Gold Nanorods and Polymer Micelles Mediated Dual TLR Stimulators Delivery System CPG@Au NRs/M-R848 Regulate Macrophages Reprogramming and DC Maturation for Enhanced Photothermal Immunotherapy of Melanoma.

Synergistic photothermal immunotherapy has emerged as a favorable therapeutic approach to fight cancer. However, design of an effective photothermal immunotherapy system to suppress tumor growth and simultaneously inhibit tumor metastases continues to be a challenge. Here a dual toll-like receptor agonists delivery system CPG@Au NRs/m-R848 for combined photothermal immunotherapy of melanoma is developed. CPG@Au NRs/m-R848 displays strong antitumor effects by promoting maturation of dendritic cells (DCs) and reprogramming of M2 macrophages into M1 phenotype. Moreover, immunogenic cell death (ICD) induced by photothermal ablation of Au NRs could synergistically produce in situ vaccination effect with CPG ODN and R848, generating systemic and lasting antitumor immunity. It is further proved that CPG@Au NRs/m-R848 treatment inhibits tumor growth in bilateral B16F10 tumors model by eliciting CD8+ T cell response. Overall, this work suggests that this strategy hold great potential in tumor immunotherapy by regulating tumor-associated macrophage polarization, triggering DCs maturation and inducing ICD.

Advancements in Hydrogel Application for Ischemic Stroke Therapy.

Ischemic stroke is a major cause of death and disability worldwide. There is almost no effective treatment for this disease. Therefore, developing effective treatment for ischemic stroke is urgently needed. Efficient delivery of therapeutic drugs to ischemic sites remained a great challenge for improved treatment of strokes. In recent years, hydrogel-based strategies have been widely investigated for new and improved therapies. They have the advantage of delivering therapeutics in a controlled manner to the poststroke sites, aiming to enhance the intrinsic repair and regeneration. In this review, we discuss the pathophysiology of stroke and the development of injectable hydrogels in the application of both stroke treatment and neural tissue engineering. We also discuss the prospect and the challenges of hydrogels in the treatment of ischemic strokes.

Cyclophosphamide loaded thermo-responsive hydrogel system synergize with a hydrogel cancer vaccine to amplify cancer immunotherapy in a prime-boost manner.

Although neoantigen-based cancer vaccines show great potential in cancer immunotherapy due to their ability to induce effective and long-lasting anti-tumor immunity, their development is hindered by the limitations of neoantigens identification, low immunogenicity, and weak immune response. Cyclophosphamide (CTX) not only directly kills tumors but also causes immunogenic cell death, providing a promising source of antigens for cancer vaccines. Herein, a combined immunotherapy strategy based on temperature-sensitive PLEL hydrogel is designed. First, CTX-loaded hydrogel is injected intratumorally into CT26 bearing mice to prime anti-tumor immunity, and then 3 days later, PLEL hydrogels loaded with CpG and tumor lysates are subcutaneously injected into both groins to further promote anti-tumor immune responses. The results confirm that this combined strategy reduces the toxicity of CTX, and produces the cytotoxic T lymphocyte response to effectively inhibit tumor growth, prolong survival, and significantly improve the tumor cure rate. Moreover, a long-lasting immune memory response is observed in the mice. About 90% of the cured mice survive for at least 60 days after being re-inoculated with tumors, and the distant tumor growth is also well inhibited. Hence, this PLEL-based combination therapy may provide a promising reference for the clinical promotion of chemotherapy combined with cancer vaccines.

Gold nanorods and nanohydroxyapatite hybrid hydrogel for preventing bone tumor recurrence via postoperative photothermal therapy and bone regeneration promotion.

Osteosarcoma is a malignant bone tumor, which often occurs in adolescents. However, surgical resection usually fails to completely remove the tumor clinically, which has been the main cause of postoperative recurrence and metastasis, resulting in the high death rate of patients. At the same time, osteosarcoma invades a large area of the bone defect, which cannot be self-repaired and seriously affects the life quality of the patients. Herein, a bifunctional methacrylated gelatin/methacrylated chondroitin sulfate hydrogel hybrid gold nanorods (GNRs) and nanohydroxyapatite (nHA), which possessed excellent photothermal effect, was constructed to eradicate residual tumor after surgery and bone regeneration. In vitro, K7M2wt cells (a mouse bone tumor cell line) can be efficiently eradicated by photothermal therapy of the hybrid hydrogel. Meanwhile, the hydrogel mimics the extracellular matrix to promote proliferation and osteogenic differentiation of mesenchymal stem cells. The GNRs/nHA hybrid hydrogel was capable of photothermal treatment of postoperative tumors and bone defect repair in a mice model of tibia osteosarcoma. Therefore, the hybrid hydrogel possesses dual functions of tumor therapy and bone regeneration, which shows great potential in curing bone tumors and provides a new hope for tumor-related bone complex disease.

Advanced biomaterials for cancer immunotherapy.

Immunotherapy, as a powerful strategy for cancer treatment, has achieved tremendous efficacy in clinical trials. Despite these advancements, there is much to do in terms of enhancing therapeutic benefits and decreasing the side effects of cancer immunotherapy. Advanced nanobiomaterials, including liposomes, polymers, and silica, play a vital role in the codelivery of drugs and immunomodulators. These nanobiomaterial-based delivery systems could effectively promote antitumor immune responses and simultaneously reduce toxic adverse effects. Furthermore, nanobiomaterials may also combine with each other or with traditional drugs via different mechanisms, thus giving rise to more accurate and efficient tumor treatment. Here, an overview of the latest advancement in these nanobiomaterials used for cancer immunotherapy is given, describing outstanding systems, including lipid-based nanoparticles, polymer-based scaffolds or micelles, inorganic nanosystems, and others.

Physical-, chemical-, and biological-responsive nanomedicine for cancer therapy.

Cancer therapy is unsatisfactory as it typically has serious side effects, because normal cells in healthy organs are destroyed along with the tumor. Thus, researchers have tried to develop effective therapies with minimal side effects. One such method is to use nanotechnology to carry the drugs or therapeutic agents to the tumor region by secure encapsulation without leakage. Once the nanomedicine enters the target tumor site, it can release therapeutic agents in an effective manner. Accordingly, various nanomedicines have been developed to enhance the efficiency of cancer therapy and minimize the systematic toxicity. Here, we provide an overview and discuss the different types of responsive nanomedicines including physically, chemically, biologically, dual, and multi-responsive nanomedicines, for the in situ release of cargos in recent years. We propose critical considerations that must be considered for the design of excellent stimuli-nanomedicine. Furthermore, the possible directions for the development of successful stimuli-responsive (smart) nanomedicine are highlighted. With the development of responsive nanomedicines, precise and personalized nanomedicine will be realized with great promise in the future. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Erratum: Negative regulation of cationic nanoparticle-induced inflammatory toxicity through the increased production of prostaglandin E2 via mitochondrial DNA-activated Ly6C+ monocytes: Erratum.

[This corrects the article DOI: 10.7150/thno.21693.].

Magnetic/Gold Core-Shell Hybrid Particles for Targeting and Imaging-Guided Photothermal Cancer Therapy.

The development of hybrid particles for tumor diagnosis and therapy has received considerable attention because they are capable of combining tumor diagnosis and treatment concurrently. So far hybrid particles for efficient and safe tumor theranostics are still very limited. Herein we have designed a new type of hybrid particles and evaluated its potential to be used in image-guided cancer diagnosis and therapy without the need of any toxic anticancer or contrast agents. The hybrid particles, consist of magnetic nanoparticles which are embedded in the poly(methyl methacrylate) (PMMA) cores and gold shells on chitosan (CTS) (γ-Fe2O3 @PMMA/CTS@Au). The hybrid particles were synthesized through initial formation of the core-shell structured γ-Fe2O3 @PMMA/CTS particles containing approximately 20% loading of magnetic nanoparticles. A gold layer was then built on top of the core-shell magnetic particles via a reduction of gold salt by amines from the chitosan assisted with the reducing agent NaBH4, followed by growing to complete gold shells in the presence of ascorbic acid (42.6% Au content). The properties of the composite particles including their chemical composition, morphology, particle size, size distribution, surface charge, magnetic responsiveness and photothermal ability were systematically characterized. The potential application of the γ-Fe2O3 @PMMA/CTS@Au hybrid particles in tumor diagnosis and therapy was assessed in vitro and in vivo using 4T1 tumor cells and 4T1 tumor-bearing mice through combining magnetic targeting, photoacoustic (PA)/computed tomography (CT) imaging and photothermal therapy. Results suggest that the γ-Fe2O3 @PMMA/CTS@Au particles can serve as a multifunctional tumor theranostic nanoplatform for magnetically targeted photothermal therapy. Breast cancer has been effectively eliminated without the use of any anticancer drugs or contrast agents. Therefore, this type of core-shell hybrid particles represents a new composite particle design for effective and safe tumor theranostics.

Synthesis and Application of a Novel Gene Delivery Vector for Non-Small-Cell Lung Cancer Therapy.

Human Wnt inhibitory factor-1 (hWIF-1), as an anti-oncogene, holds great promise for non-small-cell lung cancer (NSCLC) therapy. However, the clinical application of hWIF-1 in cancer therapy is limited by elimination and degradation of free hWIF-1 in vivo. Therefore, it is necessary to develop safe and effective gene delivery vectors for hWIF-1 delivery in vivo. In this paper, we synthesized a novel polyethylenimine (PEI) derivative PEI-SP5-2 (PES) based on branched PEI1800 and NSCLC-targeting peptide SP5-2 to deliver hWIF-1 for NSCLC therapy. PES had excellent gene delivery capacity, and the transfection efficiency reached 50.02% ± 4.75% in A549 cell lines when the weight ratio of PES/gene was 100. Besides, the PES/gene particles were monodispersed, and the hydrodynamic diameter and zeta potential were 47.55 nm and 24.9 mV, respectively. In addition, PES/hWIF-1 complexes could inhibit the tumor growth in vitro and in vivo when it was used for non-small-cell lung cancer therapy. We concluded that PES would be promising as a novel gene delivery vector, and PES/hWIF-1 complexes inhibited the tumor growth and showed potential for non-small-cell lung cancer therapy.

Graphene-Nanoparticle-Based Self-Healing Hydrogel in Preventing Postoperative Recurrence of Breast Cancer.

Hydrogel is an ideal scaffold in the fields of regenerative medicine and tumor therapy because of its biomimetic ability to modulate tissue microenvironment. Herein, we fabricated a new kind of self-healing hydrogel based on graphene nanoparticle and expanded its application in postoperative recurrence of breast cancer. First, a facile method was used to prepare self-healing hydrogel via Schiff-base linkage, which composed of chondroitin sulfate multialdehyde (CSMA), branched polyethylenimine (BPEI) and BPEI conjugated graphene (BPEI-GO). BPEI-GO was doped in the network and participated in Schiff-base reaction and stabilized the structure, as well as provided sustained drug delivery, and near-infrared laser (NIR)-triggered photothermal effect. The hydrogels exhibited excellent self-healing (∼100%) and improved mechanical properties (7,000 Pa). Further, in vitro breast cancer cell inhibition study showed enhanced cell killing efficiency with synergistic chemo-photothermal therapy. In the breast cancer postoperative recurrence prevention mice model, we found that combination of Doxorubicin (DOX) and photothermal therapy in CSMA/BPEI/BPEI-GO hydrogels group reduced tumor recurrence to 33.3%, compared with 66.7% for DOX-loaded hydrogels without NIR irradiation, 66.7% for local administration of free DOX, 100% for hydrogels with NIR irradiation, blank hydrogels, and blank control. This study suggests the great potential of CSMA/BPEI/BPEI-GO hydrogels for postoperative recurrence prevention of breast cancer.

Photosensitizer Micelles Together with IDO Inhibitor Enhance Cancer Photothermal Therapy and Immunotherapy.

The therapeutic outcome of photothermal therapy (PTT) remains impeded by the transparent depth of light. Combining PTT with immunotherapy provides strategies to solve this problem. Regulating metabolism-related enzymes is a promising strategy to stimulate immune response. Here, a nanosystem (NLG919/IR780 micelles) with the properties of photothermal conversion and regulation of the tryptophan metabolic pathway is used to suppress the growth of the tumor margin beyond effective PTT and promote tumor PTT and immunotherapy. It is revealed that mild heat treatment promotes the growth of the tumor margin beyond effective PTT for the upregulation of heat shock protein (HSP), indoleamine 2,3-dioxygenase (IDO), and programmed death-ligand 1 (PD-L1). The NLG919/IR780 micelles can effectively inhibit the activity of IDO but do not affect the level of IDO expression. NLG919/IR780 micelles can effectively accumulate in the tumor and can migrate to lymph nodes and the lymphatic system. In vivo antitumor studies reveal that NLG919/IR780 micelles effectively suppress the growth of tumor margin following PTT in primary tumors. NLG919/IR780 micelle-mediated PTT and IDO inhibition further stimulate the activation of T lymphocytes, inhibiting the growth of distal tumors (abscopal effect). The results demonstrate that the NLG919/IR780 micelles combine PTT and immunotherapy and suppress the tumor margin as well as distal tumor growth post photothermal therapy.

Negative regulation of cationic nanoparticle-induced inflammatory toxicity through the increased production of prostaglandin E2 via mitochondrial DNA-activated Ly6C+ monocytes.

Rationale: Cationic nanocarriers present with well-known toxicities, including inflammatory toxicity, which limit their clinical application. How the cationic nanocarrier-induced inflammatory response is negatively regulated is unknown. Herein, we found that following a sublethal dose of cationic nanocarriers, the induced inflammatory response is characterized by early neutrophil infiltration and spontaneous resolution within 1 week. Methods: C57BL/6 mice were intravenously injected with a dosage of 1-100 mg/kg cationic DOTAP liposomes as well as other cationic materials. Cell necrosis was detected by flow cytometry. Release of mitochondrial DNA was quantified by qPCR via Taqman probes. Signal proteins were detected by Western blotting. PGE2 production in the supernatant was quantitated using an enzyme immunoassay (EIA). The infiltrated inflammatory cells were observed in WT mice, Ccr2-/- mice, Sting-/- mice and Tlr9-/- mice. Results: The early stage (24-48 h) inflammatory neutrophil infiltration was followed by an increasing percentage of monocytes; and, compared with WT mice, Ccr2-/- mice presented with more severe pulmonary inflammation. A previously uncharacterized population of regulatory monocytes expressing both inflammatory and immunosuppressive cytokines was identified in this model. The alteration in monocyte phenotype was directly induced by mtDNA release from cationic nanocarrier-induced necrotic cells via a STING- or TLR9-dependent pathway. Neutrophil activation was specifically inhibited by PGE2 from Ly6C+ inflammatory monocytes, and intravenous injections of dual-phenotype monocytes beneficially modified the immune response; this inhibitory effect was abolished after treatment with indomethacin. Moreover, we provide clear evidence that mitochondrial DNA activated Ly6C+ monocytes and increased PGE2 production through TLR9- or STING-mediated MAPK-NF-κB-COX2 pathways. Conclusion: Our findings suggest that Ly6C+ monocytes and mtDNA-induced Ly6C+ monocyte PGE2 production may be part of a feedback mechanism that contributes to the resolution of cationic nanocarrier-induced inflammatory toxicity and may have important implications for understanding nanoparticle biocompatibility and designing better, safer drug delivery systems.

Tumor-Targeting Anti-MicroRNA-155 Delivery Based on Biodegradable Poly(ester amine) and Hyaluronic Acid Shielding for Lung Cancer Therapy.

Anti-microRNA-155 (anti-miR-155), an oligonucleotide with a complimentary sequence to microRNA-155, holds great promise for lung cancer therapy, and thus some cationic materials have been used to deliver anti-miR-155 into lung tumors. Although the gene delivery capacity in vitro was favorable, the application in vivo was limited by rapid removal and significant cytotoxicity, which were mainly caused by the positive charge of the gene complexes. Therefore, it was necessary to develop a novel carrier to decrease the positive charge and increase the gene delivery capacity into the tumor site. In this paper, biodegradable poly(ester amine) (PEA) was used to condense anti-miR-155 into PEA/anti-miR-155 complexes, and natural anionic polysaccharide hyaluronic acid (HA) was modified with a lung tumor cell targeting peptide and then coated on the surface of gene complexes. The formed hyaluronic acid shielding, PEA/anti-miR-155/HA-peptide complexes were monodispersed, and the particle size and zeta potential were 362.7 nm and -10.17 mV, respectively. In addition, the PEA/anti-miR-155/HA-peptide complexes had good biocompatibility and stability in vitro, and the lung tumor growth inhibitions of PEA/anti-miR-155/HA-peptide in vitro and in vivo were also excellent. The PEA/anti-miR-155/HA-peptide complexes play an active role in tumor growth inhibition and could be useful for lung cancer therapy.

Injectable Hybrid Poly(ε-caprolactone)-b-poly(ethylene glycol)-b-poly(ε-caprolactone) Porous Microspheres/Alginate Hydrogel Cross-linked by Calcium Gluconate Crystals Deposited in the Pores of Microspheres Improved Skin Wound Healing.

In our study, a hybrid alginate hydrogel cross-linked by calcium gluconate crystals deposited in poly(ε-caprolactone)-b-poly(ethylene glycol)-b-poly(ε-caprolactone) (PCL-PEG-PCL, abbreviated as PCEC) porous microspheres was developed for skin engineering. The diameter of microspheres was ∼212 µm, and the pore size was ∼8 µm. The PCEC porous microspheres supplied different functions in the hydrogel: (1) Calcium gluconate crystals were loaded in the inner pores of the microspheres, which can induce alginate hydrogel to cross-link in a few minutes once they were mixed. (2) The porous structure of the microspheres provided more anchor points for fibroblast attachment and growth, resulting in the enhancement of cell growth in the hybrid hydrogel. The PCEC microspheres/Alg hydrogel (MPs/Alg hydrogel) possessed excellent compatibility, because cell viability remained around 100% even at a concentration of 500 µg/mL. Meanwhile, the morphology of 3T3 and L929 cells attached on both PCEC porous microspheres and MPs/Alg hydrogel were confirmed by confocal laser spectrometry (CLSM). What's more, MPs/Alg hydrogel promoted wound regeneration in a full-thickness skin defect model of rats. The mild inflammation reaction existed at the early stage of wound repair and gradually disappeared. These findings suggested that MPs/Alg hydrogel may possess great potential in the application of skin tissue engineering.

Novel Approach of Using Near-Infrared Responsive PEGylated Gold Nanorod Coated Poly(l-lactide) Microneedles to Enhance the Antitumor Efficiency of Docetaxel-Loaded MPEG-PDLLA Micelles for Treating an A431 Tumor.

The combination of chemotherapy and photothermal therapy (PTT) plays a significant role in synergistic tumor therapy. However, a high dosage of chemotherapy drugs or photothermal agents may cause series side effects. To overcome these challenges, we designed a near-infrared (NIR) responsive PEGylated gold nanorod (GNR-PEG) coated poly(l-lactide) microneedle (PLLA MN) system (GNR-PEG@MN) to enhance antitumor efficiency of docetaxel-loaded MPEG-PDLLA (MPEG-PDLLA-DTX) micelles for treating an A431 tumor. The as-made GNR-PEG@MNs contained only 31.83 ± 1.22 µg of GNR-PEG per patch and exhibited excellent heating efficacy both in vitro and in vivo. Meanwhile, GNR-PEG@MN with the height of 480 µm had good skin insertion ability and was harmless to the skin. On the other hand, GNR-PEG@MN had good heating transfer ability in vivo, and the tumor sites could reach 50 °C within 5 min. In comparison with chemotherapy and PTT alone, the combination of low dosage MPEG-PDLLA-DTX micelles (5 mg/kg) and GNR-PEG@MNs completely eradicated the A431 tumor without recurrence in vivo, demonstrating a remarkable synergetic effect. Hence, GNR-PEG@MN could be a promising carrier to enhance the antitumor effect of MPEG-PDLLA-DTX micelles for treating superficial tumors and is expected to have a great potential in clinical translation for human epidermoid cancer therapy.

A novel gene delivery composite system based on biodegradable folate-poly (ester amine) polymer and thermosensitive hydrogel for sustained gene release.

Local anti-oncogene delivery providing high local concentration of gene, increasing antitumor effect and decreasing systemic side effects is currently attracting interest in cancer therapy. In this paper, a novel local sustained anti-oncogene delivery system, PECE thermoresponsive hydrogel containing folate-poly (ester amine) (FA-PEA) polymer/DNA (tumor suppressor) complexes, is demonstrated. First, a tumor-targeted biodegradable folate-poly (ester amine) (FA-PEA) polymer based on low-molecular-weight polyethyleneimine (PEI) was synthesized and characterized, and the application for targeted gene delivery was investigated. The polymer had slight cytotoxicity and high transfection efficiency in vitro compared with PEI 25k, which indicated that FA-PEA was a potential vector for targeted gene delivery. Meanwhile, we successfully prepared a thermoresponsive PECE hydrogel composite containing FA-PEA/DNA complexes which could contain the genes and slowly release the genes into cells. We concluded the folate-poly (ester amine) (FA-PEA) polymer would be useful for targeted gene delivery, and the novel gene delivery composite based on biodegradable folate-poly (ester amine) polymer and thermosensitive PECE hydrogel showed potential for sustained gene release.