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.

Perfluorocarbon nanodroplets stabilized with cisplatin-prodrug-constructed lipids enable efficient tumor oxygenation and chemo-radiotherapy of cancer.

Concurrent chemo-radiotherapy has been widely applied for the treatment of a wide range of cancers, but its therapeutic efficacy against most solid tumors is severely impaired by their intrinsic hypoxic microenvironments. Utilizing the high oxygen loading capacity of perfluoro-15-crown-5-ether (PFCE), herein, we prepare PFCE nanodroplets with cisplatin prodrug (cisPt(iv)) conjugated phospholipids and other commercial lipids as the stabilizer to enable tumor targeted oxygen shuttling. The obtained PFCE@cisPt(iv)-Lip shows high physiological stability and efficient oxygen loading capacity. As vividly visualized under an in vivo photoacoustic imaging system, tumors on the mice with intravenous injection of such PFCE@cisPt(iv)-Lip show effective tumor oxygenation. Together with X-ray exposure, such PFCE@cisPt(iv)-Lip upon intravenous injection could induce severe DNA damage of cells, thereby remarkably suppressing the tumor growth and significantly prolonging their survival time without causing obvious toxic side effects. This work highlights PFCE@cisPt(iv)-Lip as an adjuvant nanomedicine for enhanced chemo-radiotherapy of tumors by attenuating hostile tumor hypoxia, indicating its promising potential for future clinical translation ascribed to its straightforward synthesis and notable tumor growth inhibition at a safe dose.

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.

Surfactant-Stripped Micelles of Near Infrared Dye and Paclitaxel for Photoacoustic Imaging Guided Photothermal-Chemotherapy.

Development of nanoagents with strong near-infrared (NIR) absorbance and high photothermal conversion capacity is highly desired for efficient photoacoustic (PA) imaging and photothermal therapy of cancers. Herein, surfactant-stripped micelles with photostable near-infrared dye, ß-thiophene-fused BF2 -azadipyrromethene (aza-BDTP), are prepared in the presence of paclitaxel (PTX) with Pluronic F127 as the surfactant. Distinct from hydrophobic aza-BDTP and PTX, the obtained surfactant-stripped micelles aza-BDTP/PTX show excellent solubility, physiological stability, and high loading efficiencies for corresponding aza-BDTP and PTX. Intriguingly, these aza-BDTP/PTX micelles exhibit high photothermal conversion efficiency at 33.9%, significantly higher than 16.9% for bare aza-BDTP molecules, owing to aggregation-induced quenching of aza-BDTP fluorescence. With excellent photostability, aza-BDTP/PTX micelles appear to be a highly stable photoacoustic imaging probe and show efficient tumor accumulation as visualized under photoacoustic imaging upon intravenous injection. After being irradiated with a 785 nm laser, 4T1 tumors on the mice with systemic administration of aza-BDTP/PTX micelles are fully eradiated without any recurrences within 60 d. This work presents a general method for efficient encapsulation of hydrophobic aza-BDTP and PTX, obtaining hybrid aza-BDTP/PTX micelles as promising nanotheranostics for imaging guided cancer combination therapy.

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.

Near-infrared light activation of quenched liposomal Ce6 for synergistic cancer phototherapy with effective skin protection.

Current photodynamic therapy (PDT) is suffering from limited efficacy towards hypoxia tumors and severe post-treatment photo-toxicity such as light-induced skin damages. To make PDT more effective in cancer treatment while being patient-comfortable, herein, a hexylamine conjugated chlorin e6 (hCe6) as the photosensitizer together with a lipophilic near-infrared (NIR) dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) are co-encapsulated into polyethylene glycol (PEG) shelled liposomes. In the obtained DiR-hCe6-liposome, the photosensitizing effect of hCe6 is quenched by DiR via fluorescence resonance energy transfer (FRET). Interestingly, upon irradiation with a 785-nm NIR laser to photobleach DiR, both fluorescence and photodynamic effect of hCe6 in DiR-hCe6-liposome would be activated. Meanwhile, such NIR irradiation applied on tumors of mice with intravenous injection of DiR-hCe6-liposome could result in mild photothermal heating, which in turn would promote intra-tumor blood flow and relieve tumor hypoxia, contributing to the enhanced photodynamic tumor treatment. Importantly, compared to hCe6-loaded liposomes, DiR-hCe6-liposome without being activated by the 785-nm laser shows much lower skin photo-toxicity, demonstrating its great skin protection effect. This work demonstrates a promising yet simple strategy to prepare NIR-light-activatable photodynamic theranostics for synergistic cancer phototherapy, which is featured high specificity/efficacy in tumor treatment with minimal photo-toxicity towards the skin.

Theranostic Liposomes with Hypoxia-Activated Prodrug to Effectively Destruct Hypoxic Tumors Post-Photodynamic Therapy.

Photodynamic therapy (PDT), a noninvasive cancer therapeutic method triggered by light, would lead to severe tumor hypoxia after treatment. Utilizing a hypoxia-activated prodrug, AQ4N, which only shows toxicity to cancer cells under hypoxic environment, herein, a multipurpose liposome is prepared by encapsulating hydrophilic AQ4N and hydrophobic hexadecylamine conjugated chlorin e6 (hCe6), a photosensitizer, into its aqueous cavity and hydrophobic bilayer, respectively. After chelating a 64Cu isotope with Ce6, the obtained AQ4N-64Cu-hCe6-liposome is demonstrated to be an effective imaging probe for in vivo positron emission tomography, which together with in vivo fluorescence and photoacoustic imaging uncovers efficient passive homing of those liposomes after intravenous injection. After being irradiated with the 660 nm light-emitting diode light, the tumor bearing mice with injection of AQ4N-hCe6-liposome show severe tumor hypoxia, which in turn would trigger activation of AQ4N, and finally contributes to remarkably improved cancer treatment outcomes via sequential PDT and hypoxia-activated chemotherapy. This work highlights a liposome-based theranostic nanomedicine that could utilize tumor hypoxia, a side effect of PDT, to trigger chemotherapy, resulting in greatly improved efficacy compared to conventional cancer PDT.