NIR-triggered ligand-presenting nanocarriers for enhancing synergistic photothermal-chemotherapy.

Surface PEGylation of nanomedicine is effective for prolonging blood circulation time and facilitating the EPR effect, whereas the hydrophilic stealth surface inhibits effective cellular uptake and hinders active targeting. To address the dilemma, herein, a NIR light-triggered dePEGylation/ligand-presenting strategy based on thermal decomposition of azo bonds is developed, whereby Dox/Pz-IR nanoparticle is self-assembled from thermo-labile azo molecule-linked long PEG chain polymer (Pz-IR), cRGD-conjugated IR783 with short PEG chains (rP-IR) and doxorubicin. The long PEG chains could mask cRGD peptides in the blood circulation, preventing serum degradation and nonspecific interaction with normal cells. Once exposed to NIR laser, the PEG corona is stripped off owing to the rupture of azo bonds through the photothermal effect of IR783, and the masked cRGD peptides are exposed, which remarkably enhances cellular uptake by tumor cells and improves tumor accumulation. Dox/Pz-IR achieves the optimal synergy of photothermal-chemotherapy at mild temperature through progressive tumor accumulation, precisely regulated photothermal effect and NIR-PTT induced pulsated drug release. The strategy of NIR photo-driven dePEGylation/targeting offers a new approach to overcoming the "PEG dilemma", and provides a noval avenue for programmed tumor-targeted drug delivery.

Reversing insufficient photothermal therapy-induced tumor relapse and metastasis by regulating cancer-associated fibroblasts.

Insufficient tumor accumulation and distribution of photosensitizers as well as low antitumor immunity severely restrict the therapeutic efficacy of photothermal therapy (PTT). Cancer-associated fibroblasts (CAFs) play a key role in tumor extracellular matrix (ECM) remodeling and immune evasion. Reshaping tumor microenvironment via CAF regulation might provide a potential approach for complete tumor elimination in combination with PTT. Here, tumor cell-derived microparticles co-delivering calcipotriol and Indocyanine green (Cal/ICG@MPs) are developed to modulate CAFs for improved PTT efficacy. Cal/ICG@MPs efficiently target tumor tissues and regulate CAFs to reduce tumor ECM, resulting in enhanced tumor accumulation and penetration of ICG to generate strong PTT efficacy and activate CD8+ T cell-mediated antitumor immunity. In addition, Cal/ICG@MPs-triggered CAF regulation enhances tumor infiltration of CD8+ T cells and ameliorates CAF-induced antigen-mediated activation-induced cell death of tumor-specific CD8+ T cells in response to PTT, eliciting long-term antitumor immune memory to inhibit tumor recurrence and metastasis. Our results support Cal/ICG@MPs as a promising drug to improve PTT efficacy in cancer treatment.

Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles.

The main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8+ T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8+ T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy.

Manganese porphyrin-based metal-organic framework for synergistic sonodynamic therapy and ferroptosis in hypoxic tumors.

Development of efficient therapeutic strategy to incorporate ultrasound (US)-triggered sonodynamic therapy (SDT) and ferroptosis is highly promising in cancer therapy. However, the SDT efficacy is severely limited by the hypoxia and high glutathione (GSH) in the tumor microenvironment, and ferroptosis is highly associated with reactive oxygen species (ROS) and GSH depletion. Methods: A manganese porphyrin-based metal-organic framework (Mn-MOF) was constructed as a nanosensitizer to self-supply oxygen (O2) and decrease GSH for enhanced SDT and ferroptosis. In vitro and in vivo analysis, including characterization, O2 generation, GSH depletion, ROS generation, lipid peroxidation, antitumor efficacy and tumor immune microenvironment were systematically evaluated. Results: Mn-MOF exhibited catalase-like and GSH decreasing activity in vitro. After efficient internalization into cancer cells, Mn-MOF persistently catalyzed tumor-overexpressed H2O2 to in-situ produce O2 to relieve tumor hypoxia and decrease GSH and GPX4, which facilitated the formation of ROS and ferroptosis to kill cancer cells upon US irradiation in hypoxic tumors. Thus, strong anticancer and anti-metastatic activity was found in H22 and 4T1 tumor-bearing mice after a single administration of Mn-MOF upon a single US irradiation. In addition, Mn-MOF showed strong antitumor immunity and improved immunosuppressive microenvironment upon US irradiation by increasing the numbers of activated CD8+ T cells and matured dendritic cells and decreaing the numbers of myeloid-derived suppressor cells in tumor tissues. Conclusions: Mn-MOF holds great potential for hypoxic cancer therapy.

Injectable in Situ Forming Hydrogels of Thermosensitive Polypyrrole Nanoplatforms for Precisely Synergistic Photothermo-Chemotherapy.

The combination of photothermal therapy (PTT) with chemotherapy has great potential to maximize the synergistic effect of thermo-induced chemosensitization and improve treatment performance. To achieve high drug-loading capacity as well as precise synchronization between the controllable release of chemotherapeutics and the duration of near-infrared PTT, in this work, a facile one-step method was first developed to fabricate a novel injectable in situ forming photothermal modulated hydrogel drug delivery platform (D-PPy@PNAs), in which a PNIPAM-based temperature-sensitive acidic triblock polymer [poly(acrylic acid-b-N-isopropylamide-b-acrylic acid (PNA)] was utilized as the stabilizing agent in the polymerization of polypyrrole (PPy). The in situ forming hydrogels showed a sensitive temperature-responsive sol-gel phase-transition behavior, as well as an excellent photothermal property. The strong interaction of ionic bonds together with π-π stacking interactions resulted in high doxorubicin (DOX) loading capacity and controlled/sustained drug release behavior. In addition, D-PPy@PNAs also displayed enhanced cellular uptake and promoted intratumoral penetration of DOX upon NIR laser irradiation. The synergistic photothermal therapy-chemotherapy of D-PPy@PNA hydrogels greatly improved the antitumor efficacy in vivo. Therefore, thermosensitive polypyrrole-based D-PPy@PNA hydrogels may be powerful drug delivery nanoplatforms for precisely synergistic photothermo-chemotherapy of tumors.

NaCeF4:Gd,Tb Scintillator as an X-ray Responsive Photosensitizer for Multimodal Imaging-Guided Synchronous Radio/Radiodynamic Therapy.

Photosensitizers (PSs) that are directly responsive to X-ray for radiodynamic therapy (RDT) with desirable imaging abilities have great potential applications in cancer therapy. Herein, the cerium (Ce)-doped NaCeF4:Gd,Tb scintillating nanoparticle (ScNP or scintillator) is first reported. Due to the sensitization effect of the Ce ions, Tb ions can emit fluorescence under X-ray irradiation to trigger X-ray excited fluorescence (XEF). Moreover, Ce and Tb ions can absorb the energy of secondary electrons generated by X-ray to produce reactive oxide species (ROS) for RDT. With the intrinsic absorption of X-ray by lanthanide elements, the NaCeF4:Gd,Tb ScNPs also act as a computed tomography (CT) imaging contrast agent and radiosensitizers for radiotherapy (RT) sensitization synchronously. Most importantly, the transverse relaxation time of Gd3+ ions is shortened due to the doping of Ce and Tb ions, leading to the excellent performance of our ScNPs in T2-weighted MR imaging for the first time. Both in vitro and in vivo studies verify that our synthesized ScNPs have good performance in XEF, CT, and T2-weighted MR imaging, and a synchronous RT/RDT is achieved with significant suppression on tumor progression under X-ray irradiation. Importantly, no systemic toxicity is observed after intravenous injection of ScNPs. Our work highlights that ScNPs have potential in multimodal imaging-guided RT/RDT of deep tumors.

Spatiotemporally Light-Activatable Platinum Nanocomplexes for Selective and Cooperative Cancer Therapy.

Highly efficient nanoarchitectures are of great interest for achieving precise chemotherapy with minimized adverse side effects in cancer therapy. However, a major challenge remains in exploring a rational approach to synthesize spatiotemporally selective vehicles for precise cancer chemotherapy. Here, we demonstrate a rational design of bifunctional light-activatable platinum nanocomplexes (PtNCs) that produce dually cooperative cancer therapy through spatiotemporally selective thermo-chemotherapy. The Pt4+-coordinated polycarboxylic nanogel is explored as the nanoreactor template, which is exploited to synthesize bifunctional PtNCs consisting of a zero-valent Pt0 core and a surrounding bivalent Pt2+ shell with tunable ratios through a facile and controllable reduction. Without light exposure, chemotherapeutic Pt2+ ions are tightly bound on the surface of PtNCs, efficiently reducing undesirable drug leakage and nonselective damage on normal tissues/cells. Upon light exposure, PtNCs generate much heat via photothermal conversion from the Pt0 core and simultaneously trigger a rapid release of chemotherapeutic Pt2+ ions, thereby leading to the spatiotemporally light-activatable synergistic effect of thermo-chemotherapy. Moreover, PtNCs show enhanced tumor accumulation through the heat-triggered hydrophilicity-hydrophobicity transition upon immediate light exposure after injection, dramatically facilitating in vivo tumor regression through their cooperative anticancer efficiency. This rational design of spatiotemporally activatable nanoparticles provides an insightful tool for precise cancer therapy.

Polyaspartic acid-anchored mesoporous silica nanoparticles for pH-responsive doxorubicin release.

BACKGROUND: Nanotechnology-based drug delivery systems exhibit promising therapeutic efficacy in cancer chemotherapy. However, ideal nano drug carriers are supposed to be sufficiently internalized into cancer cells and then release therapeutic cargoes in response to certain intracellular stimuli, which has never been an easy task to achieve. OBJECTIVE: This study is to design mesoporous silica nanoparticles (MSNs)-based pH-responsive nano drug delivery system that is effectively internalized into cancer cells and then release drug in response to lysosomal/endosomal acidified environment. METHODS: We synthesized MSNs by sol-gel method. Doxorubicin (DOX) was encapsulated into the pores as a model drug. Polyaspartic acid (PAsA) was anchored on the surface of mesoporous MSNs (P-MSNs) as a gatekeeper via amide linkage and endowed MSNs with positive charge. RESULTS: In vitro release analysis demonstrated enhanced DOX release from DOX-loaded PAsA-anchored MSNs (DOX@P-MSNs) under endosomal/lysosomal acidic pH condition. Moreover, more DOX@P-MSNs were internalized into HepG2 cells than DOX-loaded MSNs (DOX@MSNs) and free DOX revealed by flow cytometry. Likewise, confocal microscopic images revealed that DOX@P-MSNs effectively released DOX and translocated to the nucleus. Much stronger cytotoxicity of DOX@P-MSNs against HepG2 cells was observed compared with DOX@MSNs and free DOX. CONCLUSION: DOX@P-MSNs were successfully fabricated and achieved pH-responsive DOX release. We anticipated this nanotherapeutics might be suitable contenders for future in vivo cancer chemotherapeutic applications.

Facile synthesis of pH-responsive doxorubicin-loaded layered double hydroxide for efficient cancer therapy.

Layered double hydroxides (LDHs) have attracted particular attention as drug delivery carriers due to their variable chemical composition, excellent biocompatibility, high anion exchange capacity and controlled drug release. However, their anion exchange capability only meets the requirement for encapsulating drugs with negative charge in aqueous media. Encapsulation of drugs with positive charge into LDHs still remains a big challenge. Herein, we report a facile strategy to obtain highly dispersible doxorubicin-loaded MgAl-LDH nanohybrids (DOX@MgAl-LDH). DOX@MgAl-LDH is stable under physiological conditions and releases DOX in response to an acidic tumor microenvironment. Intracellular tracking of DOX@MgAl-LDH confirms that after internalization into cancer cells via macropinocytosis, clathrin- and lipid raft/caveolae-mediated endocytosis, DOX@MgAl-LDH is transported to lysosomes and then releases DOX to the nucleus. Furthermore, DOX@MgAl-LDH exhibits good tumor targeting, enhanced cellular uptake and cytotoxicity against cancer cells compared with free DOX. In vivo anticancer experiments reveal that DOX@MgAl-LDH significantly inhibits tumor growth with decreased DOX-induced cardiotoxicity compared with free DOX. This study may provide a new approach for highly efficient DOX delivery in cancer therapy.

Draft Genome Sequence of Endophytic Herbaspirillum sp. Strain WT00C, a Tea Plant Growth-Promoting Bacterium.

Endophytic Herbaspirillum sp. strain WT00C was isolated from tea plant (Camellia sinensis L.). Here, we report the 6.08 Mb draft genome sequence of this strain, providing bioinformation about its agronomic benefits and capability to reduce selenate/selenite into red elemental selenium.