RESUMEN
Biomaterial-based implants hold great potential for postoperative cancer treatment due to the enhanced drug dosage at the disease site and decreased systemic toxicity. However, the elaborate design of implants to avoid complicated chemical modification and burst release remains challenging. Herein, we report a three-dimensional (3D) printed hydrogel scaffold to enable sustained release of drugs for postoperative synergistic cancer therapy. The hydrogel scaffold is composed of Pluronic F127 and sodium alginate (SA) as well as doxorubicin (DOX) and copper ions (F127-SA/Cu-DOX hydrogel scaffold). Benefiting from the coordination of Cu(II) with both SA and DOX, burst release of DOX can be overcome, and prolonged release time can be achieved. The therapeutic efficiency can be adjusted by altering the amount of DOX and Cu(II) in the scaffolds. Moreover, apoptosis and ferroptosis of cancer cells can be induced through the combination of chemotherapy and chemodynamic therapy. In addition, DOX supplies excess hydrogen peroxide to enhance the efficiency of Cu-based chemodynamic therapy. When implanted in the resection site, hydrogel scaffolds effectively inhibit tumor growth. Overall, this study may offer a new strategy for fabricating local implants with synergistic therapeutic performance for preventing postoperative cancer recurrence.
Asunto(s)
Cobre , Hidrogeles , Hidrogeles/química , Línea Celular Tumoral , Doxorrubicina/uso terapéutico , Impresión TridimensionalRESUMEN
Surgical resection to achieve tumor-free margins represents a difficult clinical scenario for patients with hepatocellular carcinoma. While post-surgical treatments such as chemotherapy and radiotherapy can decrease the risk of cancer recurrence and metastasis, growing concerns about the complications and side effects have promoted the development of implantable systems for locoregional treatment. Herein, 3D printed hydrogel scaffolds (designed as Gel-SA-CuO) were developed by incorporating one agent with multifunctional performance into implantable devices to simplify the fabrication process for efficiently inhibiting postoperative tumor recurrence. CuO nanoparticles can be effectively controlled and sustained released during the biodegradation of hydrogel scaffolds. Notably, the released CuO nanoparticles not only function as the reservoir for releasing Cu2+ to produce intracellular reactive oxygen species (ROS) but also serve as photothermal agent to generate heat. Remarkably, the heat generated by photothermal conversion of CuO nanoparticles further promotes the efficiency of Fenton-like reaction. Additionally, ferroptosis can be induced through Cu2+-mediated GSH depletion via the inactivation of GPX4. By implanting hydrogel scaffolds in the resection site, efficient inhibition of tumor recurrence after primary resection can be achieved in vivo. Therefore, this study may pave the way for the development of advanced multifunctional implantable platform for eliminating postoperative relapsable cancers.
Asunto(s)
Ferroptosis , Neoplasias Hepáticas , Nanopartículas , Línea Celular Tumoral , Glutatión , Humanos , Hidrogeles , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/prevención & control , Impresión TridimensionalRESUMEN
The postoperative tumor recurrence and chemotherapy resistance in clinical osteosarcoma treatment have raised an imperative need to develop local implants for selectively killing residual tumor cells and simultaneously provide a scaffold for effectively filling the tumor resection-induced bone defects. Herein, a multifunctional platform is developed through successively coating TiN microparticles and doxorubicin (DOX) on the surface of tricalcium phosphate (TCP) scaffolds to achieve synergetic effects of photothermal therapy and chemotherapy for osteosarcoma. The content of TiN and DOX in the scaffolds can be flexibly adjusted by immersing the scaffolds into the solution containing different concentrations of TiN and DOX. The excellent therapeutic effect was achieved both in vitro and in vivo through the precise photothermal therapy and localized controlled-release chemotherapy. Moreover, the overall bulk scaffolds provide the mechanical support for bone tissue when implanting scaffolds into bone defects resulting from surgical removal of osteosarcoma. Importantly, using the poly(d,l-lactide) (PDLLA) as the medium, the scaffolds can be exploited as a universal platform for loading different kinds of therapeutic agents. This study may provide insights into designing multifunctional local implantation for eradicating tumors after surgical interventions with mitigated side effects.
Asunto(s)
Cerámica/química , Osteosarcoma/terapia , Impresión Tridimensional , Andamios del Tejido/química , Fosfatos de Calcio/química , Terapia Combinada , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Osteosarcoma/tratamiento farmacológico , Fototerapia , Poliésteres/química , Propiedades de Superficie , Titanio/químicaRESUMEN
After surgical resection for a bone tumor, the uncleared bone tumor cells can multiply and cause recurrence of the bone tumor. It is worthwhile to design a scaffold that kills the remaining bone tumor cells and repairs bone defects that were given rise to by surgical resection. Additionally, it is extremely important to consider the function of angiogenesis in the process of bone regeneration because the newly formed blood vessels can offer the nutrients for bone regeneration. In this work, a novel metal-organic framework Cu-TCPP nanosheets interface-structured ß-tricalcium phosphate (TCP) (Cu-TCPP-TCP) scaffold was successfully prepared through integrating a 3D-printing technique with an in-situ growth method in a solvothermal system. Owing to the excellent photothermal effect of Cu-TCPP nanosheets, Cu-TCPP-TCP scaffolds that were illuminated by near-infrared (NIR) light demonstrated photothermal performance, which was well regulated through varying the contents of Cu-TCPP nanosheets, and the ambient humidity and power density of NIR light. When cultured with osteosarcoma cells, Cu-TCPP-TCP scaffolds killed a significant quantity of osteosarcoma cells through released heat energy after exposure to NIR light with power density 1.0 W cm-2 and duration 10 min. Similarly, Cu-TCPP-TCP scaffolds ablated subcutaneous bone tumor tissues on the backs of naked mice and suppressed their growth because of the heat energy transformed from NIR light. I n-vitro studies found that Cu-TCPP-TCP scaffolds ably supported the attachments of both human bone marrow stromal cells (HBMSCs) and human umbilical vein endothelial cells (HUVECs), and significantly stimulated expressions of osteogenesis differentiation-related genes in HBMSCs and angiogenesis differentiation-related genes in HUVECs. After implanting Cu-TCPP-TCP scaffolds into the bone defects of rabbits, they effectively promoted bone regeneration. Thus, the integration of the bone-forming bioactivity of TCP scaffolds with the photothermal properties of Cu-TCPP nanosheets and angiogenesis activity of Cu ions makes Cu-TCPP-TCP scaffolds multifunctional, representing a new horizon to develop biomaterials for simultaneously curing bone tumors and repairing bone defects.
Asunto(s)
Neoplasias Óseas/terapia , Células Madre Mesenquimatosas/citología , Estructuras Metalorgánicas/química , Nanoestructuras/química , Osteosarcoma/terapia , Andamios del Tejido/química , Animales , Bioimpresión , Neoplasias Óseas/fisiopatología , Regeneración Ósea , Trasplante Óseo , Fosfatos de Calcio/química , Proliferación Celular , Cobre/química , Humanos , Ratones , Ratones Endogámicos BALB C , Neovascularización Fisiológica , Osteosarcoma/fisiopatología , Impresión Tridimensional , Conejos , Ingeniería de TejidosRESUMEN
When osteochondral tissues suffer from focal or degenerative lesions caused by trauma or disorders, it is a tough challenge to regenerate them because of the limited self-healing capacity of articular cartilage. In this study, a series of Mo-doped bioactive glass ceramic (Mo-BGC) scaffolds were prepared and then systematically characterized. The released MoO42- ions from 7.5Mo-BGC scaffolds played a vital role in regenerating articular cartilage and subchondral bone synchronously. Methods: The Mo-BGC scaffolds were fabricated through employing both a sol-gel method and 3D printing technology. SEM, EDS, HRTEM, XRD, ICPAES and mechanical strength tests were respectively applied to analyze the physicochemical properties of Mo-BGC scaffolds. The proliferation and differentiation of rabbit chondrocytes (RCs) and human bone mesenchymal stem cells (HBMSCs) cultured with dilute solutions of 7.5Mo-BGC powder extract were investigated in vitro. The co-culture model was established to explore the possible mechanism of stimulatory effects of MoO42- ions on the RCs and HBMSCs. The efficacy of regenerating articular cartilage and subchondral bone using 7.5Mo-BGC scaffolds was evaluated in vivo. Results: The incorporation of Mo into BGC scaffolds effectively enhanced the compressive strength of scaffolds owing to the improved surface densification. The MoO42- ions released from the 7.5Mo-BGC powders remarkably promoted the proliferation and differentiation of both RCs and HBMSCs. The MoO42- ions in the co-culture system significantly stimulated the chondrogenic differentiation of RCs and meanwhile induced the chondrogenesis of HBMSCs. The chondrogenesis stimulated by MoO42- ions happened through two pathways: 1) MoO42- ions elicited anabolic responses through activating the HIF-1α signaling pathway; 2) MoO42- ions inhibited catabolic responses and protected cartilage matrix from degradation. The in vivo study showed that 7.5Mo-BGC scaffolds were able to significantly promote cartilage/bone regeneration when implanted into rabbit osteochondral defects for 8 and 12 weeks, displaying bi-lineage bioactivities. Conclusion: The 3D-printed Mo-BGC scaffolds with bi-lineage bioactivities and activated anabolic responses could offer an effective strategy for cartilage/bone interface regeneration.
Asunto(s)
Huesos/efectos de los fármacos , Cartílago/efectos de los fármacos , Vidrio , Molibdeno/metabolismo , Regeneración/efectos de los fármacos , Ingeniería de Tejidos/métodos , Andamios del Tejido , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Fenómenos Químicos , Condrocitos/efectos de los fármacos , Condrocitos/fisiología , Técnicas de Cocultivo , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/fisiología , Modelos Teóricos , Impresión Tridimensional , Conejos , Oligoelementos/metabolismo , Resultado del TratamientoRESUMEN
Nanostructures based on metal-organic frameworks (MOFs) have promising potential as theragnostic nanoplatforms for phototherapy of cancer cells. However, the MOFs alone are seldom reported to be used as photothermal agents mainly due to their poor near-infrared (NIR) light absorption. Methods: Ultrathin copper-tetrakis (4-carboxyphenyl) porphyrin (Cu-TCPP) MOF nanosheets were prepared by a facile solvothermal route. The photothermal therapy (PTT), photodynamic therapy (PDT), and T1 -weighted magnetic resonance (MR) imaging capabilities and the high biocompatibility of these composite nanosheets were evaluated in vitro as well as in vivo in a mouse tumor model. Results: The ultrathin Cu-TCPP MOF nanosheets exhibited 1) strong NIR absorption because of the d-d energy band transition of Cu2+ and the ultrathin characteristic translating into excellent photothermal performance, 2) ability to produce singlet oxygen because of the inherent characteristic of TCPP, and 3) capability for MR imaging because of the unpaired 3d electrons of copper. Conclusion: Our study demonstrated that the Cu-TCPP MOF nanosheets are a promising phototherapy nanoplatform with the synergistic ability for PTT and PDT of cancer, guided by MR and infrared thermal imaging.
Asunto(s)
Hipertermia Inducida/métodos , Imagen por Resonancia Magnética/métodos , Nanoestructuras/administración & dosificación , Neoplasias/diagnóstico , Neoplasias/terapia , Fototerapia/métodos , Nanomedicina Teranóstica/métodos , Animales , Cobre/administración & dosificación , Modelos Animales de Enfermedad , Ratones , Nanoestructuras/química , Porfirinas/administración & dosificaciónRESUMEN
Bone tumor is one of major challenging issues clinically. After surgical intervention, a few bone tumor cells still remain around bone defects and then proliferate over days. Fabrication of specific biomaterials with dual functions of bone tumor therapy and bone regeneration is of great significance. In order to achieve this aim, we managed to prepare bioactive glass (BG) scaffolds functionalized by the CuFeSe2 nanocrystals (BG-CFS) by combining 3D printing technique with solvothermal method. During the solvothermal reaction process, CuFeSe2 nanocrystals could in situ grow on the strut surface of BG scaffolds and thus endow BG scaffolds excellent photothermal performance. The photothermal performance of BG-CFS scaffolds could be well regulated through altering the content of CuFeSe2 nanocrystals and laser power density when exposed to the near infrared laser (808â¯nm). The BG-CFS scaffolds could not only effectively ablate the bone tumor cells (Saos-2â¯cells) in vitro, but also significantly inhibit bone tumor growth in vivo. Moreover, BG-CFS scaffolds could stimulate osteogenic gene expressions of rabbit bone marrow stromal cells (rBMSCs) and finally facilitate the formation of new bone in the bone defects. Our study, for the first time, combined the photothermal performance of semiconductor CuFeSe2 nanocrystals with the bone-forming activity of bioactive glass scaffolds, which can offer a more extensive horizon for developing novel biomaterials with dual functions of bone tumor therapy and bone regeneration.