Mineral Nanomedicine to Enhance the Efficacy of Adjuvant Radiotherapy for Treating Osteosarcoma.

It is vital to remove residual tumor cells after resection to avoid the recurrence and metastasis of osteosarcoma. In this study, a mineral nanomedicine, europium-doped calcium fluoride (CaF2:Eu) nanoparticles (NPs), is developed to enhance the efficacy of adjuvant radiotherapy (i.e., surgical resection followed by radiotherapy) for tumor cell growth and metastasis of osteosarcoma. In vitro studies show that CaF2:Eu NPs (200 µg/mL) exert osteosarcoma cell (143B)-selective toxicity and migration-inhibiting effects at a Eu dopant amount of 2.95 atomic weight percentage. These effects are further enhanced under X-ray irradiation (6 MeV, 4 Gy). Furthermore, in vivo tests show that intraosseous injection of CaF2:Eu NPs and X-ray irradiation have satisfactory therapeutic efficacy in controlling primary tumor size and inhibiting primary tumor metastasis. Overall, our results suggest that CaF2:Eu NPs with their osteosarcoma cell (143B)-selective toxicity and migration-inhibiting effects combined with radiotherapy might be nanomedicines for treating osteosarcoma after tumor resection.

Using a Hybrid Radioenhancer to Discover Tumor Cell-targeted Treatment for Osteosarcoma: An In Vitro Study.

Osteosarcoma is insensitive to radiation. High-dose radiation is often used as a treatment but causes side effects in patients. Hence, it is important to develop tumor cell-- targeted radiotherapy that could improve radiotherapy efficiency on tumor cells and reduce the toxic effect on normal cells during radiation treatment. In this study, we developed an innovative method for treating osteosarcoma by using a novel radiation-enhancer (i.e., carboxymethyl-hexanoyl chitosan-coated self-assembled Au@Fe3O4 nanoparticles; CSAF NPs). CSAF NPs were employed together with 5-aminolevulinic acid (5- ALA) to achieve tumor cell-targeted radiotherapy. In this study, osteosarcoma cells (MG63) and normal cells (MC3T3-E1) were used for an in vitro investigation, in which reactive oxygen species (ROS) assay, cell viability assay, clonogenic assay, and western blot were used to confirm the treatment efficiency. The ROS assay showed that the combination of CSAF NPs and 5-ALA enhanced radiation-induced ROS production in tumor cells (MG63); however, this was not observed in normal cells (MC3T3-E1). The cell viability ratio of normal cells to tumor cells after treatment with CSAF NPs and 5-ALA reached 2.79. Moreover, the clonogenic assay showed that the radiosensitivity of MG63 cells was increased by the combination use of CSAF NPs and 5-ALA. This was supported by performing a western blot that confirmed the expression of cytochrome c (a marker of cell mitochondria damage) and caspase-3 (a marker of cell apoptosis). The results provide an essential basis for developing tumor-cell targeted radiotherapy by means of low-- dose radiation.

Circulating tumor-cell-targeting Au-nanocage-mediated bimodal phototherapeutic properties enriched by magnetic nanocores.

Metastasis resulting from circulating tumor cells (CTCs) is associated with 90% of all cancer mortality. To disrupt cancer dissemination, therapeutic targeting of CTCs by extracorporeal photodynamic therapy (PDT) has emerged; however, it still remains impractical due to its limited therapeutic window. Herein, we developed a photosensitive and magnetic targeted core-satellite nanomedicine (TCSN) to augment the light-induced damage to the targeted cells. The magnetic nanocore (MNC) with multiple iron oxide nanoparticles stabilized using thiolated polyvinyl alcohol can magnetize the CTCs to achieve magnetic enrichment under a magnetic field. Multiple gold nanocage (AuNC) satellites were conjugated on the MNC to facilitate bimodal photothermal therapy and PDT. Adjusting the thiol content in the MNC allows manipulating the AuNC density on TCSNs, which has been found to demonstrate a density-dependent bimodal phototherapeutic effect under laser irradiation at 808 and 940 nm. Moreover, with the immobilization of anti-epithelial cell adhesion molecule (anti-EpCAM), TCSN exhibited an enhanced affinity toward EpCAM-expressing 4T1 cells. We demonstrate that TCSN-labeled 4T1 cells can be isolated and photo-eradicated in a microfluidic channel with a dynamic flow. Our studies showed that TCSN with the complementary properties of MNC and AuNCs can largely augment the therapeutic window by magnetic enrichment and bimodal phototherapy, serving as an advanced extracorporeal strategy to remove CTCs.

Ibuprofen-conjugated hyaluronate/polygalacturonic acid hydrogel for the prevention of epidural fibrosis.

The formation of fibrous tissue is part of the natural healing response following a laminectomy. Severe scar tissue adhesion, known as epidural fibrosis, is a common cause of failed back surgery syndrome. In this study, by combining the advantages of drug treatment with a physical barrier, an ibuprofen-conjugated crosslinkable polygalacturonic acid and hyaluronic acid hydrogel was developed for epidural fibrosis prevention. Conjugation was confirmed and measured by 1D(1)H NMR spectroscopy.In vitroanalysis showed that the ibuprofen-conjugated polygalacturonic acid-hyaluronic acid hydrogel showed low cytotoxicity. In addition, the conjugated ibuprofen decreased prostaglandin E2production of the lipopolysaccharide-induced RAW264.7 cells. Histological data inin vivostudies indicated that the scar tissue adhesion of laminectomized male adult rats was reduced by the application of our ibuprofen-conjugated polygalacturonic acid-hyaluronic acid hydrogel. Its use also reduced the population of giant cells and collagen deposition of scar tissue without inducing extensive cell recruitment. The results of this study therefore suggest that the local delivery of ibuprofenviaa polygalacturonic acid-hyaluronic acid-based hydrogel reduces the possibility of epidural fibrosis.

A theranostic nrGO@MSN-ION nanocarrier developed to enhance the combination effect of sonodynamic therapy and ultrasound hyperthermia for treating tumor.

Sonodynamic therapy (SDT), which induces activation of sonosensitizers in cancer cells through ultrasound irradiation, has emerged as an alternative and promising noninvasive therapeutic approach to kill both superficial and deep parts of tumors. In this study, mesoporous silica (MSN) grown on reduced graphene oxide nanosheet (nrGO) capped with Rose Bengal (RB)-PEG-conjugated iron-oxide nanoparticles (IONs), nrGO@MSN-ION-PEG-RB, was strategically designed to have targeted functionality and therapeutic efficacy under magnetic guiding and focused ultrasound (FUS) irradiation, respectively. The singlet oxygen produced by ultrasound-activated RB and the ultrasound-induced heating effect was enhanced by rGO and IONs, which improved the cytotoxic effect in cancer cells. In an animal experiment, we demonstrated that the combination of sonodynamic/hyperthermia therapy with magnetic guidance using this nanocomposite therapeutic agent can produce remarkable efficacious therapy in tumor growth inhibition. Furthermore, the combination effect induced by FUS irradiation produces significant damage to both superficial and deep parts of the targeted tumor.

In situ forming hydrogel composed of hyaluronate and polygalacturonic acid for prevention of peridural fibrosis.

Hyaluronic acid-based hydrogels can reduce postoperative adhesion. However, the long-term application of hyaluronic acid is limited by tissue mediated enzymatic degradation. To overcome this limitation, we developed a polygalacturonic acid and hyaluronate composite hydrogel by Schiff's base crosslinking reaction. The polygalacturonic acid and hyaluronate composite hydrogels had short gelation time (less than 15 s) and degraded by less than 50 % in the presence of hyaluronidase for 7 days. Cell adhesion and migration assays showed polygalacturonic acid and hyaluronate composite hydrogels prevented fibroblasts from adhesion and infiltration into the hydrogels. Compared to hyaluronate hydrogels and commercial Medishield™ gels, polygalacturonic acid and hyaluronate composite hydrogel was not totally degraded in vivo after 4 weeks. In the rat laminectomy model, polygalacturonic acid and hyaluronate composite hydrogel also had better adhesion grade and smaller mean area of fibrous tissue formation over the saline control and hyaluronate hydrogel groups. Polygalacturonic acid and hyaluronate composite hydrogel is a system that can be easy to use due to its in situ cross-linkable property and potentially promising for adhesion prevention in spine surgeries.