Rational Design of Biomaterials to Potentiate Cancer Thermal Therapy.

Cancer thermal therapy, also known as hyperthermia therapy, has long been exploited to eradicate mass lesions that are now defined as cancer. With the development of corresponding technologies and equipment, local hyperthermia therapies such as radiofrequency ablation, microwave ablation, and high-intensity focused ultrasound, have has been validated to effectively ablate tumors in modern clinical practice. However, they still face many shortcomings, including nonspecific damages to adjacent normal tissues and incomplete ablation particularly for large tumors, restricting their wide clinical usage. Attributed to their versatile physiochemical properties, biomaterials have been specially designed to potentiate local hyperthermia treatments according to their unique working principles. Meanwhile, biomaterial-based delivery systems are able to bridge hyperthermia therapies with other types of treatment strategies such as chemotherapy, radiotherapy and immunotherapy. Therefore, in this review, we discuss recent progress in the development of functional biomaterials to reinforce local hyperthermia by functioning as thermal sensitizers to endow more efficient tumor-localized thermal ablation and/or as delivery vehicles to synergize with other therapeutic modalities for combined cancer treatments. Thereafter, we provide a critical perspective on the further development of biomaterial-assisted local hyperthermia toward clinical applications.

MSCs-engineered biomimetic PMAA nanomedicines for multiple bioimaging-guided and photothermal-enhanced radiotherapy of NSCLC.

BACKGROUND: The recently developed biomimetic strategy is one of the mostly effective strategies for improving the theranostic efficacy of diverse nanomedicines, because nanoparticles coated with cell membranes can disguise as "self", evade the surveillance of the immune system, and accumulate to the tumor sites actively. RESULTS: Herein, we utilized mesenchymal stem cell memabranes (MSCs) to coat polymethacrylic acid (PMAA) nanoparticles loaded with Fe(III) and cypate-an derivative of indocyanine green to fabricate Cyp-PMAA-Fe@MSCs, which featured high stability, desirable tumor-accumulation and intriguing photothermal conversion efficiency both in vitro and in vivo for the treatment of lung cancer. After intravenous administration of Cyp-PMAA-Fe@MSCs and Cyp-PMAA-Fe@RBCs (RBCs, red blood cell membranes) separately into tumor-bearing mice, the fluorescence signal in the MSCs group was 21% stronger than that in the RBCs group at the tumor sites in an in vivo fluorescence imaging system. Correspondingly, the T1-weighted magnetic resonance imaging (MRI) signal at the tumor site decreased 30% after intravenous injection of Cyp-PMAA-Fe@MSCs. Importantly, the constructed Cyp-PMAA-Fe@MSCs exhibited strong photothermal hyperthermia effect both in vitro and in vivo when exposed to 808 nm laser irradiation, thus it could be used for photothermal therapy. Furthermore, tumors on mice treated with phototermal therapy and radiotherapy shrank 32% more than those treated with only radiotherapy. CONCLUSIONS: These results proved that Cyp-PMAA-Fe@MSCs could realize fluorescence/MRI bimodal imaging, while be used in phototermal-therapy-enhanced radiotherapy, providing desirable nanoplatforms for tumor diagnosis and precise treatment of non-small cell lung cancer.

H2O2-responsive liposomal nanoprobe for photoacoustic inflammation imaging and tumor theranostics via in vivo chromogenic assay.

Abnormal H2O2 levels are closely related to many diseases, including inflammation and cancers. Herein, we simultaneously load HRP and its substrate, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), into liposomal nanoparticles, obtaining a Lipo@HRP&ABTS optical nanoprobe for in vivo H2O2-responsive chromogenic assay with great specificity and sensitivity. In the presence of H2O2, colorless ABTS would be converted by HRP into the oxidized form with strong near-infrared (NIR) absorbance, enabling photoacoustic detection of H2O2 down to submicromolar concentrations. Using Lipo@HRP&ABTS as an H2O2-responsive nanoprobe, we could accurately detect the inflammation processes induced by LPS or bacterial infection in which H2O2 is generated. Meanwhile, upon systemic administration of this nanoprobe we realize in vivo photoacoustic imaging of small s.c. tumors (∼2 mm in size) as well as orthotopic brain gliomas, by detecting H2O2 produced by tumor cells. Interestingly, local injection of Lipo@HRP&ABTS further enables differentiation of metastatic lymph nodes from those nonmetastatic ones, based on their difference in H2O2 contents. Moreover, using the H2O2-dependent strong NIR absorbance of Lipo@HRP&ABTS, tumor-specific photothermal therapy is also achieved. This work thus develops a sensitive H2O2-responsive optical nanoprobe useful not only for in vivo detection of inflammation but also for tumor-specific theranostic applications.

Amplification of Tumor Oxidative Stresses with Liposomal Fenton Catalyst and Glutathione Inhibitor for Enhanced Cancer Chemotherapy and Radiotherapy.

Amplification of intracellular oxidative stress has been found to be an effective strategy to induce cancer cell death. To this end, we prepare a unique type of ultrasmall gallic acid-ferrous (GA-Fe(II)) nanocomplexes as the catalyst of Fenton reaction to enable persistent conversion of H2O2 to highly cytotoxic hydroxyl radicals (•OH). Then, both GA-Fe(II) and l-buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, are coencapsulated within a stealth liposomal nanocarrier. Interestingly, the obtained BSO/GA-Fe(II)@liposome is able to efficiently amplify intracellular oxidative stress via increasing •OH generation and reducing GSH biosynthesis. After chelating with 99mTc4+ radioisotope, such BSO/GA-Fe(II)@liposome could be tracked under in vivo single-photon-emission-computed-tomography (SPECT) imaging, which illustrates the time-dependent tumor homing of such liposomal nanoparticles after intravenous injection. With GA-Fe(II)-mediated •OH production and BSO-mediated GSH depletion, treatment with such BSO/GA-Fe(II)@liposome would lead to dramatically enhanced intratumoral oxidative stresses, which then result in remarkably improved therapeutic efficacies of concurrently applied chemotherapy or radiotherapy. This work thus presents the concise fabrication of biocompatible BSO/GA-Fe(II)@liposome as an effective adjuvant nanomedicine to promote clinically used conventional cancer chemotherapy and radiotherapy, by greatly amplifying the intratumoral oxidative stress.

Synthesis of Hollow Biomineralized CaCO3-Polydopamine Nanoparticles for Multimodal Imaging-Guided Cancer Photodynamic Therapy with Reduced Skin Photosensitivity.

The development of activatable nanoplatforms to simultaneously improve diagnostic and therapeutic performances while reducing side effects is highly attractive for precision cancer medicine. Herein, we develop a one-pot, dopamine-mediated biomineralization method using a gas diffusion procedure to prepare calcium carbonate-polydopamine (CaCO3-PDA) composite hollow nanoparticles as a multifunctional theranostic nanoplatform. Because of the high sensitivity of such nanoparticles to pH, with rapid degradation under a slightly acidic environment, the photoactivity of the loaded photosensitizer, i.e., chlorin e6 (Ce6), which is quenched by PDA, is therefore increased within the tumor under reduced pH, showing recovered fluorescence and enhanced singlet oxygen generation. In addition, due to the strong affinity between metal ions and PDA, our nanoparticles can bind with various types of metal ions, conferring them with multimodal imaging capability. By utilizing pH-responsive multifunctional nanocarriers, effective in vivo antitumor photodynamic therapy (PDT) can be realized under the precise guidance of multimodal imaging. Interestingly, at normal physiological pH, our nanoparticles are quenched and show much lower phototoxicity to normal tissues, thus effectively reducing skin damage during PDT. Therefore, our work presents a unique type of biomineralized theranostic nanoparticles with inherent biocompatibility, multimodal imaging functionality, high antitumor PDT efficacy, and reduced skin phototoxicity.

Surface coating-dependent cytotoxicity and degradation of graphene derivatives: towards the design of non-toxic, degradable nano-graphene.

With the increasing interests of using graphene and its derivatives in the area of biomedicine, the systematic evaluation of their potential risks and impacts to biological systems is becoming critically important. In this work, we carefully study how surface coatings affect the cytotoxicity and extracellular biodegradation behaviors of graphene oxide (GO) and its derivatives. Although naked GO could induce significant toxicity to macrophages, coating those two-dimensional nanomaterials with biocompatible macromolecules such as polyethylene glycol (PEG) or bovine serum albumin (BSA) could greatly attenuate their toxicity, as independently evidenced by several different assay approaches. On the other hand, although GO can be gradually degraded through enzyme induced oxidization by horseradish peroxidase (HRP), both PEG and BSA coated GO or reduced GO (RGO) are rather resistant to HRP-induced biodegradation. In order to obtain biocompatible functionalized GO that can still undergo enzymatic degradation, we conjugate PEG to GO via a cleavable disulfide bond, obtaining GO-SS-PEG with negligible toxicity and considerable degradability, promising for further biomedical applications.

Polyethylene glycol and polyethylenimine dual-functionalized nano-graphene oxide for photothermally enhanced gene delivery.

Graphene oxide (GO) has been extensively explored in nanomedicine for its excellent physiochemical, electrical, and optical properties. Here, polyethylene glycol (PEG) and polyethylenimine (PEI) are covalently conjugated to GO via amide bonds, obtaining a physiologically stable dual-polymer-functionalized nano-GO conjugate (NGO-PEG-PEI) with ultra-small size. Compared with free PEI and the GO-PEI conjugate without PEGylation, NGO-PEG-PEI shows superior gene transfection efficiency without serum interference, as well as reduced cytotoxicity. Utilizing the NIR optical absorbance of NGO, the cellular uptake of NGO-PEG-PEI is shown to be enhanced under a low power NIR laser irradiation, owing to the mild photothermal heating that increases the cell membrane permeability without significantly damaging cells. As the results, remarkably enhanced plasmid DNA transfection efficiencies induced by the NIR laser are achieved using NGO-PEG-PEI as the light-responsive gene carrier. More importantly, it is shown that our NGO-PEG-PEI is able to deliver small interfering RNA (siRNA) into cells under the control of NIR light, resulting in obvious down-regulation of the target gene, Polo-like kinase 1 (Plk1), in the presence of laser irradiation. This study is the first to use photothermally enhanced intracellular trafficking of nanocarriers for light-controllable gene delivery. This work also encourages further explorations of functionalized nano-GO as a photocontrollable nanovector for combined photothermal and gene therapies.

Immunogenic nanomedicine based on GSH-responsive nanoscale covalent organic polymers for chemo-sonodynamic therapy.

Sonodynamic therapy (SDT) is emerging as a non-invasive strategy to eradicate tumors, but its therapeutic efficacy is still not ideal. To achieve more effective SDT, water insoluble sonosensitizer meso-5, 10, 15, 20-tetra(4-hydroxylphenyl)porphyrin (THPP) is here esterified with succinic acid conjugated oxaliplatin prodrug (Oxa(IV)SA2) and carboxyl group terminated PEG (PEG5k-COOH). The obtained covalent organic polymer (COP) of THPP-Oxa(IV)-PEG with good physiological stability, sonosensitization efficacy and glutathione (GSH) responsive oxalipatin responsive behaviors can induce effective immunogenic cancer cell death upon the ultrasound exposure. In addition, THPP-Oxa(IV)-PEG is shown to be a versatile carrier for both hydrophobic near infrared dye and radioisotope 99mTc, thereby enabling real-time tracking of its pharmacokinetics behavior under corresponding imaging facilities. Furthermore, treatment with THPP-Oxa(IV)-PEG injection and ultrasound exposure is shown to be most effectively in suppressing tumor growth, with 3 of 6 CT26 tumor bearing mice fully cured, ascribing to its high potency in eliciting profound antitumor immune responses. This work highlights a promising strategy in constructing multifunctional nanosonosensitizer as a potent immunogenic nanomedicine to enhance the treatment outcome of SDT.

Perfluorocarbon loaded fluorinated covalent organic polymers with effective sonosensitization and tumor hypoxia relief enable synergistic sonodynamic-immunotherapy.

Relieving tumor hypoxia has recently been found to be a promising approach to reverse tumor immunosuppression and thus enhance the treatment outcomes of diverse cancer treatments. Herein, we prepared a type of fluorinated covalent conjugate polymers (COPs) with sonosensitizer meso-5, 10, 15, 20-tetra (4-hydroxylphenyl) porphyrin (THPP) and perfluorosebacic acid (PFSEA) as cross-linkers, yielding THPPpf-COPs with efficient sonodynamic efficacy and loading capacity towards perfluoro-15-crown-5-ether (PFCE), a model perfluorocarbon molecule. Upon intratumoral injection, such PFCE@THPPpf-COPs could not only attenuate tumor hypoxia, but also exhibit the most effective suppression effect on tumor growth in the presence of ultrasound exposure by inducing immunogenic cell death of cancer cells. Furthermore, we found that the sonodynamic therapy of PFCE@THPPpf-COPs together with anti-CD47 immunotherapy would synergistically suppress tumor growth by increasing the tumor-infiltrating frequencies of phagocytic M1 macrophages and cytotoxic CD3+CD8+ T cells, while reducing the frequency of immunosuppressive regulatory T cells. Moreover, such combination treatment could also elicit potent protective memory antitumor immunity to prevent tumor challenge. Therefore, this work presents PFCE@THPPpf-COPs are a type of multifunctional nano-sonosensitizers potent in removing negative impacts of inherent tumor hypoxia and immunosuppression, and suppressing tumor growth and tumor recurrence by priming host's antitumor immunity, particularly in synergizing with anti-CD47 immunotherapy.

Liposomal oxaliplatin prodrugs loaded with metformin potentiate immunotherapy for colorectal cancer.

Tumor hypoxia is confirmed to be associated with the formation of tumor immunosuppression, a general feature of solid tumors, and thus attenuates the effectiveness of various cancer therapies in clinic. We herein develop a tumor microenvironment (TME) modulating liposomal nanomedicine by encapsulating metformin with amphiphilic oxaliplatin prodrug constructed liposomes to potentiate cancer immunotherapy. While metformin could regulate metabolisms of tumor cells to reduce their oxygen consumption and relieve tumor hypoxia, oxaliplatin is a chemotherapy drug that induces immunogenic cell death (ICD). The obtained met-oxa(IV)-liposome upon intravenous injection effectively attenuates tumor hypoxia and induce ICD of cancer cells, thereby collectively suppresses the growth of murine colorectal tumors by eliciting potent antitumor immunity and reversing the immunosuppressive TME. As the result, the treatment with met-oxa(IV)-liposome effectively potentiates the immune checkpoint blockade (ICB) therapy against murine colorectal tumors. This liposomal nanomedicine is highlighted to be a TME modulating liposomal nanomedicine with high potency in suppressing tumor growth, particularly promising in synergizing with ICB therapy by boosting antitumor immune responses.

Coordination Polymer-Coated CaCO3 Reinforces Radiotherapy by Reprogramming the Immunosuppressive Metabolic Microenvironment.

Radiotherapy is widely exploited for the treatment of a large range of cancers in clinic, but its therapeutic effectiveness is seriously crippled by the tumor immunosuppression, mainly driven by the altered metabolism of cancer cells. Here, a pH-responsive nanomedicine is prepared by coating calcium carbonate (CaCO3 ) nanoparticles with 4-phenylimidazole (4PI), an inhibitor against indoleamine 2,3-dioxygenase 1 (IDO-1), together with zinc ions via the coordination reaction, aiming at reinforcing the treatment outcome of radiotherapy. The obtained pH-responsive nanomedicine, coined as acidity-IDO1-modulation nanoparticles (AIM NPs), is able to instantly neutralize protons, and release 4PI to suppress the IDO1-mediated production of kynurenine (Kyn) upon tumor accumulation. As a result, treatment with AIM NPs can remarkably enhance the therapeutic efficacy of radiotherapy against both murine CT26 and 4T1 tumors by eliciting potent antitumor immunity. Furthermore, it is shown that such combination treatment can effectively suppress the growth of untreated distant tumors via the abscopal effect, and result in immune memory responses to reject rechallenged tumors. This work highlights a novel strategy of simultaneous tumor acidity neutralization and IDO1 inhibition to potentiate radiotherapy, with great promises to suppress tumor metastasis and recurrence by eliciting robust antitumor immunity.

Tumor-killing nanoreactors fueled by tumor debris can enhance radiofrequency ablation therapy and boost antitumor immune responses.

Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. Here we develop a CaCO3-assisted double emulsion method to encapsulate lipoxidase and hemin with poly(lactic-co-glycolic acid) (PLGA) to enhance RFA. We show the HLCaP nanoreactors (NRs) with pH-dependent catalytic capacity can continuously produce cytotoxic lipid radicals via the lipid peroxidation chain reaction using cancer cell debris as the fuel. Upon being fixed inside the residual tumors post RFA, HLCaP NRs exhibit a suppression effect on residual tumors in mice and rabbits by triggering ferroptosis. Moreover, treatment with HLCaP NRs post RFA can prime antitumor immunity to effectively suppress the growth of both residual and metastatic tumors, also in combination with immune checkpoint blockade. This work highlights that tumor-debris-fueled nanoreactors can benefit RFA by inhibiting tumor recurrence and preventing tumor metastasis.

Oxaliplatin-/NLG919 prodrugs-constructed liposomes for effective chemo-immunotherapy of colorectal cancer.

High expression of indoleamine 2,3-dioxygenase 1 (IDO1) is a major cause of tumor induced immunosuppression, and appears to be associated with poor prognosis in human colorectal cancer and some others. In this study, we construct a bifunctional liposome by self-assembly of oxaliplatin-prodrug (Oxa(IV)) conjugated phospholipid and alkylated NLG919 (aNLG), an IDO1 inhibitor, together with other commercial lipids. The obtained aNLG/Oxa(IV)-Lip can not only release cytotoxic oxaliplatin inside the reductive cytosol to trigger immunogenic cell death (ICD) of cancer cells, but also efficiently retard the degradation of tryptophan to immunosuppressive kynurenine via the NLG919 mediated inhibition of IDO1. Moreover, in vivo pharmacokinetic studies indicate that such aNLG/Oxa(IV)-Lip has a long blood circulation time, thereby enables highly-efficient passive tumor homing. Upon tumor accumulation, such aNLG/Oxa(IV)-Lip presents superior synergistic antitumor efficacies to both subcutaneous and orthotopic CT26 tumors, ascribing to significantly primed anti-tumor immunity of enhanced intratumoral infiltration of CD8+ T cells, scretion of cytotoxic cytokines and downregulation of immunosuppressive regulatory T cells. This work highlights that such bifunctional aNLG/Oxa(IV)-Lip is a potent candidate for future clinical translation owing to its excellent biocompatibility and high therapeutic efficacy.

Red-blood-cell-membrane-enveloped magnetic nanoclusters as a biomimetic theranostic nanoplatform for bimodal imaging-guided cancer photothermal therapy.

The use of red blood cell (RBC) membrane coatings has recently been found to be a biomimetic strategy to confer inner core nanomaterials with improved pharmacokinetic profiles by utilizing the intrinsic long blood circulation time of RBCs. Here, we envelope superparamagnetic nanoclusters (MNCs) with RBC membrane ghosts to obtain MNC@RBCs with significantly improved physiological stability compared to that of bare MNCs. After being loaded with near-infrared (NIR) cypate molecules, the as-prepared Cyp-MNC@RBCs show remarkably increased NIR absorbance and resultant efficient photothermal conversion efficacy. By tracking the NIR fluorescence of cypate in an in vivo fluorescence imaging system, we uncover that such Cyp-MNC@RBCs upon intravenous injection show significantly improved tumor-homing capacity as compared to bare cypate-loaded MNCs. A similar result is further evidenced by recording the T2-weighted magnetic resonance imaging (MRI) signal of MNCs. Furthermore, upon exposure to 808 nm laser irradiation, the tumors grown on the mice with the intravenous injection of Cyp-MNC@RBCs show a higher temperature increase than the tumors grown on the mice injected with plain MNC@RBCs and thus are significantly suppressed via photothermal ablation. This study presents the preparation of biomimetic Cyp-MNC@RBCs with greatly improved tumor-homing capacity as multifunctional nanotheranostic agents for fluorescence and MRI bimodal imaging-guided cancer photothermal therapy.

Reactive Oxygen Species-Scavenging Scaffold with Rapamycin for Treatment of Intervertebral Disk Degeneration.

The chronic inflammatory microenvironment is characterized by the elevated level of reactive oxygen species (ROS). Here, it is hypothesized that developing an ROS-scavenging scaffold loaded with rapamycin (Rapa@Gel) may offer a new strategy for modulating the local inflammatory microenvironment to improve intervertebral disk tissue regeneration. The therapeutic scaffold consisting of ROS-degradable hydrogel can be injected into the injured degeneration site of intervertebral disk (IVD) and can release therapeutics in a programmed manner. The ROS scavenged by scaffold reduces the inflammatory responses. It is found that when rats are treated with Rapa@Gel, this results in an increase in the percentage of M2-like macrophages and a decrease in M1-like macrophages in the inflammatory environment, respectively. Regeneration of IVD is achieved by Rapa@Gel local treatment, due to the increased M2 macrophages and reduced inflammation. This strategy may be extended to the treatment of many other inflammatory diseases.

Ultrasmall Oxygen-Deficient Bimetallic Oxide MnWOX Nanoparticles for Depletion of Endogenous GSH and Enhanced Sonodynamic Cancer Therapy.

Sonodynamic therapy (SDT) triggered by ultrasound (US) has attracted increasing attention owing to its abilities to overcome critical limitations including low tissue-penetration depth and phototoxicity in photodynamic therapy. Herein, the design of a new type of sonosensitizer is revealed, namely, ultrasmall oxygen-deficient bimetallic oxide MnWOX nanoparticles, for multimodal imaging-guided enhanced SDT against cancer. As-made MnWOX nanoparticles with poly(ethylene glycol) (PEG) modification show high physiological stability and biocompatibility. Interestingly, such MnWOX -PEG nanoparticles exhibit highly efficient US-triggered production of 1 O2 and •OH, higher than that of previously reported sonosensitizers (e.g., protoporphyrin IX and titanium dioxide), because the oxygen-deficient structure of MnWOX serves as an electron trap site to prevent electron-hole recombination. The glutathione depletion capability of MnWOX -PEG can also further favor SDT-triggered cancer cell killing. With efficient tumor homing as illustrated by computer tomography and magnetic resonance imaging, MnWOX -PEG enables effective destruction of mouse tumors under US stimulation. After accomplishing its therapeutic functions, MnWOX -PEG can be metabolized by the mouse body without any long-term toxicity. Herein, a new type of sono-sensitizing agent with high SDT efficacy, multimodal imaging functions, and rapid clearance is presented, an agent which is promising for noninvasive SDT cancer treatment.

Iridium nanocrystals encapsulated liposomes as near-infrared light controllable nanozymes for enhanced cancer radiotherapy.

Owing to the existence of severe tumor hypoxia and limited X-ray absorption of solid tumors, the therapeutic efficacy of radiotherapy is far from satisfactory. Herein, ultrasmall iridium nanocrystals (IrNCs) with homogeneous size distribution are successfully synthesized. The obtained IrNCs show catalase-like catalytic activity towards hydrogen peroxide (H2O2) with great temperatures/pH stability. As free IrNCs are prone to be toxified by thiol-containing biomolecules, we encapsulate as-prepared IrNCs within stealth liposomal carriers, obtaining Ir@liposome with well-protected catalytic activity in physiological conditions. By utilizing its efficient photothermal conversion ability, such Ir@liposome shows effective near-infrared-(NIR)-responsive catalytic activity towards H2O2 decomposition. As revealed by in vivo photoacoustic imaging, our Ir@liposome exhibits efficient passive tumor accumulation upon intravenous injection, and could efficiently decompose the tumor endogenous H2O2 into O2, particularly upon exposure to the NIR laser. As the results of relieved tumor hypoxia after such treatment and the radiosensitization capability of Ir as a high-Z element, greatly enhanced radio-therapeutic efficacy with Ir@liposome is then achieved. This work thus presents a unique type of NIR light controllable theranostic nanozyme based on noble metal nanocrystals as a nanoscale radiosensitizer with great performance in enhancing cancer radiotherapy.

Semiconducting polymer-based nanoparticles with strong absorbance in NIR-II window for in vivo photothermal therapy and photoacoustic imaging.

Near-infrared (NIR) light-induced photothermal therapy (PTT) has attracted much interest in recent years. In the NIR region, tissue penetration ability of the second biological near-infrared window (1000-1350 nm) is recognized to be stronger than that of the first window (650-950 nm). However, NIR light absorbers in the second NIR region (NIR-II) have been scant even though various NIR light absorbers in the first NIR region (NIR-I) have been widely explored. In this work, a thieno-isoindigo derivative-based semiconducting polymer, PBTPBF-BT, were formulated into PEGylated nanoparticles. The obtained nanoparticle NPPBTPBF-BT exhibited strong absorption in NIR-II region, inherent high photothermal conversion efficacy, and excellent photostability. The in vitro and in vivo PTT study employing 1064 nm laser in NIR-II window revealed that NPPBTPBF-BT could efficiently ablate tumor cell at a power density of 0.42 W/cm2 (the skin tolerance threshold value). Moreover, NPPBTPBF-BT with excellent photostability exhibited enhanced photoacoustic (PA) imaging of tumor in living mice, suggesting the great probability of using NPPBTPBF-BT for in vivo PA imaging-guided PTT in the NIR-II window.

Glucose & oxygen exhausting liposomes for combined cancer starvation and hypoxia-activated therapy.

Starvation therapy to slow down the tumor growth by cutting off its energy supply has been proposed to be an alternative therapeutic strategy for cancer treatment. Herein, glucose oxidase (GOx) is loaded into stealth liposomes and act as the glucose and oxygen elimination agent to trigger the conversion of glucose and oxygen into gluconic acid and H2O2. Such liposome-GOx after intravenous injection with effective tumor retention is able to exhaust glucose and oxygen within the tumor, producing cytotoxic H2O2 and enhancing hypoxia, as vividly visualized by non-invasive in vivo photoacoustic imaging. By further combination treatment with stealth liposomes loaded with banoxantrone dihydrochloride (AQ4N), a hypoxia-activated pro-drug, a synergistically enhanced tumor growth inhibition effect is achieved in the mouse model of 4T1 tumor. Hence, by combining starvation therapy and hypoxia-activated therapy tactfully utilizing liposomal nanocarriers to co-deliver both enzymes and prodrugs, an innovative strategy is presented in this study for effective cancer treatment.

One-pot synthesis of pH-responsive charge-switchable PEGylated nanoscale coordination polymers for improved cancer therapy.

Nanoscale coordination polymers (NCPs) are promising nanomedicine platforms featured with biodegradability and versatile functionalities. However, multi-step post-synthesis surface modification is usually required to functionalize as-made NCPs before their biomedical applications. Moreover, efforts are still required to design therapeutic NCPs responsive to the unique tumor microenvironment to achieve more specific and effective therapy. Herein, we uncover a simple yet general strategy to synthesize a series of polyethylene glycol (PEG) modified NCPs via a one-step method by adding poly-histidine-PEG co-polymer into the mixture of metal ions and organic ligands during NCPs formation. With NCPs consisting Ca2+/dicarboxylic cisplatin (IV) prodrug as the example, we show that such Ca/Pt(IV)@pHis-PEG NCPs are highly sensitive to pH changes. With slightly negative charges and compact structure under pH 7.4 during blood circulation, those NCPs exhibit efficient passive accumulation in the tumor, in which the reduced pH (c.a. 6.5) would trigger charge conversion and size expansion to enhance their tumor retention and cell internationalization. After cellular uptake, NCPs within cell endo-/lysosomes with further reduced pH would then lead to decomposition of those NCPs and thus drug release. Chemotherapy with Ca/Pt(IV)@pHis-PEG NCPs in our animal tumor model demonstrates great efficacy under low drug doses, and is found to be particularly effective towards solid tumors with reduced pH.