Multifunctional Therapeutic Platform Research Articles

Computed Tomography Imaging Guided Microenvironment-Responsive Ir@WO3-x Dual-Catalytic Nanoreactor for Selective Radiosensitization.

Radiotherapy (RT) is often administered, either alone or in combination with other therapies, for most malignancies. However, the degree of tumor oxygenation, damage to adjacent healthy tissues, and inaccurate guidance remain issues that result in discontinuation or failure of RT. Here, a multifunctional therapeutic platform based on Ir@WO3-x is developed which simultaneously addresses these critical issues above for precision radiosensitization. Ir@WO3-x nanoreactors exhibit strong absorption of X-ray, acting as radiosensitizers. Moreover, ultrasmall Ir enzyme-mimic nanocrystals (NCs) are decorated onto the surface of the nanoreactor, where NCs have catalyst-like activity and are sensitive to H2O2 in the tumor microenvironment (TME) under near infrared-II (NIR-II) light stimulation. They efficiently catalyze the conversion of H2O2 to O2, thereby ameliorating hypoxia, inhibiting the expression of HIF-1α, and enhancing RT-induced DNA damage in cancerous tissue, further improving the efficiency of RT. Additionally, in response to high H2O2 levels in TME, the Ir@WO3-x nanoreactor also exerts peroxidase-like activity, boosting exogenous ROS, which increases oxidative damage and enhances ROS-dependent death signaling. Furthermore, Ir@WO3-x can serve as a high-quality computed tomography contrast agent due to its high X-ray attenuation coefficient and generation of pronounced tumor-tissue contrast. This report highlights the potential of advanced health materials to enhance precision therapeutic modalities.

Macrophage Membrane-Encapsulated Dopamine-Modified Poly Cyclodextrin Multifunctional Biomimetic Nanoparticles for Atherosclerosis Therapy.

Atherosclerotic plaques exhibit high cholesterol deposition and oxidative stress resulting from high reactive oxygen species (ROS). These are the major components in plaques and the main pro-inflammatory factor. Therefore, it is crucial to develop an effective therapeutic strategy that can simultaneously address the multiple pro-inflammatory factors via removing cholesterol and inhibiting the overaccumulated ROS. In this study, we constructed macrophage membrane-encapsulated biomimetic nanoparticles (MM@DA-pCD@MTX), which not only alleviate cholesterol deposition at the plaque lesion via reverse cholesterol transport but also scavenge the overaccumulated ROS. β-Cyclodextrin (β-CD) and the loaded methotrexate (MTX) act synergistically to induce cholesterol efflux for inhibiting the formation of foam cells. Among them, MTX up-regulated the expression of ABCA1, CYP27A1, and SR-B1. β-CD increased the solubility of cholesterol crystals. In addition, the ROS scavenging property of dopamine (DA) was perfectly preserved in MM@DA-pCD@MTX, which could scavenge the overaccumulated ROS to alleviate the oxidative stress at the plaque lesion. Last but not least, MM-functionalized "homing" targeting of atherosclerotic plaques not only enables the targeted drug delivery but also prolongs in vivo circulation time and drug half-life. In summary, MM@DA-pCD@MTX emerges as a potent, multifunctional therapeutic platform for AS treatment, offering a high degree of biosafety and efficacy in addressing the complex pathophysiology of atherosclerosis.

Bioinspired soft-hard combined system with mild photothermal therapeutic activity promotes diabetic bone defect healing via synergetic effects of immune activation and angiogenesis.

Background: The comprehensive management of diabetic bone defects remains a substantial clinical challenge due to the hostile regenerative microenvironment characterized by aggravated inflammation, excessive reactive oxygen species (ROS), bacterial infection, impaired angiogenesis, and unbalanced bone homeostasis. Thus, an advanced multifunctional therapeutic platform capable of simultaneously achieving immune regulation, bacterial elimination, and tissue regeneration is urgently designed for augmented bone regeneration under diabetic pathological milieu. Methods and Results: Herein, a photoactivated soft-hard combined scaffold system (PGCZ) was engineered by introducing polydopamine-modified zeolitic imidazolate framework-8-loaded double-network hydrogel (soft matrix component) into 3D-printed poly(ε-caprolactone) (PCL) scaffold (hard matrix component). The versatile PGCZ scaffold based on double-network hydrogel and 3D-printed PCL was thus prepared and features highly extracellular matrix-mimicking microstructure, suitable biodegradability and mechanical properties, and excellent photothermal performance, allowing long-term structural stability and mechanical support for bone regeneration. Under periodic near-infrared (NIR) irradiation, the localized photothermal effect of PGCZ triggers the on-demand release of Zn2+, which, together with repeated mild hyperthermia, collectively accelerates the proliferation and osteogenic differentiation of preosteoblasts and potently inhibits bacterial growth and biofilm formation. Additionally, the photoactivated PGCZ system also presents outstanding immunomodulatory and ROS scavenging capacities, which regulate M2 polarization of macrophages and drive functional cytokine secretion, thus leading to a pro-regenerative microenvironment in situ with enhanced vascularization. In vivo experiments further demonstrated that the PGCZ platform in conjunction with mild photothermal therapeutic activity remarkably attenuated the local inflammatory cascade, initiated endogenous stem cell recruitment and neovascularization, and orchestrated the osteoblast/osteoclast balance, ultimately accelerating diabetic bone regeneration. Conclusions: This work highlights the potential application of a photoactivated soft-hard combined system that provides long-term biophysical (mild photothermal stimulation) and biochemical (on-demand ion delivery) cues for accelerated healing of diabetic bone defects.

PH-Responsive Sorafenib/Iron-Co-Loaded Mesoporous Polydopamine Nanoparticles for Synergistic Ferroptosis and Photothermal Therapy.

Ferroptosis has attracted significant attention as a new mechanism of cell death. Sorafenib (SRF) is widely considered a prototypical ferroptosis-inducing drug, particularly for liver cancer treatment. However, the low solubility and hydrophobic nature of SRF, along with the absence of synergistic therapeutic strategies, still limit its application in cancer treatment. Herein, we report a dual therapeutic method incorporating photothermal therapy and ferroptosis by using Fe-doped mesoporous polydopamine nanoparticles (Fe-mPDA@SRF-TPP) as a carrier for loading SRF and targeting triphenylphosphine (TPP). SRF molecules are efficiently encapsulated within the polydopamine nanospheres with a high loading ratio (80%) attributed to the porosity of Fe-mPDA, and the inherent biocompatibility and hydrophilicity of Fe-mPDA@SRF-TPP facilitate the transport of SRF to the target cancer cells. Under the external stimuli of acidic environment (pH 5.0), glutathione (GSH), and laser irradiation, Fe-mPDA@SRF-TPP shows sustained release of SRF and Fe ions with the ratio of 72 and 50% within 48 h. Fe-mPDA@SRF-TPP nanoparticles induce intracellular GSH depletion, inhibit glutathione peroxidase 4 (GPX4) activity, and generate hydroxyl radicals, all of which are essential components of the therapeutic ferroptosis process for killing MDA-MB-231 cancer cells. Additionally, the excellent near-infrared (NIR) light absorption of Fe-mPDA@SRF-TPP nanoparticles demonstrates their capability for photothermal therapy and further enhances the therapeutic efficiency. Therefore, this nanosystem provides a multifunctional therapeutic platform that overcomes the therapeutic limitations associated with standalone ferroptosis and enhances the therapeutic efficacy of SRF for breast cancer.

Multifunctional 3D-printed scaffolds eradiate orthotopic osteosarcoma and promote osteogenesis via microwave thermo-chemotherapy combined with immunotherapy

Tumor recurrence and a lack of bone-tissue integration are two critical concerns in the surgical treatment of osteosarcoma. Thus, an advanced multifunctional therapeutic platform capable of simultaneously eliminating residual tumor cells and promoting bone regeneration is urgently needed for efficient osteosarcoma treatment. Herein, to thoroughly eliminate tumors and simultaneously promote bone regeneration, an intelligent multifunctional therapeutic scaffold has been engineered by integrating microwave-responsive zeolitic imidazolate framework 8 (ZIF-8) nanomaterials loaded with a chemotherapeutic drug and an immune checkpoint inhibitor onto 3D-printed titanium scaffolds. The constructed scaffold features distinct microwave-thermal sensitization and tumor microenvironment-responsive characteristics, which can induce tumor immunogenic death by microwave hyperthermia and chemotherapy. Orthotopic implantation of the nanocomposite scaffold results in an enhanced immune response against osteosarcoma that may effectively inhibit tumor recurrence through synergistic immunotherapy. During long-term implantation, the zinc ions released from the degradation of ZIF-8 can induce the osteogenic differentiation of stem cells. The porous structure and mechanical properties of the 3D-printed titanium scaffolds provide a structural microenvironment for bone regeneration. This study provides a paradigm for the design of multifunctional microwave-responsive composite scaffolds for use as a therapy for osteosarcoma, which could lead to improved strategies for the treatment of the disease.

Lupeol-loaded chitosan-Ag+ nanoparticle/sericin hydrogel accelerates wound healing and effectively inhibits bacterial infection

Lupeol, a pentacyclic triterpene, has demonstrated significant wound healing properties; however, its low water solubility has limited its clinical applicability. To overcome this limitation, we utilized Ag+-modified chitosan (CS-Ag) nanoparticles to deliver lupeol, resulting in the formation of CS-Ag-L-NPs. These nanoparticles were then encapsulated within a temperature-sensitive, self-assembled sericin hydrogel. Various analytical methods, including SEM, FTIR, XRD, HPLC, TGA assay, hemolysis and antibacterial activity tests, were employed to characterize the nanoparticles. Additionally, an infectious wound model was used to evaluate the therapeutic and antibacterial efficacy of the CS-Ag-L-NPs modified sericin hydrogel. Our results showed that the encapsulation efficiency of lupeol in CS-Ag-L-NPs reached 62.1 %, with good antibacterial activity against both gram-positive and gram-negative bacteria and a low hemolysis ratio (<5 %). The CS-Ag-L-NPs sericin gel exhibited multiple beneficial effects, including inhibiting bacterial proliferation in wound beds, promoting wound healing via accelerated re-epithelialization, reducing inflammation, and enhancing collagen fiber deposition. We conclude that the CS-Ag-L-NPs loaded sericin hydrogel has tremendous potential for development as a multifunctional therapeutic platform capable of accelerating wound healing and effectively suppressing bacterial infections in clinical settings.

A dual functional polypeptide with antibacterial and anti-inflammatory properties for the treatment of periodontitis

Periodontitis has been reported as the sixth most prevalent disease in human beings. This destructive disease is closely related to systemic diseases. Existing local drug delivery systems for periodontitis suffer from poor antibacterial effect and drug resistance. Inspired by the pathogenesis of periodontitis, we implemented a strategy to construct a dual functional polypeptide LL37-C15, which exhibited remarkable antibacterial effect against P. gingivalis and A. actinomycetemcomitans. In addition, LL37-C15 inhibits the release of pro-inflammatory cytokines by controlling the inflammatory pathway and reversing macrophage M1. Furthermore, the anti-inflammatory effect of LL37-C15 was also verified in vivo in a periodontitis rat model through the morphometry and histological observations of alveolar bone, hematoxylin-eosin, and Trap staining in gingival tissue. The results of molecular dynamics simulations showed that LL37-C15 could selectively destroy the bacterial cell membrane and protect the animal cell membrane in a self-destructive manner. The results showed that the polypeptide LL37-C15, as a novel promising therapeutic agent, exhibited a great potential for the periodontitis management. What's more, this dual functional polypeptide provides a promising strategy for building a multifunctional therapeutic platform against the inflammation and other diseases.

Self-actuated biomimetic nanocomposites for photothermal therapy and PD-L1 immunosuppression.

Biomimetic nanocomposites are widely used in the biomedical field because they can effectively solve the problems existing in the current cancer treatment by realizing multi-mode collaborative treatment. In this study, we designed and synthesized a multifunctional therapeutic platform (PB/PM/HRP/Apt) with unique working mechanism and good tumor treatment effect. Prussian blue nanoparticles (PBs) with good photothermal conversion efficiency were used as nuclei and coated with platelet membrane (PM). The ability of platelets (PLTs) to specifically target cancer cells and inflammatory sites can effectively enhance PB accumulation at tumor sites. The surface of the synthesized nanocomposites was modified with horseradish peroxidase (HRP) to enhance the deep penetration of the nanocomposites in cancer cells. In addition, PD-L1 aptamer and 4T1 cell aptamer AS1411 were modified on the nanocomposite to achieve immunotherapy and enhance targeting. The particle size, UV absorption spectrum and Zeta potential of the biomimetic nanocomposite were determined by transmission electron microscope (TEM), Ultraviolet-visible (UV-Vis) spectrophotometer and nano-particle size meter, and the successful preparation was proved. In addition, the biomimetic nanocomposites were proved to have good photothermal properties by infrared thermography. The cytotoxicity test showed that it had a good killing ability of cancer cells. Finally, thermal imaging, tumor volume detection, immune factor detection and Haematoxilin-Eosin (HE) staining of mice showed that the biomimetic nanocomposites had good anti-tumor effect and could trigger immune response in vivo. Therefore, this biomimetic nanoplatform as a promising therapeutic strategy provides new inspiration for the current diagnosis and treatment of cancer.

Verteporfin Loaded Graphitic Carbon Nitride Nanosheets for Combined Photo‐Chemotherapy

AbstractVerteporphin loaded g‐C3N4 represents a multifunctional therapeutic platform for synchronous cancer imaging and treatment through the synergistic effect of phototherapy and chemotherapy. A biocompatible nanocarrier using g‐C3N4 nanosheets for high loading and anticancer activity of photosensitizer drug verteporfin (VP) is designed. The drug encapsulation efficiency (%) of optimized mannose functionalized g‐C3N4 formulation was observed to be 68.5 % for 5 mg of nanocarrier. It was found that 63.3 % and 81 % of the total bound drug was released from the nanocarrier at pH 5.4 and pH 1.2 respectively after 48 h. Under neutral conditions (pH 7.4), 45.2 % of the drug was released from the nanocarrier in the first 48 h. The % cytotoxicity of the free drug, the drug loaded nanocarrier against human breast cancer cell line (MCF‐7) was found to be 91.47 % and 91.23 % respectively at the dose of 40 μg/mL and 5 mg/mL after 48 h. IC50 values also manifest the significantly lower cytotoxicity of drug loaded nanocarriers (IC50=0.195 mg/mL) as compared to free‐drug (IC50=0.156 μg/mL). For mannosylated graphitic carbon nitride (g‐C3N4), verteporfin and man‐g‐C3N4@VP the values of mean ± std. deviation were found to be 4.14±2.46; 55.39±2.76; 63.27±1.74 respectively. Terephthalic acid assay confirmed formation of hydroxyl radicals in the solution treated with nanocarrier. This study suggests that g‐C3N4 is a promising use in drug carrier, cancer diagnosis and therapy. The combined effects of the high efficacy of ROS generation under UV light irradiation, low toxicity, and bio‐compatibility highlight the potential of verteporphin loaded g‐C3N4 for PDT.

A dual-nanozyme-loaded black phosphorus multifunctional therapeutic platform for combined photothermal/photodynamic/starvation cancer therapy.

The typical hypoxia of tumor microenvironments seriously affects the efficacy of starvation therapy (ST) and photodynamic therapy (PDT). Therefore, it is of great significance to prepare a multimodal combined therapy nanocomposite with the ability to relieve tumor hypoxia. It is an effective method to release oxygen into the tumor microenvironment using a nanoenzyme. In this work, two-dimensional black phosphorus nanosheets (BPNSs) were used as photothermal reagents and photosensitized agents due to the unique physical properties and also used as nano-carriers for the in situ reduction deposition of Au nanoparticles and fragmented MnO2 coatings. Finally, polyethylene glycol was introduced to obtain the nanocomposite BP@Au@MnO2-PEG (i.e., AMGP). In the tumor microenvironment, MnO2 can catalyze endogenous H2O2 to produce oxygen, improving the effect of ST and PDT. H2O2 generated via the catalytic oxidation of glucose by Au nanoparticles can continue to be used as the substrate catalyzed by MnO2. Meanwhile, black phosphorus nanosheets have excellent photothermal properties for photothermal treatment. The results of in vitro and in vivo experiments indicated that AMGP nanocomposites have good combined antitumor efficacies and biosafety.

Mitochondrial targeting half-sandwich iridium(III) and ruthenium(II) dppf complexes and in vitro anticancer assay

Considering the potential application of half-sandwich and ferrocenyl-containing organometallic complexes in the area of anticancer, four half-sandwich iridium(III) (IrIII) and ruthenium(II) (RuII) diphenylphosphino ferrocene (dppf) complexes were prepared in this study. Complexes showed favorable anti-proliferation activity towards A549 cell lines compared to cisplatin, meanwhile, which could effectively inhibit cell migration. These complexes followed an energy dependence uptake mechanism, effectively accumulated in mitochondria with a Pearson's Colocalization Coefficient (PCC) of 0.77, decreased the mitochondrial membrane potential, induced a surge of reactive oxygen species, disturbed cell cycle, and eventually led to apoptosis. Western blot assay further confirmed that these complexes induced apoptosis following a mitochondrial pathway. Above all, half-sandwich IrIII and RuII dppf complexes show the prospect of becoming a new multifunctional therapeutic platform for mitochondrial targeted imaging and anticancer drugs.

Multifunctional Nanoparticles-Mediated PTT/PDT Synergistic Immune Activation and Antitumor Activity Combined with Anti-PD-L1 Immunotherapy for Breast Cancer Treatment.

Photoimmunotherapy is a breakthrough treatment for malignant tumors. Its uniqueness is that it uses antibody mediated targeted delivery to achieve high tumor specificity and uses laser-activated biophysical mechanism to accurately induce the rapid death of cancer cells and avoid damaging the surrounding normal tissues. In this paper, an iron-based micelle was designed to encapsulate the photothermal agent indocyanine green (ICG) and a cyclic tripeptide of arginine-glycine-aspartic acid (cRGD) as targeted multifunctional ICG@SANPs-cRGD nanoparticles for combined photothermal/photodynamic/immune therapy of breast cancer. The experimental results show that ICG@SANPs-cRGD nanoparticles have good biocompatibility and photothermal conversion ability. Photothermal therapy (PTT) and photodynamic therapy (PDT) based on ICG@SANPs-cRGD can not only inhibit the proliferation, invasion and migration of tumor cells, but also directly kill tumor cells by inducing apoptosis or necrosis. Dual-mode fluorescence light (FL) and magnetic resonance imaging (MRI) imaging in mice confirmed the selective accumulation at tumor sites and imaging ability of ICG@SANPs-cRGD. PTT/PDT combined with Anti-PD-L1 immunotherapy based on ICG@SANPs-cRGD mediated the immunogenic cell death (ICD) of tumor cells by regulating the expression of immune-related indicators and activated the body's immune response mechanism, which enhanced the immunotherapy effect of immune checkpoint block (ICB). PTT/PDT combined with Anti-PD-L1 therapy not only prevented the progression of the primary tumor but also inhibited the distant metastasis of the tumor. This study explores the biomedical application of PTT/PDT combined with Anti-PD-L1 based on ICG@SANPs-cRGD nanomaterials for breast cancer treatment and demonstrates the potential of ICG@SANPs-cRGD as a multifunctional therapeutic platform for future cancer therapy.

Core-satellite porphyrinic MOF@CuS nanoconstructs for combined chemodynamic/photodynamic/photothermal therapy

Combined therapy has attracted extensive attention as a potential solution to overcome tumor heterogeneity and drug resistance. However, developing simple and effective multifunctional therapeutic platforms remain to be further explored. Herein, we have constructed a hybrid nanoplatform composed of a hierarchically porous porphyrinic coordination network (HP-PCN) as the core and copper sulfide (CuS) nanoparticles (NPs) as the satellites to realize combined chemodynamic therapy (CDT)/photodynamic therapy (PDT)/photothermal therapy (PTT) of cancer. HP-PCN exhibits excellent photodynamic properties but its antitumor effect is limited by the insufficient penetration depth of laser and hypoxic tumor microenvironment (TME). To overcome the shortcomings of photodynamic monotherapy, we introduce negatively charged CuS NPs on the HP-PCN surface taking advantage of its porous structure and positive surface charge to fabricate core-satellite HP-PCN@CuS nanoplatform. CuS NPs have excellent photothermal performances and additional CDT function by reacting with hydrogen peroxide in the TME. The integration of HP-PCN and CuS NPs enables the hybrid nanosystem more potent antitumor efficiency. In vitro and in vivo experiments have shown that HP-PCN@CuS presents an combined CDT/PDT/PTT effect to significantly inhibit tumor growth with low systemic toxicity. This study provides a promising strategy to fabricate multifunctional therapeutic nanoplatforms for effective and combined antitumor applications.

Injectable hyaluronan/MnO2 nanocomposite hydrogel constructed by metal-hydrazide coordinated crosslink mineralization for relieving tumor hypoxia and combined phototherapy

Hydrogel-based drug delivery holds great promise in topical tumor treatment. However, the simple construction of multifunctional therapeutic hydrogels under physiological conditions is still a huge challenge. Herein, for the first time, a multifunctional hyaluronan/MnO2 nanocomposite (HHM) hydrogel with injectable and self-healing capabilities was constructed under physiological conditions through innovative in situ mineralization-triggered Mn-hydrazide coordination crosslinking. The hydrogel formed from Mn2+ and hydrazided hyaluronan under optimized conditions exhibited a high elastic modulus >1 kPa, injectability, self-healing function, stimuli-responsiveness and catalase-like activity. In vitro and in vivo biological experiments demonstrated that our HHM hydrogel could not only efficiently relieve hypoxia by in situ catalytic decomposition of endogenous H2O2 into O2 but also achieve synergistic photodynamic/photothermal therapy of 4T1 breast cancer in a mouse tumor model. This study presented a novel mineralization-driven metal-hydrazide coordination crosslinking approach and developed a multifunctional therapeutic platform for O2-enhanced efficient topical dual-phototherapy of breast cancer.

Construction of multifunctional carboxymethyl cellulose nanohydrogel carriers based on near-infrared DNA-templated quantum dots for tumor theranostics

Multifunctional therapeutic platforms with targeted delivery, fast diagnosis, and efficient therapy could effectively reduce side effects and improve treatment in the clinical therapy of tumors. Near-infrared DNA-templated CdTeSe quantum dots (DNA-CdTeSe QDs) were developed as building blocks to construct a multifunctional carboxymethyl cellulose (CMC)-based nanohydrogel as a nanocarrier to address the challenges of serious side effects and precise treatment in cancer theranostics, including active tumor targeting, fluorescence tracking, controlled drug release, chemotherapy and gene regulation. Single-stranded DNA containing the complementarity sequence of miRNA and cystine, as co-crosslinkers, initiated hybridization between the DNA-CdTeSe QD-modified CMC chain with the anti-nucleolin aptamer DNA (AS1411)-modified CMC chain to form the hydrogels. DOX, as a model drug, was successfully incorporated into the hydrogels. The synthesized multifunctional hydrogel nanocarriers with an average diameter of 150 nm could be taken up through targeting and achieved the controlled release of DOX by triggering both glutathione (GSH) and miRNA in the tumor microenvironment. The CdTeSe QDs trapped in nanohydrogels acted as fluorophores for bioimaging in the diagnosis and treatment process. The proposed multifunctional delivery system provided a potential platform for tumor imaging and precise therapy.

Synthesis of Monodisperse ZIF-67@CuSe@PVP Nanoparticles for pH-Responsive Drug Release and Photothermal Therapy.

In recent years, the combination treatment of chemotherapy and photothermal therapy (PTT) has emerged as an efficient approach to improve anticancer activity. Here, we combine zeolitic imidazolate framework-67 (ZIF-67) and CuSe to build a multifunctional therapeutic platform (ZIF-67@CuSe@PVP) with an efficient chemo-photothermal therapy for cancer treatment. ZIF-67@CuSe@PVP nanoparticles were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), dynamic light scattering (DLS), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV-vis, Fourier transform infrared (FT-IR), and nitrogen adsorption-desorption isotherms. These nanoparticles exhibited excellent pH-responsive doxorubicin hydrochloride (DOX) releases due to the decomposition of ZIF-67 and excellent photothermal conversion efficiency (36%) without apparent deterioration during three cycles. In vivo biodistribution evaluation revealed the passive tumor-targeting ability of ZIF-67@CuSe@PVP@DOX via the enhanced permeability and retention (EPR) effect. Both in vitro and in vivo data demonstrated excellent anticancer efficacy of ZIF-67@CuSe@PVP in tumor-bearing mice. This multifunctional therapeutic platform could have certain clinical application potential.

Polyelectrolyte-Coated Mesoporous Bioactive Glasses via Layer-by-Layer Deposition for Sustained Co-Delivery of Therapeutic Ions and Drugs.

In the field of bone regeneration, considerable attention has been addressed towards the use of mesoporous bioactive glasses (MBGs), as multifunctional therapeutic platforms for advanced medical devices. In fact, their extremely high exposed surface area and pore volume allow to load and the release of several drugs, while their framework can be enriched with specific therapeutic ions allowing to boost the tissue regeneration. However, due to the open and easily accessible mesopore structure of MBG, the release of the incorporated therapeutic molecules shows an initial burst effect leading to unsuitable release kinetics. Hence, a still open challenge in the design of drug delivery systems based on MBGs is the control of their release behavior. In this work, Layer-by-layer (LbL) deposition of polyelectrolyte multi-layers was exploited as a powerful and versatile technique for coating the surface of Cu-substituted MBG nanoparticles with innovative multifunctional drug delivery systems for co-releasing of therapeutic copper ions (exerting pro-angiogenic and anti-bacterial effects) and an anti-inflammatory drug (ibuprofen). Two different routes were investigated: in the first strategy, chitosan and alginate were assembled by forming the multi-layered surface, and, successively, ibuprofen was loaded by incipient wetness impregnation, while in the second approach, alginate was replaced by ibuprofen, introduced as polyelectrolyte layer. Zeta-potential, TGA and FT-IR spectroscopy were measured after the addition of each polyelectrolyte layer, confirming the occurrence of the stepwise deposition. In addition, the in vitro bioactivity and the ability to modulate the release of the cargo were evaluated. The polyelectrolyte coated-MBGs were proved to retain the peculiar ability to induce hydroxyapatite formation after 7 days of soaking in Simulated Body Fluid. Both copper ions and ibuprofen were co-released over time, showing a sustained release profile up to 14 days and 24 h, respectively, with a significantly lower burst release compared to the bare MBG particles.

Glucose/Glutathione Co-triggered Tumor Hypoxia Relief and Chemodynamic Therapy to Enhance Photothermal Therapy in Bladder Cancer.

Photothermal therapy (PTT) is a potential treatment for cancer that makes use of near-infrared (NIR) laser irradiation and is expected to assist traditional anti-cancer drug therapies; however, the therapeutic efficacy of PTT is restricted by thermal resistance due to the overexpression of heat shock proteins and insufficient penetration depth of lasers. Thus, PTT needs to be combined with additional therapeutic methods to obtain the optimal therapeutic efficacy for cancer. Herein, a multifunctional therapeutic platform combining PTT with glucose-triggered chemodynamic therapy (CDT) and glutathione (GSH)-triggered hypoxia relief was developed via GOx@MBSA-PPy-MnO2 NPs (GOx for glucose oxidase, M for Fe3O4, BSA for bovine serum albumin, and PPy for polypyrrole). GOx@MBSA-PPy-MnO2 NPs have excellent photothermal efficiency and can release Mn2+, which catalyzes the transformation of H2O2 into hydroxyl radicals (·OH) and O2 via a Fenton-like reaction, effectively destroying cancer cells and relieving tumor hypoxia. Meanwhile, a high content of H2O2 was produced via GOx catalysis of glucose, further enhancing the CDT efficiency. In addition, in vitro and in vivo experiments showed that the inhibition of cancer cell proliferation and effective inhibition of tumors could be caused by the combined PTT/glucose-triggered CDT effects and hypoxia relief of the GOx@MBSA-PPy-MnO2 NPs. Overall, this work provides evidence of a synergistic therapy that remarkably improves therapeutic efficacy and significantly prolongs the lifetime of mice compared with controls.

3D-printed bioceramic scaffolds with Fe3S4 microflowers for magnetothermal and chemodynamic therapy of bone tumor and regeneration of bone defects

Elimination of residual osteosarcoma cells and repair of bone defects remain major challenges for osteosarcoma in clinic. To address this problem, it is required that multifunctional therapeutic platform possess high tumor-killing efficiency and simultaneous bone regeneration capabilities. In this work, an intelligent therapeutic platform was developed to achieve highly-efficient tumor therapy and simultaneous significantly improved bone defect repairing ability, which was realized by in situ growing ferromagnetic Fe3S4 layers with tuned microstructures on the surface of 3D-printed akermanite bioceramic scaffolds via hydrothermal method. The Fe3S4 layers exploited magnetic thermal energy to enhance chemodynamic treatment, thus achieving a synergistic effect between magnetothermal and chemodynamic therapy on the elimination of residual tumor cells. Moreover, the micro-structured surface of the 3D-printed bioceramic scaffolds further enhanced the osteogenic activity in vitro and accelerated the bone regeneration in vivo. The scaffolds with multi-mode tumor-killing and bone repairing capabilities indicated that such a therapeutic platform is applicable for a stepwise treatment strategy of osteosarcoma and provides inspiration for the design of multifunctional biomaterials.

A Novel Stimuli-Responsive Injectable Antibacterial Hydrogel to Achieve Synergetic Photothermal/Gene-Targeted Therapy towards Uveal Melanoma.

Uveal melanoma (UM) is the most prevalent primary intraocular malignant tumor with a high lethal rate. Patients who undergo conventional enucleation treatments consistently suffer permanent blindness, facial defects, and mental disorders, therefore, novel therapeutic modalities are urgently required. Herein, an injectable and stimuli‐responsive drug delivery antibacterial hydrogel (CP@Au@DC_AC50) is constructed via a facile grinding method that is inspired by the preparation process of traditional Chinese medicine. The incorporation of gold nanorods can enhance the mechanical strength of the hydrogel and realize photothermal therapy (PTT) and thermosensitive gel‐sol transformation to release the gene‐targeted drug DC_AC50 on demand in response to low‐density near‐infrared (NIR) light. The orthotopic model of UM is built successfully and indicates the excellent efficiency of CP@Au@DC_AC50 in killing tumors without damage to normal tissue because of its synergistic mild temperature PTT and gene‐targeted therapy. Moreover, the eyeball infection model reveals the remarkable antibacterial properties of the hydrogel which can prevent endophthalmitis in the eyeball. There is negligible difference between the CP@Au@DC_AC50+NIR group and normal group. This NIR light‐triggered gene‐targeted therapy/PTT/antibacterial treatment pattern provides a promising strategy for building multifunctional therapeutic platform against intraocular tumors and exhibits great potential for the clinical treatment of UM.