Dual-Programmable Semiconducting Polymer NanoPROTACs for Deep-Tissue Sonodynamic-Ferroptosis Activatable Immunotherapy.

Proteolysis-targeting chimeras (PROTACs) can provide promising opportunities for cancer treatment, while precise regulation of their activities remains challenging to achieve effective and safe therapeutic outcomes. A semiconducting polymer nanoPROTAC (SPNFeP ) is reported that can achieve ultrasound (US) and tumor microenvironment dual-programmable PROTAC activity for deep-tissue sonodynamic-ferroptosis activatable immunotherapy. SPNFeP is formed through a nano-precipitation of a sonodynamic semiconducting polymer, a ferroptosis inducer, and a newly synthesized PROTAC molecule. The semiconducting polymers work as sonosensitizers to produce singlet oxygen (1 O2 ) via sonodynamic effect under US irradiation, and ferroptosis inducers react with intratumoral hydrogen peroxide (H2 O2 ) to generate hydroxyl radical (·OH). Such a dual-programmable reactive oxygen species (ROS) generation not only triggers ferroptosis and immunogenic cell death (ICD), but also induces on-demand activatable delivery of PROTAC molecules into tumor sites. The effectively activated nanoPROTACs degrade nicotinamide phosphoribosyl transferase (NAMPT) to suppress tumor infiltration of myeloid-derived suppressive cells (MDSCs), thus promoting antitumor immunity. In such a way, SPNFeP mediates sonodynamic-ferroptosis activatable immunotherapy for entirely inhibiting tumor growths in both subcutaneous and 2-cm tissue-covered deep tumor mouse models. This study presents a dual-programmable activatable strategy based on PROTACs for effective and precise cancer combinational therapy.

Dual-Targeting Biomimetic Semiconducting Polymer Nanocomposites for Amplified Theranostics of Bone Metastasis.

Bone metastasis is a type of metastatic tumors that involves the spreads of malignant tumor cells into skeleton, and its diagnosis and treatment remain a big challenge due to the unique tumor microenvironment. We herein develop osteoclast and tumor cell dual-targeting biomimetic semiconducting polymer nanocomposites (SPFeNOC ) for amplified theranostics of bone metastasis. SPFeNOC contain semiconducting polymer and iron oxide (Fe3 O4 ) nanoparticles inside core and surface camouflaged hybrid membrane of cancer cells and osteoclasts. The hybrid membrane camouflage enables their targeting to both metastatic tumor cells and osteoclasts in bone metastasis through homologous targeting mechanism, thus achieving an enhanced nanoparticle accumulation in tumors. The semiconducting polymer mediates near-infrared (NIR) fluorescence imaging and sonodynamic therapy (SDT), and Fe3 O4 nanoparticles are used for magnetic resonance (MR) imaging and chemodynamic therapy (CDT). Because both cancer cells and osteoclasts are killed synchronously via the combinational action of SDT and CDT, the vicious cycle in bone metastasis is broken to realize high antitumor efficacy. Therefore, 4T1 breast cancer-based bone metastasis can be effectively detected and cured by using SPFeNOC as dual-targeting theranostic nanoagents. This study provides an unusual biomimetic nanoplatform that simultaneously targets osteoclasts and cancer cells for amplified theranostics of bone metastasis.

Sono-Triggered Cascade Lactate Depletion by Semiconducting Polymer Nanoreactors for Cuproptosis-Immunotherapy of Pancreatic Cancer.

The high level of lactate in tumor microenvironment not only promotes tumor development and metastasis, but also induces immune escape, which often leads to failures of various tumor therapy strategies. We here report a sono-triggered cascade lactate depletion strategy by using semiconducting polymer nanoreactors (SPNLCu) for cancer cuproptosis-immunotherapy. The SPNLCu mainly contain a semiconducting polymer as sonosensitizer, lactate oxidase (LOx) conjugated via a reactive oxygen species (ROS)-cleavable linker and chelated Cu2+. Upon ultrasound (US) irradiation, the semiconducting polymer generates singlet oxygen (1O2) to cut ROS-cleavable linker to allow the release of LOx that catalyzes lactate depletion to produce hydrogen peroxide (H2O2). The Cu2+ will be reduced to Cu+ in tumor microenvironment, which reacts with the produced H2O2 to obtain hydroxyl radical (⋅OH) that further improves LOx release via destroying ROS-cleavable linkers. As such, sono-triggered cascade release of LOx achieves effective lactate depletion, thus relieving immunosuppressive roles of lactate. Moreover, the toxic Cu+ induces cuproptosis to cause immunogenic cell death (ICD) for activating antitumor immunological effect. SPNLCu are used to treat both subcutaneous and deep-tissue orthotopic pancreatic cancer with observably enhanced efficacy in restricting the tumor growths. This study thus provides a precise and effective lactate depletion tactic for cancer therapy.

Activatable Semiconducting Polymer Pro-nanomodulators for Deep-Tissue Sono-immunotherapy of Orthotopic Pancreatic Cancer.

Immunotherapy has provided a promising modality for cancer treatment, while it often has the issues of limited response rates and potential off-target side effects in clinical practice. We herein report the construction of semiconducting polymer pro-nanomodulators (SPpMs) with ultrasound (US)-mediated activatable pharmacological actions for deep-tissue sono-immunotherapy of orthotopic pancreatic cancer. Such SPpMs consist of a sonodynamic semiconducting polymer backbone grafted with poly(ethylene glycol) chains linked with two immunomodulators (a programmed death-ligand 1 blocker and an indoleamine 2,3-dioxygenase inhibitor) via a singlet oxygen (1 O2 )-cleavable segment. In view of the excellent sonodynamic property of the semiconducting polymer core, SPpMs enable effective generation of 1 O2 under US treatment, even in a deep-tissue depth up to 12 cm. The generated 1 O2 not only ablates tumors via a sonodynamic effect and induces immunogenic cell death, but also destroys the 1 O2 -cleavable segments to allow in situ release of immunomodulators in tumors. This synergetic action results in boosted antitumor immune response via reversing two tumor immunosuppressive pathways. As such, SPpMs mediate deep-tissue sono-immunotherapy to completely eradicate orthotopic pancreatic cancer and effectively prevent tumor metastasis. Moreover, such an immune activation reduces the possibility of immune-related adverse events. This study thus provides a smart activatable nanoplatform for precise immunotherapy of deep-seated tumors.

Tumor-targeting polymer nanohybrids with amplified ROS generation for combined photodynamic and chemodynamic therapy.

Reactive oxygen species (ROS) generating strategies have been widely adopted for cancer therapy, but therapeutic efficacies are often low due to the complicated tumor microenvironment. In this study, we present the development of tumor-targeting polymer nanohybrids that amplify ROS generation by combining photodynamic therapy (PDT) and chemodynamic therapy (CDT) for cancer treatment. Such polymer nanohybrids contained three main components: a semiconducting polymer (SP) that acted as the photosensitizer for PDT, manganese dioxide (MnO2) that acted as the catalyst for CDT, and transferrin that mediated tumor targeting via binding to transferrin receptors overexpressed on the surface of tumor cells. The formed nanohybrids (TSM) showed obviously enhanced accumulation efficacy in tumor sites because of their targeting ability. In tumor sites, TSM produced singlet oxygen (1O2) under near-infrared (NIR) laser irradiation and a hydroxyl radical (˙OH) via reacting with hydrogen peroxide (H2O2), which resulted in amplified generation of ROS to achieve PDT/CDT combinational therapy. The growth of subcutaneous 4T1 tumors was remarkably inhibited via TSM-mediated treatment. In addition, this therapeutic efficacy could suppress tumor metastasis in the liver and lungs. This study presents a targeting hybrid nanoplatform to combine different ROS generating strategies for effective cancer therapy.

Near-infrared photoactivatable three-in-one nanoagents to aggravate hypoxia and enable amplified photo-chemotherapy.

Solid tumors create a hypoxic microenvironment and this character can be utilized for cancer therapy, but the hypoxia levels are insufficient to achieve satisfactory therapeutic benefits. Some tactics have been used to improve hypoxia, which however will cause side effects due to the uncontrolled drug release. We herein report near-infrared (NIR) photoactivatable three-in-one nanoagents (PCT) to aggravate tumor hypoxia and enable amplified photo-combinational chemotherapy. PCT are formed based on a thermal-responsive liposome nanoparticle containing three therapeutic agents: a hypoxia responsive prodrug tirapazamine (TPZ) for chemotherapy, a vascular targeting agent combretastatin A-4 (CA4) for vascular disturbance and a semiconducting polymer for both photodynamic therapy (PDT) and photothermal therapy (PTT). With NIR laser irradiation, PCT generate heat for PTT and destructing thermal-responsive liposomes to achieve activatable releases of TPZ and CA4. Moreover, PCT produce singlet oxygen (1O2) for PDT via consuming tumor oxygen. CA4 can disturb the blood vessels in tumor microenvironment to aggravate the hypoxic microenvironment, which results in the activation of TPZ for amplified chemotherapy. PCT thus enable PTT, PDT and hypoxia-amplified chemotherapy to afford a high therapeutic efficacy to almost absolutely eradicate subcutaneous 4 T1 tumors and effectively inhibit tumor metastases in lung and liver. This work presents an activatable three-in-one therapeutic nanoplatform with remotely controllable and efficient therapeutic actions to treat cancer.

Sono-Activatable Semiconducting Polymer Nanoreshapers Multiply Remodel Tumor Microenvironment for Potent Immunotherapy of Orthotopic Pancreatic Cancer.

Due to the complicated tumor microenvironment that compromises the efficacies of various therapies, the effective treatment of pancreatic cancer remains a big challenge. Sono-activatable semiconducting polymer nanoreshapers (SPNDN H) are constructed to multiply remodel tumor microenvironment of orthotopic pancreatic cancer for potent immunotherapy. SPNDN H contain a semiconducting polymer, hydrogen sulfide (H2 S) donor, and indoleamine 2,3-dioxygenase (IDO) inhibitor (NLG919), which are encapsulated by singlet oxygen (1 O2 )-responsive shells with modification of hyaluronidase (HAase). After accumulation in orthotopic pancreatic tumor sites, SPNDN H degrade the major content of tumor microenvironment hyaluronic acid to promote nanoparticle enrichment and immune cell infiltration, and also release H2 S to relieve tumor hypoxia via inhibiting mitochondrion functions. Moreover, the relieved hypoxia enables amplified sonodynamic therapy (SDT) under ultrasound (US) irradiation with generation of 1 O2 , which leads to immunogenic cell death (ICD) and destruction of 1 O2 -responsive components to realize sono-activatable NLG919 release for reversing IDO-based immunosuppression. Through such a multiple remodeling mechanism, a potent antitumor immunological effect is triggered after SPNDN H-based treatment. Therefore, the growths of orthotopic pancreatic tumors in mouse models are almost inhibited and tumor metastases are effectively restricted. This study offers a sono-activatable nanoplatform to multiply remodel tumor microenvironment for effective and precise immunotherapy of deep-tissue orthotopic tumors.

Augmenting Immunogenic Cell Death and Alleviating Myeloid-Derived Suppressor Cells by Sono-Activatable Semiconducting Polymer Nanopartners for Immunotherapy.

Inducing immunogenic cell death (ICD) by sonodynamic therapy (SDT) is promising for cancer immunotherapy, which however is inefficient due to oxygen depletion that compromises SDT effect and mediates recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs). The fabrication of sono-activatable semiconducting polymer nanopartners (SPNTi ) to simultaneously augment ICD and alleviate MDSCs for immunotherapy is reported. A sonodynamic semiconducting polymer, hydrophobic hypoxia-responsive tirapazamine (TPZ)-conjugate, and MDSC-targeting drug (ibrutinib) are encapsulated inside such SPNTi with surface shell of a singlet oxygen (1 O2 )-cleavable amphiphilic polymer. TPZ and ibrutinib serve as drug partners to enlarge immunotherapeutic effect. Upon sono-activation, SPNTi generate 1 O2 to break 1 O2 -cleavable polymers for in situ liberations of TPZ-conjugate and ibrutinib in tumor sites, and oxygen is consumed to create severe hypoxic tumor microenvironment, in which, TPZ-conjugate is activated for augmenting ICD action, while ibrutinib alleviates MDSCs for promoting antitumor immunological effect. In a bilateral tumor mouse model, SPNTi -mediated sono-activatable immunotherapy results in growth restraints of primary and distant tumors and noteworthy precaution of tumor metastases. This study thus provides a sono-activatable immunotherapeutic strategy with high precision and safety for cancer via overcoming post-treatment hypoxia and targeting MDSCs.

Prodrug-loaded semiconducting polymer hydrogels for deep-tissue sono-immunotherapy of orthotopic glioblastoma.

Although immunotherapy has achieved great success in the treatment of a variety of tumors, its efficacy for glioblastoma (GBM) is still limited. Both the immunosuppressive tumor microenvironment (TME) and poor penetration of immunotherapeutic agents into tumors contributed to the poor anti-glioma immunity. Herein, we develop an injectable prodrug-loaded hydrogel delivery system with sono-activatable properties for sonodynamic therapy (SDT)-triggered immunomodulation for GBM treatment. The prodrug alginate hydrogels (APN), which contain semiconducting polymer nanoparticles (SPNs) and the NLG919 prodrug linked by singlet oxygen (1O2)-cleavable linkers, are in situ formed via coordination of alginate solution with Ca2+ in the TME. SPNs serve as sonosensitizers to produce 1O2 upon ultrasound (US) irradiation for SDT. The generated 1O2 not only induce immunogenic cell death, but also break 1O2-cleavable linkers to precisely activate the NLG919 prodrug. Antitumor immunity is significantly amplified due to the reversal of immunosuppression mediated by indolamine 2,3-dioxygenase-dependent tryptophan metabolism. This smart prodrug hydrogel platform potently inhibits tumor growth in orthotopic glioma-bearing mice. Collectively, this work provides a sono-activatable hydrogel platform for precise sono-immunotherapy against GBM.

Tumor-targeting biomimetic sonosensitizer-conjugated iron oxide nanocatalysts for combinational chemodynamic-sonodynamic therapy of colorectal cancer.

Nanoparticle-based tumor therapy strategies have been widely developed, while the therapeutic efficacy is often limited due to poor accumulation of nanoparticles in tumor tissues and low antitumor effect of sole therapeutic modality. In this study, we report the construction of tumor-targeting biomimetic sonosensitizer-conjugated iron oxide (Fe3O4) nanocatalysts to mediate combinational action of chemodynamic therapy (CDT) and sonodynamic therapy (SDT) for the treatment of colorectal cancer. Bovine serum albumin (BSA)-modified Fe3O4 nanoparticles were synthesized using a basic co-precipitation method, and were conjugated with chlorin e6 (Ce6) as the sonosensitizers, followed by surface camouflage of a CT26 cancer cell membrane to construct the tumor-targeting biomimetic nanocatalysts (MBFC). The obtained MBFC nanocatalysts could present a strong catalysis ability and efficient sonodynamic property to generate an abundant amount of reactive oxygen species (ROS) under ultrasound (US) treatment in the tumor microenvironment. Cellular internalization experiments verified the high cellular uptake efficacy of MBFC due to the cell membrane-mediated homologous targeting mechanism. The MBFC nanocatalysts enabled the combinational action of CDT and SDT, and could markedly induce the apoptosis of CT26 cells in vitro and greatly inhibit the growth of CT26 tumors in living mice. This study thus provides a tumor-targeting biomimetic nanoplatform for the effective therapy of tumors.

A prodrug hydrogel with tumor microenvironment and near-infrared light dual-responsive action for synergistic cancer immunotherapy.

Immunotherapy has been used for cancer treatment, while it faces the common dilemmas of low therapeutic efficacy and serious immunotoxicity. In this study, we report the construction of a tumor microenvironment and near-infrared (NIR) light dual-responsive prodrug hydrogel for cancer synergistic immunotherapy in a more effective and safe manner. Such prodrug hydrogels were in-situ formed via calcium-induced gelation of alginate solution containing protoporphyrin IX (PpIX)-modified iron oxide (Fe3O4) nanoparticles and programmed death ligand 1 antibody (aPD-L1) prodrug nanoparticles crosslinked by reactive oxygen species (ROS)-responsive linkers. PpIX served as a photosensitizer to produce singlet oxygen (1O2) under NIR laser irradiation for photodynamic therapy (PDT), and Fe3O4 nanoparticles mediated chemodynamic therapy (CDT) to generate hydroxyl radical (·OH) via Fenton reaction in the tumor microenvironment. In view of the cumulative actions of PDT and CDT, amplified ROS was generated to not only induce immunogenic cell death (ICD), but also destroy ROS-responsive linkers to achieve on-demand release of aPD-L1 from prodrug nanoparticles. Boosted antitumor immunity was elicited in tumor-bearing mice due to the aPD-L1-mediated immune checkpoint blocking. As a result, the prodrug hydrogel-based synergistic immunotherapy could almost treat bilateral tumors and prevent lung and liver metastasis using 4T1 tumor mouse models. This study thus offers a dual-responsive prodrug hydrogel platform for precision cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Via calcium-induced gelation of alginate, we constructed a prodrug hydrogel with tumor microenvironment and near-infrared light dual-responsive action for synergistic cancer immunotherapy. Such hydrogels can achieve on-demand release of aPD-L1 upon photoactivation in the tumor microenvironment. Through mediating photodynamic and chemodynamic therapy, the prodrug hydrogels can induce enhanced immunogenic cell death and synergistically improve the efficacy of aPD-L1-mediated immune checkpoint blocking. The prodrug hydrogel-based synergistic therapy almost deracinates the primary and distant tumors, and prevents lung and liver metastasis in tumor mouse models.

Antibody-conjugated gold nanoparticles as nanotransducers for second near-infrared photo-stimulation of neurons in rats.

Infrared neural stimulation with the assistance of photothermal transducers holds great promise as a mini-invasive neural modulation modality. Optical nanoparticles with the absorption in the near-infrared (NIR) window have emerged as excellent photothermal transducers due to their good biocompatibility, surface modifiability, and tunable optical absorption. However, poor activation efficiency and limited stimulation depth are main predicaments encountered in the neural stimulation mediated by these nanoparticles. In this study, we prepared a targeted polydopamine (PDA)-coated gold (Au) nanoparticles with specific binding to thermo-sensitive ion channel as nanotransducers for second near-infrared (NIR-II) photo-stimulation of neurons in rats. The targeted Au nanoparticles were constructed via conjugation of anti-TRPV1 antibody with PEGylated PDA-coated Au nanoparticles and thus exhibited potent photothermal performance property in the second NIR (NIR-II) window and converted NIR-II light to heat to rapidly activate Ca2+ influx of neurons in vitro. Furthermore, wireless photothermal stimulation of neurons in living rat successfully evoke excitation in neurons in the targeted brain region as deep as 5 mm beneath cortex. This study thus demonstrates a remote-controlled strategy for neuromodulation using photothermal nanotransducers.

Radioactive organic semiconducting polymer nanoparticles for multimodal cancer theranostics.

Theranostics with integrations of both imaging and therapeutic elements can enable early diagnosis and effective treatment of cancer. Herein, we report the development of radioactive semiconducting polymer nanoparticles (rSPNs) for multimodal cancer theranostics. Such rSPNs constructed through labeling poly(ethylene glycol) (PEG) grafted SPNs with iodine-131 (131I) exhibit ideal photothermal property, excellent singlet oxygen (1O2) generating ability and good radiolabeling stability. Owing to their small particle dimension and PEG surface corona, rSPNs show an effective accumulation into subcutaneous tumors of living mice after systemic administration. The good fluorescence property and stable radiolabeling of rSPNs enable contrast signals for near-infrared (NIR) fluorescence and single photon emission computed tomography (SPECT) dual-model imaging of tumors. Moreover, rSPNs provide combinational action of photothermal therapy (PTT), photodynamic therapy (PDT) and radiotherapy under NIR laser irradiation, resulting in much higher therapeutic efficacy in inhibiting tumor growth and metastasis relative to SPNs-mediated treatment. This study thus offers a multifunctional organic nanosystem for multimodal cancer theranostics.

Prodrug and Glucose Oxidase Coloaded Photodynamic Hydrogels for Combinational Therapy of Melanoma.

With the advantages of high safety and selectivity, photodynamic therapy (PDT) has been widely used for cancer treatments, while the anticancer efficacy is often limited because of its relying on oxygen concentrations. Therefore, sole PDT fails to achieve the desired therapeutic effect for hypoxic tumors. To address this issue, we herein report the construction of prodrug and glucose oxidase (GOx) coloaded alginate (ALG) hydrogels for PDT-combined chemotherapy of melanoma. The hydrogels are in situ formed in tumor sites after injection of ALG solution containing semiconducting polymer nanoparticles, hypoxia-responsive prodrug tirapazamine (TPZ), and GOx, which is based on chelation of ALG by endogenous Ca2+. Due to the presence of semiconducting polymer nanoparticles acting as photosensitizers, the hydrogels mediate PDT to produce singlet oxygen (1O2) for directly killing tumor cells, in which oxygen is consumed to create a more hypoxic tumor microenvironment. Moreover, the loaded GOx within hydrogels can deplete oxygen to further aggravate tumor hypoxia. As such, TPZ is effectively activated by hypoxia to cause cancer cell death via chemotherapy. Thus, the hydrogels with laser irradiation achieve a combinational action of PDT with chemotherapy to almost completely eradicate tumors, leading to a much higher therapeutic efficacy relative to sole PDT. This study will provide a promising injectable hydrogel platform for effective treatments of cancer.

Tumor immunosuppressive microenvironment modulating hydrogels for second near-infrared photothermal-immunotherapy of cancer.

Immunotherapy has recently been seen as a hopeful therapeutic device to inhibit tumor growth and metastasis, while the curative efficacy is limited by intrinsic immunosuppressive tumor microenvironment. Herein, we reported a tumor immunosuppressive microenvironment modulating hydrogel (TIMmH) platform to achieve second near-infrared (NIR-II) photothermal therapy (PTT) combined immunotherapy for durable inhibition of breast cancer. This TIMmH platform was synthesized through co-loading of NIR-II photothermal nanoagent and an immunoadjuvant cytosine-phosphateguanosine oligodeoxynucleotides (CpG ODNs) into the alginate hydrogel (ALG). Upon the administration of ALG into the tumor, the TIMmH was in situ formed via the coordination effect with Ca2+, locally encapsulating the semiconducting polymer nanoparticles (SPIIN) and CpG in the colloid, achieving to prolong the accumulation time and prevent the premature damage and release of immunotherapeutic agents. Upon 1064-nm photoirradiation, the TIMmHSD was able to elevate the intratumoral temperature for the ablation of tumors, which could induce the apoptosis of tumor cells and achieve thermal immune activation by regulating of an immunosuppressive microenvironment. The TIMmH-mediated combined treatment effectively suppressed the growths of breast cancers, and even acquired a sustained inhibition of the lung metastasis. This study provides a novel tumor immunosuppressive microenvironment modulating hydrogel platform with NIR-II photoexcited capacity for the safe, effective and durable lung metastasis-inhibiting breast cancer treatment.

Near-Infrared Photoactivatable Immunomodulatory Nanoparticles for Combinational Immunotherapy of Cancer.

As a promising treatment option for cancer, immunotherapy can eliminate local and distant metastatic tumors and even prevent recurrence through boosting the body's immune system. However, immunotherapy often encounters the issues of limited therapeutic efficacy and severe immune-related adverse events in clinical practices, which should be mainly due to the non-specific accumulations of immunotherapeutic agents. Activatable immunomodulatory agents that are responsive to endogenous stimuli in tumor microenvironment can afford controlled immunotherapeutic actions, while they still face certain extent of off-target activation. Since light has the advantages of noninvasiveness, simple controllability and high spatio-temporal selectivity, therapeutic agents that can be activated by light, particularly near-infrared (NIR) light with minimal phototoxicity and strong tissue penetrating ability have been programmed for cancer treatment. In this mini review, we summarize the recent progress of NIR photoactivatable immunomodulatory nanoparticles for combinational cancer immunotherapy. The rational designs, constructions and working mechanisms of NIR photoactivatable agents are first briefly introduced. The uses of immunomodulatory nanoparticles with controlled immunotherapeutic actions upon NIR photoactivation for photothermal and photodynamic combinational immunotherapy of cancer are then summarized. A conclusion and discussion of the existing challenges and further perspectives for the development and clinical translation of NIR photoactivatable immunomodulatory nanoparticles are finally given.

131I-Labeled gold nanoframeworks for radiotherapy-combined second near-infrared photothermal therapy of cancer.

Photothermal therapy (PTT) has shown great promise for cancer treatment via light-triggered heat generation, while the anticancer efficacy of sole PTT is often limited. In this study, we report the use of radionuclide 131I-labeled gold nanoframeworks (131I-AuNFs) for radiotherapy-combined second near-infrared (NIR-II) PTT of breast cancer. AuNFs synthesized via a simple reduction approach are surface functionalized with polydopamine and poly(ethylene glycol), followed by labeling with 131I. The formed 131I-AuNFs with a high photothermal conversion efficacy and stable radioactivity can effectively accumulate into subcutaneous 4T1 mouse models as confirmed by in vivo single photon emission computed tomography (SPECT) imaging. Upon 1064 nm laser irradiation of tumors, local heat is generated for NIR-II PTT, which combines with radiotherapy to achieve a much higher therapeutic efficacy relative to sole treatment. As such, 131I-AuNFs-mediated radiotherapy-combined NIR-II PTT results in the effective inhibition of the growth of subcutaneous tumors. This study thus provides a facile nanoplatform for effective combination cancer therapy.

Enzyme-Loaded pH-Sensitive Photothermal Hydrogels for Mild-temperature-mediated Combinational Cancer Therapy.

Photothermal therapy (PTT) that utilizes hyperthermia to ablate cancer cells is a promising approach for cancer therapy, while the generated high temperature may lead to damage of surrounding normal tissues and inflammation. We herein report the construction of glucose oxidase (GOx)-loaded hydrogels with a pH-sensitive photothermal conversion property for combinational cancer therapy at mild-temperature. The hydrogels (defined as CAG) were formed via coordination of alginate solution containing pH-sensitive charge-transfer nanoparticles (CTNs) as the second near-infrared (NIR-II) photothermal agents and GOx. In the tumor sites, GOx was gradually released from CAG to consume glucose for tumor starvation and aggravate acidity in tumor microenvironment that could turn on the NIR-II photothermal conversion property of CTNs. Meanwhile, the released GOx could suppress the expression of heat shock proteins to enable mild NIR-II PTT under 1,064 nm laser irradiation. As such, CAG mediated a combinational action of mild NIR-II PTT and starvation therapy, not only greatly inhibiting the growth of subcutaneously implanted tumors in a breast cancer murine model, but also completely preventing lung metastasis. This study thus provides an enzyme loaded hydrogel platform with a pH-sensitive photothermal effect for mild-temperature-mediated combinational cancer therapy.

Oxygen-producing proenzyme hydrogels for photodynamic-mediated metastasis-inhibiting combinational therapy.

Photodynamic therapy (PDT) has provided a promising approach for the treatment of solid tumors, while the therapeutic efficacy is often limited due to the hypoxic tumor microenvironment, resulting in tumor metastasis. Herein, we report an oxygen-producing proenzyme hydrogel (OPeH) with photoactivatable enzymatic activity for PDT enabled metastasis-inhibiting combinational therapy of breast cancer. This OPeH based on alginate is composed of protoporphyrin IX (PpIX) conjugated manganese oxide (MnO2) nanoparticles, which act as both the photosensitizer and oxygen-producing agent, and singlet oxygen (1O2)-responsive proenzyme nanoparticles. In the hypoxic and acidic tumor microenvironment, MnO2 can generate 1O2 to promote PpIX-mediated PDT with an amplified 1O2 generation efficiency, which also triggers the cleavage of 1O2-responsive linkers and cascade activation of proenzymes for cancer cell death. This combinational therapy upon photoactivation not only greatly inhibited the tumor growth, but also suppressed lung metastasis in a mouse xenograft breast tumor model, which is impossible in the case of PDT alone. This study thus provides a proenzyme hydrogel platform with photoactivatable activity for metastasis-inhibiting cancer therapy with high efficacy and safety.