Iron Oxide Nanoparticles in Mesenchymal Stem Cell Detection and Therapy.

Mesenchymal stem cells (MSCs) exhibit regenerative and reparative properties. However, most MSC-related studies remain to be translated for regular clinical usage, partly due to challenges in pre-transplantation cell labelling and post-transplantation cell tracking. Amidst this, there are growing concerns over the toxicity of commonly used gadolinium-based contrast agents that mediate in-vivo cell detection via MRI. This urges to search for equally effective but less toxic alternatives that would facilitate and enhance MSC detection post-administration and provide therapeutic benefits in-vivo. MSCs labelled with iron oxide nanoparticles (IONPs) have shown promising results in-vitro and in-vivo. Thus, it would be useful to revisit these studies before inventing new labelling approaches. Aiming to inform regenerative medicine and augment clinical applications of IONP-labelled MSCs, this review collates and critically evaluates the utility of IONPs in enhancing MSC detection and therapeutics. It explains the rationale, principle, and advantages of labelling MSCs with IONPs, and describes IONP-induced intracellular alterations and consequent cellular manifestations. By exemplifying clinical pathologies, it examines contextual in-vitro, animal, and clinical studies that used IONP-labelled bone marrow-, umbilical cord-, adipose tissue- and dental pulp-derived MSCs. It compiles and discusses studies involving MSC-labelling of IONPs in combinations with carbohydrates (Venofer, ferumoxytol, dextran, glucosamine), non-carbohydrate polymers [poly(L-lysine), poly(lactide-co-glycolide), poly(L-lactide), polydopamine], elements (ruthenium, selenium, gold, zinc), compounds/stains (silica, polyethylene glycol, fluorophore, rhodamine B, DAPI, Prussian blue), DNA, Fibroblast growth Factor-2 and the drug doxorubicin. Furthermore, IONP-labelling of MSC exosomes is reviewed. Also, limitations of IONP-labelling are addressed and methods of tackling those challenges are suggested.

A cell-free ROS-responsive hydrogel/oriented poly(lactide-co-glycolide) hybrid scaffold for reducing inflammation and restoring full-thickness cartilage defectsin vivo.

The modulation of inflammation in tissue microenvironment takes an important role in cartilage repair and regeneration. In this study, a novel hybrid scaffold was designed and fabricated by filling a reactive oxygen species (ROS)-scavenging hydrogel (RS Gel) into a radially oriented poly(lactide-co-glycolide) (PLGA) scaffold. The radially oriented PLGA scaffolds were fabricated through a temperature gradient-guided phase separation and freeze-drying method. The RS Gel was formed by crosslinking the mixture of ROS-responsive hyperbranched polymers and biocompatible methacrylated hyaluronic acid (HA-MA). The hybrid scaffolds exhibited a proper compressive modulus, good ROS-scavenging capability, and cell compatibility.In vivotests showed that the hybrid scaffolds significantly regulated inflammation and promoted regeneration of hyaline cartilage after they were implanted into full-thickness cartilage defects in rabbits for 12 w. In comparison with the PLGA scaffolds, the neo-cartilage in the hybrid scaffolds group possessed more deposition of glycosaminoglycans and collagen type II, and were well integrated with the surrounding tissue.

pH-Triggered Poly(ethylene glycol)-Poly(lactic acid/glycolic acid)/Croconaine Nanoparticles-Assisted Multiplexed Photoacoustic Imaging and Enhanced Photothermal Cancer Therapy.

The most advantageous and attractive property of photoacoustic imaging is its capability to visualize and differentiate multiple species according to their unique absorbance profiles simultaneously in a single mixture. We here report the pH-sensitive near-infrared (NIR) croconaine (Croc) dyes-loaded copolymeric PEG-PLGA nanoparticles (NPs) for in vivo multiplexed PA imaging and pH-responsive photothermal therapy (PTT) in an orthotopic xenograft model. PEG chains on the polymeric NPs shell were conjugated with iRGD in another set of NPs to realize efficient tumor targeting. The distribution and the intensity of two sets of iRGD-targeted and nontargeted NPs inside tumors are simultaneously imaged and monitored in vivo. Meanwhile, the utilization of iRGD-targeted PPC815 NPs as a pH-active photothermal agent with promising tumor-inhibition efficacy was demonstrated. As a result, this nanoplatform is capable of assisting multiwavelength unmixing of PA imaging as well as providing remarkable photothermal ablation for anticancer treatment.

NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer.

The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an adaptive resistance mechanism in vivo. Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line chemotherapy in various types of cancer, including colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture tumor cells treated with gefitinib or NDAT. The gene expression of PD-L1 and other tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft tumors was characterized by specialized immunohistochemistry (IHC) and the hematoxylin and eosin stain (H&E stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. (3) The PD-L1 was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the PD-L1 expression was decreased by gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM gefitinib stimulated PD-L1 expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced PD-L1 expression and proliferation in CRC Colo_160224 cells. Gefitinib didn't inhibit PD-L1 expression and PI3K activation in gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and tumor growth in the HCT116 (K-RAS mutant) xenograft experiment. (4) Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs.

Fixed-point "blasting" triggered by second near-infrared window light for augmented interventional photothermal therapy.

One of the major limitations of current cancer therapy is the inability to destroy tumors with high efficacy and minimal invasiveness. Herein, we developed a proof-of-concept fixed-point "blasting" strategy to destroy the "castle" of tumors and realized efficient interventional photothermal therapy. The "blasting" materials were composed of photothermal nanoparticles (ancient ink nanoparticles, AINP) and a low boiling point phase change agent (perfluoromethylcyclopentane, FMCP). An injectable in situ-forming thermal-responsive hydrogel composed of biodegradable and biocompatible polymers was employed as a carrier to load the AINP and FMCP. The obtained hydrogel system was a flowable aqueous solution at low or room temperature for facile injection; meanwhile, once administered, it rapidly transformed into a fixed gel at a body temperature of about 37 °C. This unique property could effectually fix the AINP and FMCP and thus restrict the destruction region inside the tumor. Subsequently, triggered by second window near-infrared light, the solid tumors were effectively destroyed by a mild photothermal effect and the subsequent gas mechanical damage. We envisage that this fixed-point "blasting" strategy will pave a new way for the next generation of cancer-interventional photothermal therapy.

NDAT suppresses pro-inflammatory gene expression to enhance resveratrol-induced anti-proliferation in oral cancer cells.

Nano-diamino-tetrac (NDAT), a tetraiodothyroxine deaminated nano-particulated analog, has shown to inhibit expression of pro-inflammatory genes. NDAT inhibits expression of programmed death-ligand 1 (PD-L1). On the other hand, in addition to inhibiting inflammatory effect, the stilbene, resveratrol induces expression of cyclooxygenase-2 (COX-2) and its accumulation. Sequentially, inducible COX-2 complexes with p53 and induces p53-dependent anti-proliferation. In current study, we investigated mechanisms involved in combined treatment of NDAT and resveratrol on anti-proliferation in human oral cancer cells. Both resveratrol and NDAT inhibited expression of pro-inflammatory IL-1ß and TNF-α. They also inhibited expression of CCND1 and PD-L1. Both resveratrol and NDAT induced BAD expression but only resveratrol induced COX-2 expression in both OEC-M1 and SCC-25 cells. Combined treatment attenuated gene expression significantly compared with resveratrol treatment in both cancer cell lines. Resveratrol reduced nuclear PD-L1 accumulation which was enhanced by a STAT3 inhibitor, S31-201 or NDAT suggesting that NDAT may inactivate STAT3 to inhibit PD-L1 accumulation. In the presence of T4, NDAT further enhanced resveratrol-induced anti-proliferation in both cancer cell lines. These findings provide a novel understanding of the inhibition of NDAT in thyroxine-induced pro-inflammatory effect on resveratrol-induced anticancer properties.

Enhancement by Nano-Diamino-Tetrac of Antiproliferative Action of Gefitinib on Colorectal Cancer Cells: Mediation by EGFR Sialylation and PI3K Activation.

Drug resistance complicates the clinical use of gefitinib. Tetraiodothyroacetic acid (tetrac) and nano-diamino-tetrac (NDAT) have been shown in vitro and in xenografts to have antiproliferative/angiogenic properties and to potentiate antiproliferative activity of other anticancer agents. In the current study, we investigated the effects of NDAT on the anticancer activities of gefitinib in human colorectal cancer cells. ß-Galactoside α-2,6-sialyltransferase 1 (ST6Gal1) catalyzes EGFR sialylation that is associated with gefitinib resistance in colorectal cancers, and this was also investigated. Gefitinib inhibited cell proliferation of HT-29 cells (K-ras wild-type), and NDAT significantly enhanced the antiproliferative action of gefitinib. Gefitinib inhibited cell proliferation of HCT116 cells (K-ras mutant) only in high concentration, and this was further enhanced by NDAT. NDAT enhancedd gefitinib-induced antiproliferation in gefitinib-resistant colorectal cancer cells by inhibiting ST6Gal1 activity and PI3K activation. Furthermore, NDAT enhanced gefitinib-induced anticancer activity additively in colorectal cancer HCT116 cell xenograft-bearing nude mice. Results suggest that NDAT may have an application with gefitinib as combination colorectal cancer therapy.

Nanovaccine Incorporated with Hydroxychloroquine Enhances Antigen Cross-Presentation and Promotes Antitumor Immune Responses.

Induction of effective antigen-specific CD8+ T-cell responses is critical for cancer immunotherapy success. Hydroxychloroquine (HCQ) is a widely used classical antimalarial and antirheumatic drug. HCQ is also an endosomal membrane disrupting agent that can lead to vesicular swelling and membrane permeabilization, which likely facilitates the release of therapeutic agents from lysosomes into the cytoplasm. Here, we develop a minimalistic nanovaccine, which is composed of poly(lactide- co-glycolide)acid (PLGA) nanoparticles (NPs) encapsulating a physical mixture of ovalbumin (OVA, a model antigen) and HCQ (HCQ-OVA-PLGA NPs). We tested whether HCQ could spatiotemporally control the cytosolic delivery of antigens, enhance antigen processing and presentation via the major histocompatibility complex (MHC)-I pathway, and thus generate a sufficient antitumor cytotoxic T-cell response. The results of in vitro experiments showed that HCQ-OVA-PLGA NPs significantly enhanced OVA escape from lysosomes into the cytoplasm within bone-marrow-derived dendritic cells. We also observed that HCQ-OVA-PLGA NPs enhanced the expression level of MHC-I on dendritic cells and improved cross-presentation of antigen, compared to free OVA or OVA-PLGA NPs. Results of in vivo experiments confirmed that HCQ initiated Th1-type responses and strong CD8+ T-cell responses that induced tumor cell apoptosis. Moreover, vaccination of mice with HCQ-OVA-PLGA NPs effectively generated memory immune responses in vivo and prevented tumor progression. We conclude that co-encapsulation of HCQ with antigens in nanovaccines can boost antigen-specific antitumor immune responses, particularly through CD8+ T-cells, serving as a simple and effective platform for the treatment of tumors and infectious diseases.

Nano-Diamino-Tetrac (NDAT) Enhances Resveratrol-Induced Antiproliferation by Action on the RRM2 Pathway in Colorectal Cancers.

Cancer resistance to chemotherapeutic agents is a major issue in the management of cancer patients. Overexpression of the ribonucleotide reductase regulatory subunit M2 (RRM2) has been associated with aggressive cancer behavior and chemoresistance. Nano-diamino-tetrac (NDAT) is a nanoparticulate derivative of tetraiodothyroacetic acid (tetrac), which exerts anticancer properties via several mechanisms and downregulates RRM2 gene expression in cancer cells. Resveratrol is a stilbenoid phytoalexin which binds to a specific site on the cell surface integrin αvß3 to trigger cancer cell death via nuclear translocation of COX-2. Here we report that resveratrol paradoxically activates RRM2 gene expression and protein translation in colon cancer cells. This unanticipated effect inhibits resveratrol-induced COX-2 nuclear accumulation. RRM2 downregulation, whether achieved by RNA interference or treatment with NDAT, enhanced resveratrol-induced COX-2 gene expression and nuclear uptake which is essential to integrin αvß3-mediated-resveratrol-induced antiproliferation in cancer cells. Elsewhere, NDAT downregulated resveratrol-induced RRM2 expression in vivo but potentiated the anticancer effect of the stilbene. These findings suggest that RRM2 appears as a cancer cell defense mechanism which can hinder the anticancer effect of the stilbene via the integrin αvß3 axis. Furthermore, the antagonistic effect of RRM2 against resveratrol is counteracted by the administration of NDAT.

Poly(Lactide-Co-Glycolide)-Monomethoxy-Poly-(Polyethylene Glycol) Nanoparticles Loaded with Melatonin Protect Adipose-Derived Stem Cells Transplanted in Infarcted Heart Tissue.

Stem cell transplantation is a promising therapeutic strategy for myocardial infarction. However, transplanted cells face low survival rates due to oxidative stress and the inflammatory microenvironment in ischemic heart tissue. Melatonin has been used as a powerful endogenous antioxidant to protect cells from oxidative injury. However, melatonin cannot play a long-lasting effect against the hostile microenvironment. Nano drug delivery carriers have the ability to protect the loaded drug from degradation in physiological environments in a controlled manner, which results in longer effects and decreased side effects. Therefore, we constructed poly(lactide-co-glycolide)-monomethoxy-poly-(polyethylene glycol) (PLGA-mPEG) nanoparticles to encapsulate melatonin. We tested whether the protective effect of melatonin encapsulated by PLGA-mPEG nanoparticles (melatonin nanoparticles [Mel-NPs]) on adipose-derived mesenchymal stem cells (ADSCs) was enhanced compared to that of free melatonin both in vitro and in vivo. In the in vitro study, we found that Mel-NPs reduced formation of the p53- cyclophilin D complex, prevented mitochondrial permeability transition pores from opening, and rescued ADSCs from hypoxia/reoxygenation injury. Moreover, Mel-NPs can achieve higher ADSC survival rates than free melatonin in rat myocardial infarction areas, and the therapeutic effects of ADSCs pretreated with Mel-NPs were more apparent. Hence, the combination of Mel-NPs and stem cell transplantation may be a promising strategy for myocardial infarction therapy. Stem Cells 2018;36:540-550.

Biodegradable composite porous poly(dl-lactide-co-glycolide) scaffold supports mesenchymal stem cell differentiation and calcium phosphate deposition.

In recent decades, tissue engineering strategies have been proposed for the treatment of musculoskeletal diseases and bone fractures to overcome the limitations of the traditional surgical approaches based on allografts and autografts. In this work we report the development of a composite porous poly(dl-lactide-co-glycolide) scaffold suitable for bone regeneration. Scaffolds were produced by thermal sintering of porous microparticles. Next, in order to improve cell adhesion to the scaffold and subsequent proliferation, the scaffolds were coated with the osteoconductive biopolymers chitosan and sodium alginate, in a process that exploited electrostatic interactions between the positively charged biopolymers and the negatively charged PLGA scaffold. The resulting scaffolds were characterized in terms of porosity, degradation rate, mechanical properties, biocompatibility and suitability for bone regeneration. They were found to have an overall porosity of ∼85% and a degradation half time of ∼2 weeks, considered suitable to support de novo bone matrix deposition from mesenchymal stem cells. Histology confirmed the ability of the scaffold to sustain adipose-derived mesenchymal stem cell adhesion, infiltration, proliferation and osteo-differentiation. Histological staining of calcium and microanalysis confirmed the presence of calcium phosphate in the scaffold sections.

Development of poly(lactide-co-glycolide) nanoparticles functionalized with a mitochondria penetrating peptide.

The development of mitochondria-targeting cell permeable vectors represents a promising therapeutic approach for several diseases, such as cancer and oxidative pathologies. Nevertheless, access to mitochondria can be difficult. A new hybrid material composed by poly(lactide-co-glycolide) (PLGA) functionalized with a 6-mer mitochondria penetrating peptide (MPP), consisting in alternating arginine and unnatural cyclohexylalanine, was developed. Circular dichroism, FT-IR and DSC studies indicated that the conjugation of the peptide with the polymer led to the obtainment of a more rigid material with respect to both PLGA and MPP as such. In particular, a conformational rearrangement to a helical structure was observed for MPP. MPP-PLGA conjugates were used for the preparation of nanoparticles that showed no cytotoxicity in MTT assay, suggesting their putative use for future studies on mitochondria targeting. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Porous poly (D,L-lactide-co-glycolide) acid/biosilicate® composite scaffolds for bone tissue engineering.

This study evaluated the effects of the Biosilicate® and poly (D,L-lactic-co-glycolic) acid composites on bone repair in a tibial bone defect model in rats by means of using histological evaluation (histopathological and morphometric analysis) and gene expression analysis. Eighty male Wistar rats (12 weeks old, weighing ±300 g) were randomly divided into two groups: Biosilicate® group (BG) and Biosilicate® /PLGA group (BG/PLGA). Each group was euthanized at 3, 7, 14, and 21 days after surgery (n = 10 animals per time point). The main findings showed that the incorporation of PLGA into BG had a significant effect on the morphological structure of the material, accelerating mass loss, decreasing the pH and increasing the calcium release. Furthermore, histologic analysis revealed that the BG/PLGA showed increased material degradation, accompanied by higher bone formation compared to BG, after 21 days of implantation. In addition, qRT-PCR analysis showed that BG/PLGA induced an upregulation of the osteogenic genes related to BMP4, Runx2, ALP, and OC. These results show that the present BG/PLGA composite may be used as a bone graft for inducing bone repair. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 63-71, 2017.

Changes in expression of cartilaginous genes during chondrogenesis of Wharton's jelly mesenchymal stem cells on three-dimensional biodegradable poly(L-lactide-co-glycolide) scaffolds.

BACKGROUND: In cartilage tissue regeneration, it is important to develop biodegradable scaffolds that provide a structural and logistic template for three-dimensional cultures of chondrocytes. In this study, we evaluated changes in expression of cartilaginous genes during in vitro chondrogenic differentiation of WJ-MSCs on PLGA scaffolds. METHODS: The biocompatibility of the PLGA material was investigated using WJ-MSCs by direct and indirect contact methods according to the ISO 10993-5 standard. PLGA scaffolds were fabricated by the solvent casting/salt-leaching technique. We analyzed expression of chondrogenic genes of WJ-MSCs after a 21-day culture. RESULTS: The results showed the biocompatibility of PLGA and confirmed the usefulness of PLGA as material for fabrication of 3D scaffolds that can be applied for WJ-MSC culture. The in vitro penetration and colonization of the scaffolds by WJ-MSCs were assessed by confocal microscopy. The increase in cell number demonstrated that scaffolds made of PLGA copolymers enabled WJ-MSC proliferation. The obtained data showed that as a result of chondrogenesis of WJ-MSCs on the PLGA scaffold the expression of the key markers collagen type II and aggrecan was increased. CONCLUSIONS: The observed changes in transcriptional activity of cartilaginous genes suggest that the PLGA scaffolds may be applied for WJ-MSC differentiation. This primary study suggests that chondrogenic capacity of WJ-MSCs cultured on the PLGA scaffolds can be useful for cell therapy of cartilage.

A clinical study on the influence of suturing material on oral wound healing.

BACKGROUND/AIM: Suture materials play an important role in healing, enabling reconstruction and reassembly of tissue separated by the surgical procedure or trauma, and at the same time facilitating and promoting healing and hemostasis. Suture materials are used daily in oral surgery, and are considered to be substances most commonly implanted in human body. The aim of this clinical study was to examine the speed of wound healing and complications incidence, after the use of three different absorbable synthetic suture materials in oral surgery (catgut, Dexon and Vicryl rapide), and to ascertain which one is the most suitable for oral surgery. METHODS: The study was conducted on 96 patients undergoing root resection or surgical extraction of third molars. Each of the suture materials (catgut, Dexon and Vicryl rapide) was used for 8 root resections and 8 surgical third molar extractions in the maxilla, as well as in the mandible (a total of 32 surgical interventions for each suture material). RESULTS: The faster wound healing was obtained with Vicryl rapide compared to other two suturing material tested. There was no significant difference regarding the presence of local reaction in all the three groups of patients on the 21st postoperative day. CONCLUSION: The results of our clinical study point out that Vycril- rapid contributes more than catgut or Dexon to faster healing of human wounds, with fewer incidences of wound dehiscence and milder local reactions.

Comparison of antibacterial-coated and non-coated suture material in intraoral surgery by isolation of adherent bacteria.

OBJECTIVES: In general surgery the incidence of postoperative wound infections is reported to be lower using triclosan-coated sutures. In intraoral surgery, sutures are faced with different bacterial species and the question arises whether the antibacterial-coated suture material has the same positive effects. MATERIALS AND METHODS: Triclosan-coated and uncoated suture materials were applied in 17 patients undergoing wisdom tooth extraction. Postoperatively, sutures were removed and adherent bacteria were isolated, colony-forming units (cfu) were counted, and species identified. RESULTS: Oral bacteria were found in high numbers (cfu>10(7)) on both Vicryl and the triclosan-coated Vicryl Plus. The total number of bacteria isolated from Vicryl Plus was 37% higher than for Vicryl, mainly due to increased numbers of anaerobes. The number of bacterial strains identified was higher for Vicryl ( n=203) than for Vicryl Plus (n=198), but the number of pathogens was higher on Vicryl Plus (n=100) than on Vicryl (n=97). Fewer Gram-positive strains were found on Vicryl Plus (n=95) than on Vicryl (n=107) and, conversely, more Gram-negative strains on Vicryl Plus (103vs.96). CONCLUSIONS: In terms of the total number of oral bacteria, and especially oral pathogens, that adhered to suture material, no reduction was demonstrated for Vicryl Plus. The use of triclosan-coated suture material offers no advantage in intraoral surgery.

pH-sensitive nanoparticles of poly(L-histidine)-poly(lactide-co-glycolide)-tocopheryl polyethylene glycol succinate for anti-tumor drug delivery.

A novel pH-sensitive polymer, poly(L-histidine)-poly(lactide-co-glycolide)-tocopheryl polyethylene glycol succinate (PLH-PLGA-TPGS), was synthesized to design a biocompatible drug delivery system for cancer chemotherapy. The structure of the PLH-PLGA-TPGS copolymer was confirmed by (1)H-NMR, FTIR and GPC. The apparent pKa of the PLH-PLGA-TPGS copolymer was calculated to be 6.33 according to the acid-base titration curve. The doxorubicin (DOX)-loaded nanoparticles (PLH-PLGA-TPGS nanoparticles and PLGA-TPGS nanoparticles) and corresponding blank nanoparticles were prepared by a co-solvent evaporation method. The blank PLH-PLGA-TPGS nanoparticles showed an acidic pH-induced increase in particle size. The DOX-loaded nanoparticles based on PLH-PLGA-TPGS showed a pH-triggered drug-release behavior under acidic conditions. The results of in vitro cytotoxicity experiment on MCF-7 and MCF-7/ADR cells showed that the DOX-loaded PLH-PLGA-TPGS nanoparticles resulted in lower cell viability versus the PLGA-TPGS nanoparticles and free DOX solution. Confocal laser scanning microscopy images showed that DOX-loaded PLH-PLGA-TPGS nanoparticles were internalized by MCF-7/ADR cells after 1 and 4h incubation and most of them accumulated in lysosomes to accelerate DOX release under acidic conditions. In summary, the PLH-PLGA-TPGS nanoparticles have great potential to be used as carriers for anti-tumor drug delivery.

In vivo photoacoustic molecular imaging of breast carcinoma with folate receptor-targeted indocyanine green nanoprobes.

As an optical-acoustic hybrid imaging technology, photoacoustic imaging uniquely combines the advantages of rich optical contrast with high ultrasonic resolution in depth, opening up many new possibilities not attainable with conventional pure optical imaging technologies. To perform photoacoustic molecular imaging, optically absorbing exogenous contrast agents are needed to enhance the signals from specifically targeted disease activity. In this work, we designed and developed folate receptor targeted, indocyanine green dye doped poly(d,l-lactide-co-glycolide) lipid nanoparticles (FA-ICG-PLGA-lipid NPs) for molecular photoacoustic imaging of tumor. The fabricated FA-ICG-PLGA-lipid NPs exhibited good aqueous stability, a high folate-receptor targeting efficiency, and remarkable optical absorption in near-infrared wavelengths, providing excellent photoacoustic signals in vitro. Furthermore, after intravenous administration of FA-ICG-PLGA-lipid NPs, mice bearing MCF-7 breast carcinomas showed significantly enhanced photoacoustic signals in vivo in the tumor regions, compared with those using non-targeted ICG-PLGA-lipid NPs. Given the existing wide clinical use of ICG and PLGA, the developed FA-ICG-PLGA-lipid NPs, in conjunction with photoacoustic imaging technology, offer a great potential to be translated into the clinic for non-ionizing molecular imaging of breast cancer in vivo.

Vicryl mesh in expander/implant breast reconstruction: long-term follow-up in 38 patients.

BACKGROUND: Acellular dermal matrix has proven to be a useful adjunct in tissue expander or direct-to-implant breast reconstruction. Although versatile, acellular dermal matrix adds considerable cost. Vicryl (polyglactin) mesh has an established track record in many fields of surgery, and is considerably less costly than acellular dermal matrix. This study examines the use and long-term follow-up of Vicryl mesh in breast reconstruction. METHODS: Vicryl mesh was used in 46 breast reconstructions (38 patients; 35 immediate and three delayed). The mesh was used along the inframammary fold to maintain position of the inferior pectoral edge, and/or along the lateral border to maintain expander position and prevent lateral migration. Eight breasts received adjuvant radiation therapy. RESULTS: Mean follow-up at the time of review was 43 months. In the nonirradiated group (38 breasts), there was one postoperative infection (2.6 percent), which required expander removal. In the irradiated group, there were three complications requiring expander removal (37.5 percent): two infections and one device exposure after irradiation. Significant malposition was not observed in any breast where Vicryl mesh was used, and no visible mesh remained at the time of implant placement. The incidence of symptomatic capsular contracture in nonirradiated breasts was 3.2 percent. At latest follow-up, nonirradiated breasts had an average Baker capsule grade of 1.1, compared with 1.5 in the irradiated group. CONCLUSIONS: Vicryl mesh is an effective alternative to acellular dermal matrix in nonirradiated breast reconstruction and is available at approximately one-twentieth the cost. Acellular dermal matrix or full muscle coverage may be preferable in irradiated reconstructions. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.