release were analyzed in vitro. The osteogenic and angiogenic properties of PTM scaffolds, as well as the biosafety after implantation were assessed in an established SAON rabbit model. Our results showed that the PTM scaffold possessed well-designed bio-mimic structure and improved mechanical properties. Findings of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and micro-computed tomography (micro CT)-based angiography indicated that PTM scaffold could increase blood perfusion and promote new vessel ingrowth at 4 weeks after surgery, meanwhile, a plenty of newly formed vessels with well-architective structure were observed at 8 weeks. Correspondingly, at 12 weeks after surgery, micro-CT, histological and mechanical properties analysis showed that PTM could significant enhance new bone formation and strengthen newly formed bone mechanical properties. The mean bone volume in PTM group was 56.3% greater than that in PT group. Biosafety assessments from 0 to 12 weeks after implantation did not induce increase in serum Mg ions concentration, and immune response, liver and kidney function parameters were all at normal level. These findings suggested that the PTM scaffold had both osteogenic and angiogenic abilities which were synergistic effect in enhancing new bone formation and strengthen newly formed bone quality in SAON. In summary, PTM scaffolds are promising composite biomaterials for repairing challenging bone defect that would have great potential for its clinical translation., (Copyright © 2019. Published by Elsevier Ltd.)

Aim: The aim of this study was to assess the local and systemic response to poly-lactic co-glycolic acid (PLGA) 50:50 membranes, developed as synthetic biodegradable alternatives to the use of human donor amniotic membrane in the treatment of limbal stem cell deficiency., Methods: PLGA membranes of 2  cm diameter and 50  µm thickness were placed on one eye of rabbits and secured in place using fibrin glue and a bandage contact lens, suturing the eye close with a single stitch. Control animals were treated identically, with the absence of the membranes. Plain and microfabricated electrospun membranes (containing micropockets which roughly emulate the native limbal niche) were examined over 29 days. All animals were subjected to a detailed gross and histopathological observation as well as a detailed examination of the eye., Results: Application of the membranes both with and without microfabricated pockets did not adversely affect animal welfare. There was complete degradation of the membranes by day 29. The membranes did not induce any significant local or systemic toxicity. Conjunctival congestion and corneal vascularisation were noted in a few control and PLGA-treated animals. Intraocular pressure was normal and the retinal status was unaltered. The ocular surface was clear and intact in all animals by the end of 29  days., Conclusion: Membranes of 50:50 PLGA can be safely applied to rabbit corneas without inducing any local or systemic toxicity and these break down completely within 29 days., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Peripheral nerve injury is an important cause of incapability and has limited available treatment. Autologous donor nerve implant is the golden standard treatment, however, may cause secondary deficits. Stem cells show positive results in preclinical settings, preserving tissue and function. We tested the efficacy of stem cells derived from human exfoliated deciduous teeth seeded in poly (lactide-co-glycolide) scaffolds in sciatic nerve transection model. Seventy-two adult male Wistar rats had 7-mm nerve gap bridge using scaffolds with (or without) stem cells. Animals were randomly divided into: sham-operated; sham-operated without scaffold; sham-operated + scaffold + stem cells; sciatic transection + no treatment; sciatic transection + acellular scaffolds; sciatic transection + scaffold + stem cells. Sciatic Functional Index and Ladder Rung Walking tests were performed before (-1), 14 and 28 days after surgery. Morphometric nerve measurement and muscle weights were assessed. Scaffolds with stem cells improved function in Sciatic Functional Index. Acellular scaffold was effective, promoting functional recovery and nerve regeneration following nerve injury. Scaffolds provide better nerve regeneration and functional recovery after sciatic transection. Despite cell therapy promoting faster recovery after sciatic transection in the Sciatic Index Score, stem cells did not improve functional and morphological recovery after nerve injury. This is the first study testing the potential use of scaffolds combined with stem cells in the early stages after injury. Scaffolds with stem cells could accelerate nerve recovery and favor adjuvant therapies, evidencing the need for further studies to increase the knowledge about stem cells' mechanisms., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Calcium phosphate materials have been employed clinically as bone void fillers for several decades. These materials are most often provided in the form of small, porous granules that can be packed to fill the wide variety of size and shape of bony defects encountered. ReBOSSIS-85 (RB-85) is a synthetic bioresorbable bone void filler for the repair of bone defects with handling characteristics of glass wool-like (or cotton ball-like). The objective of this study is to evaluate the in vivo performance of RB-85 (test material), compared to a commercially available bone void filler, Mastergraft Putty (predicate material), when combined with bone marrow aspirate and iliac crest autograft, in an established posterolateral spine fusion rabbit model., Methods: One hundred fifty skeletally mature rabbits had a single level posterolateral fusion performed. Rabbits were implanted with iliac crest bone graft (ICBG), Mastergraft Putty™ plus ICBG, or one of 4 masses of ReBOSSIS-85 (0.2, 0.3, 0.45, or 0.6 g) plus ICBG. Plain films were taken weekly until euthanasia. Following euthanasia at 4, 8, and 12 weeks, the lumbar spine were tested by manual palpation. Spinal columns in the 12 week group were also subjected to non-destructive flexibility testing. MicroCT and histology were performed on a subset of each implant group at each euthanasia period., Results: Radiographic scoring of the fusion sites indicated a normal healing response in all test groups. Bilateral radiographic fusion rates for all test groups were 0% at 4 weeks; ICBG 43%, Mastergraft Putty 50%, RB-85-0.2g 0%, RB-85-0.3g 13%, RB-85-0.45g 38%, and RB-85-0.6g 63% at 8 weeks; and ICBG 50%, Mastergraft Putty 50%, RB-85-0.2g 0%, RB-85-0.3g 25%, RB-85-0.45g 36%, and RB-85-0.6g 50% at 12 weeks.Spine fusion was assessed by manual palpation of the treated motion segments. At 12 weeks, ICBG, MGP, and RB-85-0.6g were fused mechanically in at least 50% of the rabbits. All groups demonstrated significantly less range of motion in both flexion/extension, lateral bending, and axial rotation compared to normal unfused controls.Histopathology analysis of the fusion masses, in all test groups, indicated an expected normal response of mild inflammation with macrophage and multinucleated giant cell response to the graft material at 4 weeks and resolving by 12 weeks. Regardless of test article, new bone formation and graft resorption increased from 4 to 12 weeks post-op., Conclusions: This animal study has demonstrated the biocompatibility and normal healing features associated with the ReBOSSIS-85 bone graft (test material) when combined with autograft as an extender. ReBOSSIS-85 was more effective when a larger mass of test article was used in this study., Clinical Relevance: ReBOSSIS-85 can be used as an extender negating the need for large amounts of local or iliac crest bone in posterolateral fusions., Competing Interests: Disclosures: The authors report no potential conflicts of interest related to this study., (Copyright © The Iowa Orthopaedic Journal 2019.)

An in vivo study was conducted to evaluate the effects of the incorporation of fibers of poly(lactic acid-co-glycolic acid, PLGA) and poly(isoprene) blend and recombinant human growth hormone (rhGH) in a macroporous scaffold of α-tricalcium phosphate cement (α-TCP) samples inserted into calvarial defects (8 mm in diameter) of 48 Wistar rats. The samples of α-TCP + PLGA/poly(isoprene) blend fibers were also submitted to a mechanical test of flexural strength. The animals of the different experimental groups [1] α-TCP (n = 6); [2] α-TCP + PLGA/poly(isoprene) blend fibers (n = 6); [3] α-TCP + rhGH, (n = 6) and [4] α-TCP + PLGA/poly(isoprene) blend fibers + rhGH, (n = 6) (the numbers within square brackets identify the experimental groups), after two weeks (subdivision "a") and four weeks (subdivision "b"), were euthanized and the implants removed for histological analysis. There was no statistical difference (p > 0.05) between the samples with and without fibers in the mechanical test. Light microscopy revealed good integration of the material in the host tissue, represented by tissue penetration into the macropores and adequate angiogenesis. In the two-week period, the groups [3a] and [4a] were significantly superior (p < 0.05) to the other groups with regard to angiogenesis and bone neoformation. In the four-week period, the group [3b] was significantly superior (p < 0.05) to the other groups with regard to bone neoformation. We conclude that the macroporous α-TCP scaffold used in this study has low mechanical resistance, is biocompatible and has significantly improved the osteoconductive capacity when rhGH is incorporated into its structure.

Most neurodegenerative disorders are characterized by deposits of misfolded proteins and neuronal degeneration in specific brain regions. Growing evidence indicates that lysosomal impairment plays a primary pathogenic role in these diseases, in particular, the occurrence of increased lysosomal pH. Thus, therapeutic development aiming at restoring lysosomal function represents a novel, precise, and promising strategy for the treatment of these pathologies. Herein we demonstrate that acidic oil-in-water nanoemulsions loaded with poly(dl-lactide- co-glycolide) (PLGA) are able to rescue impaired lysosomal pH in genetic cellular models of Parkinson's disease. For in vivo assays, nanoemulsions were labeled with an original synthetic hydrophobic far red-emitting dye to allow fluorescence monitoring. Following stereotaxic injection in the mouse brain, widespread diffusion of the nanocarrier was observed, up to 500 μm from the injection site, as well as internalization into the lysosomal compartment in brain cells. Finally, promising preliminary assays of systemic administration demonstrate that a fraction of the formulation crosses the blood brain barrier, penetrates the brain parenchyma, is internalized by cells, and colocalizes with lysosomal markers. Overall, these results suggest the feasibility and the therapeutic potential of this new nanoformulation as an effective drug delivery tool to the brain, with the potential to rescue pathological lysosomal deficits.

Purpose: The aim of this study is to follow morphological imaging characteristics and osteointegration of TruFit ® bone graft substitute (BGS) plugs in cases of chondral and osteochondral defects of the articular surface of the knee joint, using high-quality cartilage-sensitive 3-T magnetic resonance imaging (MRI), linked to clinical outcomes., Methods: The MRI was used to assess osteointegration and biological evolution of the TruFit ® BGS plugs in cases with minimum 5-year follow-up: The TruFit ® plug was used in 46 patients for a total of 47 cases with mean age of 57.89 (range 32-80). In this study, we reviewed only the cases with minimum follow-up of 5 years: 5 patients with mean age 64.4 years (minimum 38, maximum 80). The mean follow-up was 71 months (range 63-77). Patients were evaluated clinically, with Lysholm Knee Scoring Scale and MOCART Scale., Results: 3-T MRI, which is preferable to 1.5 T for the better signal-to-noise ratio, contrast and the ability to acquire morphological images at higher spatial resolution, shows a satisfactory integration of bone scaffolds in studied cases for more than 5 years and a satisfactory restoration of the articular cartilage, with the exception of a case of which we still have to consider the factors age, type of lesion and the relationship between the plugs implanted., Conclusion: Clinical and radiological results significantly improve in a longer follow-up time.

Inflammation is involved in many human pathologies, including osteoarthritis (OA). Hydrogen (H 2 ) is known to have anti-inflammatory effects; however, the bioavailability of directly administered H 2 gas is typically poor. Herein, a local delivery system that can provide a high therapeutic concentration of gaseous H 2 at inflamed tissues is proposed. The delivery system comprises poly(lactic-co-glycolic acid) microparticles that contain magnesium powder (Mg@PLGA MPs). Mg@PLGA MPs that are intra-muscularly injected close to the OA knee in a mouse model can act as an in situ depot that can evolve gaseous H 2 continuously, mediated by the cycle of passivation/activation of Mg in body fluids, at a concentration that exceeds its therapeutic threshold. The analytical data that are obtained in the biochemical and histological studies indicate that the proposed Mg@PLGA MPs can effectively mitigate tissue inflammation and prevent cartilage from destruction, arresting the progression of OA changes., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Polymeric nanoparticles (NPs) represent one of the most promising tools in nanomedicine and have been extensively studied for the delivery of water-insoluble drugs. However, the efficient loading of therapeutic enzymes and proteins in polymer-based nanostructures remains an open challenge. Here, we report a synthesis method for a new enzyme delivery system based on cross-linked enzyme aggregates (CLEAs) encapsulation into poly(lactide- co-glycolide) (PLGA) NPs. We tested the encapsulation strategy on four enzymes currently investigated for enzyme replacement therapy: palmitoyl protein thioesterase 1 (PPT1; defective in NCL1 disease), galactosylceramidase (GALC; defective in globoid cell leukodystrophy), alpha glucosidase (aGLU; defective in Pompe disease), and beta glucosidase (bGLU; defective in Gaucher's disease). We demonstrated that our system allows encapsulation of enzymes with excellent activity retention (usually around 60%), thus leading to functional and targeted nanostructures suitable for enzyme delivery. We then demonstrated that CLEA NPs efficiently deliver PPT1 in cultured cells, with almost complete enzyme release occurring in 48 h. Finally, we demonstrated that enzymatic activity is fully recovered in primary NCL1 fibroblasts upon treatment with PPT1 CLEA NPs.