Hypoxia Alleviated and One Photo-Triggered Thermal/Dynamic Nanoplatform for Immunogenic Cell Death-Initiated Cancer Immunotherapy

Immunogenic cell death (ICD) induced by treatment modalities like chemotherapy, radiotherapy, and photothermal and photodynamic therapy has shown great potential to improve the low response rate of various solid tumors in cancer immunotherapy. However, extensive studies have revealed that the efficacy of cancer treatment is limited by the hypoxia and immunosuppression in the tumor microenvironment (TME). To address these challenges, a hypoxia alleviated and one phototriggered thermal/dynamic nanoplatform based on MnO2@PDA/ICG-BSA (MPIB) is developed for oxygen (O2) self-supply enhanced cancer phototherapy (PT). First, MnO2 transfers intracellular overexpression H2O2 into O2 in the acidic TME through its catalase-like activity to improve the hypoxia and also provide O2 for the following photodynamic therapy. Then, under single NIR-808 nm light irradiation (called the “phototherapeutic window”), excellent photothermal and photodynamic performance of the MPIB is activated for combined PT. Finally, assisted with immune adjuvant cytosine-phospho-guanine, obvious ICD and systemic antitumor immunity was elicited in PT-treated mice and demonstrated significant growth inhibition on distant tumors. This MPIB-based nanoplatform highlights the promise to overcome the limitations of hypoxia and also challenges of immunosuppressive tumor microenvironments for improved cancer immunotherapy

GSH/pH Cascade-Responsive Nanoparticles Eliminate Methicillin-Resistant Staphylococcus aureus Biofilm via Synergistic Photo-Chemo Therapy

Bacterial biofilm infection threatens public health, and efficient treatment strategies are urgently required. Phototherapy is a potential candidate, but it is limited because of the off-targeting property, vulnerable activity, and normal tissue damage. Herein, cascade-responsive nanoparticles (NPs) with a synergistic effect of phototherapy and chemotherapy are proposed for targeted elimination of biofilms. The NPs are fabricated by encapsulating IR780 in a polycarbonate-based polymer that contains disulfide bonds in the main chain and a Schiff-base bond connecting vancomycin (Van) pendants in the side chain (denoted as SP–Van@IR780 NPs). SP–Van@IR780 NPs specifically target bacterial biofilms in vitro and in vivo by the mediation of Van pendants. Subsequently, SP–Van@IR780 NPs are decomposed into small size and achieve deep biofilm penetration due to the cleavage of disulfide bonds in the presence of GSH. Thereafter, Van is then detached from the NPs because the Schiff base bonds are broken at low pH when SP@IR780 NPs penetrate into the interior of biofilm. The released Van and IR780 exhibit a robust synergistic effect of chemotherapy and phototherapy, strongly eliminate the biofilm both in vitro and in vivo. Therefore, these biocompatible SP–Van@IR780 NPs provide a new outlook for the therapy of bacterial biofilm infection

Injectable and Self-Healing Thermosensitive Magnetic Hydrogel for Asynchronous Control Release of Doxorubicin and Docetaxel to Treat Triple-Negative Breast Cancer

Integration of two or more drugs into a multiagent delivery system has been considered to have profound impact on both in vitro and in vivo cancer treatment due to their efficient synergistic effect. This study presents a cheap and simple chitosan hydrogel cross-linked with telechelic difunctional poly­(ethylene glycol) (DF-PEG-DF) for synthesis of an injectable and self-healing thermosensitive dual-drug-loaded magnetic hydrogel (DDMH), which contains both doxorubicin (DOX) and docetaxel (DTX) for chemotherapy and iron oxide for magnetic hyperthermia induced stimuli responsive drug release. The as-prepared DDMH not only have good biocompatibility but also exhibit unique self-healing, injectable, asynchronous control release properties. Meanwhile, it shows an excellent magnetic field responsive heat-inducing property, which means that DDMH will produce a large amount of heat to control the surrounding temperature under the alternative magnetic field (AMF). A remarkably improved synergistic effect to triple negative breast cancer cell line is obtained by comparing the therapeutic effect of codelivery of DOX and DTX/PLGA nanoparticles (DTX/PLGA NPs) with DOX or DTX/PLGA NPs alone. In vivo results showed that DDMH exhibited significant higher antitumor efficacy of reducing tumor size compared to single drug-loaded hydrogel. Meanwhile, the AMF-trigger control release of drugs in codelivery system has a more efficient antitumor effect of cancer chemotherapy, indicating that DDMH was a promising multiagent codelivery system for synergistic chemotherapy in the cancer treatment field

Poly(d‑amino acid) Nanoparticles Target <i>Staphylococcal</i> Growth and Biofilm Disassembly by Interfering with Peptidoglycan Synthesis

d-Amino acids are signals for biofilm disassembly. However, unexpected metabolic pathways severely attenuate the utilization of d-amino acids in biofilm disassembly, resulting in unsatisfactory efficiency. Herein, three-dimensional poly(d-amino acid) nanoparticles (NPs), which possess the ability to block intracellular metabolism, are constructed with the aim of disassembling the biofilms. The obtained poly(α-N-acryloyl-d-phenylalanine)-block-poly(β-N-acryloyl-d-aminoalanine NPs (denoted as FA NPs) present α-amino groups and α-carboxyl groups of d-aminoalanine on their surface, which guarantees that FA NPs can effectively insert into bacterial peptidoglycan (PG) via the mediation of PG binding protein 4 (PBP4). Subsequently, the FA NPs trigger the detachment of amyloid-like fibers that connect to the PG and reduce the number of polysaccharides and proteins in extracellular polymeric substances (EPS). Finally, FA NPs damage the structural stability of EPS and lead to the disassembly of the biofilm. Based on this feature, FA NPs significantly enhance the killing efficacy of encapsulated sitafloxacin sesquihydrate (Sita) by facilitating the penetration of Sita within the biofilm, achieving complete elimination of Staphylococcal biofilm in mice. Therefore, this study strongly demonstrates that FA NPs can effectively improve biofilm disassembly efficacy and provide great potential for bacterial biofilm infection treatment

Photoinduced Mild Hyperthermia and Synergistic Chemotherapy by One-Pot-Synthesized Docetaxel-Loaded Poly(lactic-<i>co</i>-glycolic acid)/Polypyrrole Nanocomposites

Mild hyperthermia has shown great advantages when combined with chemotherapy. The development of a multifunctional platform for the integration of mild hyperthermia capability into a drug-loading system is a key issue for cancer multimodality treatment application. Herein, a facile one-pot in situ fabrication protocol of docetaxel (DTX)-loaded poly­(lactic-<i>co</i>-glycolic acid) (PLGA)/polypyrrole (PPy) nanocomposites was developed. While the PLGA nanoparticles (NPs) allow efficient drug loading, the PPy nanobulges embedded within the surface of the PLGA NPs, formed by in situ pyrrole polymerization without the introduction of other template agents, can act as ideal mediators for photoinduced mild hyperthermia. Physiochemical characterizations of the as-prepared nanocomposites, including structure, morphology, photothermal effects, and an in vitro drug release profile, were systematically investigated. Further, 2-deoxyglucose-terminated poly­(ethylene glycol) (PEG) was anchored onto the surface of the nanocomposites to endow the nanoplatform with targeting ability to tumor cells, which resulted in a 17-fold increase of NP internalization within human breast cancer cells (MCF-7) as competed with PEG-modified nanocomposites. Mild hyperthermia can be successfully mediated by the nanoplatform, and the temperature can be conveniently controlled by careful modulation of the PPy contents within the nanocomposites or the laser power density. Importantly, we have demonstrated that MCF-7 cells, which are markedly resistant to heat treatment of traditional water-bath hyperthermia, became sensitive to the PLGA/PPy nanocomposite-mediated photothermal therapy under the same mild-temperature hyperthermia. Moreover, DTX-loaded PLGA/PPy-nanocomposite-induced mild hyperthermia can strongly enhance drug cytotoxicity to MCF-7 cells. Under the same thermal dose, photoinduced hyperthermia can convert the interaction between hyperthermia and drug treatment from interference to synergism. This is the first report on the one-pot synthesis of PLGA/PPy nanocomposites by in situ pyrrole polymerization, and such a multifunctional nanoplatform is demonstrated as a high-potential agent for photoinduced mild hyperthermia and enhanced chemotherapy

Compounds increase Heme Oxygenase-1 (HO-1) expression in a NRF2 dependent pattern.

<p>(A) NHBE cells were treated with 10 μM of compound for 1 h or 3 μM of compound for 24 h at 37°C and 5% CO₂, respectively. Tg (0.5 μM) and hemin (3 μM) served as controls. HO-1 protein was then determined. (B) NHBE cells were transfected with 25 nM non-target siRNA, PERK siRNA or NRF2 siRNA for 48 h, then treated with compounds at 3 μM for 24 h. HO-1 mRNA level was then analyzed. (C) NHBE cells transfected with non-targeting, NRF2 or PERK siRNA for 48 h, treated with DMSO, 0.5 μM Tg, 3 μM compound B, C or hemin for 24 h. HO-1 protein level was determined. Data was representative of 3 experiments.</p

Titration of GFP-eIF2α BacMam.

<p>(A) U-2 OS cells were mixed with different amount of GFP-eIF2α BacMam and plated to a 384 well culture plate for overnight. Cells were then treated with either DMSO or 2 μM Tg for 1 h at 37°C 5% CO₂. LanthaScreen was performed to detect eIF2α phosphorylation. Data was the average of 4 repeats. (B) U-2 OS cells were transduced with GFP-eIF2α BacMam in a culture flask with the optimized MOT for overnight. After trypsinized and washed, cells were resuspended to different cell density and plated into a 384 well plate. After the treatment with Tg for 2.5 h at 37°C and 5% CO₂, LanthaScreen assay was performed to detect the phosphorylation of GFP-eIF2α. Data was the average of 3 repeats.</p

Compounds increase NQO-1 protein expression in a NRF2 dependent pattern.

<p>(A) NHBE cells were treated with 10 μM compound for 1 h or 3 μM compound for 24 h at 37°C and 5% CO₂. NQO-1 protein level was determined by ELISA. Stars indicate p value ≤0.001 (n = 3). (B) NHBE cells were transfected 25nM siRNA for 48 h, treated with DMSO, 0.5μTg, 3 μM compound B or C for 24 h. NQO-1 mRNA level was then determined by Real-Time PCR and was normalized with DMSO control (n = 3). (C) NHBEs were transfected 25 nM siRNA for 48 h, treated with DMSO, 0.5 μM Tg, 3 μM compound B or C for 24 h. NQO-1 protein level was determined by Western blot. Data was representative of 3 experiments.</p

Compounds have insignificant activity in IRE1 branch.

<p>HT1080 cells pretransduced with XBP-1 splicing reporter gene were treated with compounds at different concentrations for 3 h at 37°C and 5% CO₂. Luciferase activity was measured with Steady Glo reagents after the treatment. Data were average of 8 repeats.</p

LanthaScreen assay signal was PERK dependent.

<p>U-2 OS cells were transduced with GFP-eIF2α BacMam under the optimized conditions for overnight. Cells were then trypsinized and plated into a 384 well plate. Different doses of a specific PERK inhibitor GSK2606414 (A) or an inactive analog (B) was incubated with cells for 30 min at 37°C and 5% CO₂. DMSO, 1 μM Tg or 5 μM Tn was then added and incubated for 2 h at 37°C 5% CO₂. Phosphorylation of GFP-eIF2α was analyzed with LanthaScreen assay. Data was the average of 2 repeats.</p