Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions.

Recent Advances on Reactive Oxygen Species-Responsive Delivery and Diagnosis System.

Chemodynamic therapy (CDT), a novel cancer therapeutic strategy defined as the treatment using Fenton or Fenton-like reaction to produce •OH in the tumor region, was first proposed by Bu, Shi, and co-workers in 2016. Recently, with the rapid development of Fenton and Fenton-like nanomaterials, CDT has attracted tremendous attention because of its unique advantages: 1) It is tumor-selective with low side effects; 2) the CDT process does not depend on external field stimulation; 3) it can modulate the hypoxic and immunosuppressive tumor microenvironment; 4) the treatment cost of CDT is low. In addition to the Fe-involved CDT strategies, the Fenton-like reaction-mediated CDT strategies have also been proposed, which are based on many other metal elements including copper, manganese, cobalt, titanium, vanadium, palladium, silver, molybdenum, ruthenium, tungsten, cerium, and zinc. Moreover, CDT has been combined with other therapies like chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy for achieving enhanced anticancer effects. Besides, there have also been studies that extend the application of CDT to the antibacterial field. This review introduces the latest advancements in the nanomaterials-involved CDT from 2018 to the present and proposes the current limitations as well as future research directions in the related field.

Chemodynamic Therapy via Fenton and Fenton-Like Nanomaterials: Strategies and Recent Advances.

The crosstalk between tumor and stroma cells is a central scenario in the tumor microenvironment (TME). While the predominant effect of tumor cells on immune cells is establishing an immunosuppressive context, tumor cell death at certain conditions will boost antitumor immunity. Herein, we report a rationally designed tumor specific enhanced oxidative stress polymer conjugate (TSEOP) for boosting antitumor immunity. The TSEOP is prepared by Passerini reaction between cinnamaldehyde (CA), 4-formylbenzeneboronic acid pinacol ester, and 5-isocyanopent-1-yne, followed by azide-alkyne click reaction with poly(l-glutamic acid)-graft-poly(ethylene glycol) monomethyl ether (PLG-g-mPEG). Under tumor stimuli condition, CA and quinone methide (QM) are quickly generated, which cooperatively induce strong oxidative stress, immunogenic tumor cell death (ICD), and activation of antigen presenting cells. In vivo studies show that the TSEOP treatment boosts tumor-specific antitumor immunity and eradicates both murine colorectal and breast tumors. This study should be inspirational for designing polymers as immunotherapeutics in cancer therapy.

Rationally Designed Polymer Conjugate for Tumor-Specific Amplification of Oxidative Stress and Boosting Antitumor Immunity.

The combination of chemotherapy and photodynamic therapy (PDT) has promising potential in the synergistic treatment of cancer. However, chemotherapy and photodynamic synergistic therapy are impeded by uncontrolled chemotherapeutics release behavior, targeting deficiencies, and hypoxia-associated poor PDT efficacy in solid tumors. Here, a platinum nanozyme (PtNP) loaded reactive oxygen species (ROS)-responsive prodrug nanoparticle (CPT-TK-HPPH/Pt NP) is created to overcome these limitations. The ROS-responsive prodrug consists of a thioketal bond linked with camptothecin (CPT) and photosensitizer-2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH). The PtNP in CPT-TK-HPPH/Pt NP can efficiently catalyze the decomposition of hydrogen peroxide (H2O2) into oxygen to relieve hypoxia. The production of oxygen can satisfy the consumption of HPPH under 660 nm laser irradiation to attain the on-demand release of CPT and ensure enhanced photodynamic therapy. As a tumor diagnosis agent, the results of photoacoustic imaging and fluorescence imaging for CPT-TK-HPPH/Pt NP exhibit desirable long circulation and enhanced in vivo targeting. CPT-TK-HPPH/Pt NPs effectively inhibit tumor proliferation and growth in vitro and in vivo. CPT-TK-HPPH/Pt NP, with its excellent ROS-responsive drug release behavior and enhanced PDT efficiency can serve as a new cancer theranostic agent, and will further promote the research of chemophotodynamic synergistic cancer therapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/advs.202001853

Polymeric Nanoparticles with ROS‐Responsive Prodrug and Platinum Nanozyme for Enhanced Chemophotodynamic Therapy of Colon Cancer

Stimulator of interferon genes (STING) activation by STING agonists has been recognized as one of important immunotherapy strategies. However, immunosuppressive tumor microenvironment always hinders the therapeutic efficacy of cancer immunotherapy. Herein, ferrocene-containing polymersome nanoreactors are engineered by co-loading glucose oxidase (GOD) and STING agonist, symmetry-linked amidobenzimidazole (DiABZI), for enhanced STING activation and combination chemodynamic-immunotherapy. After intravenous injection, the polymersomes can accumulate in tumor tissues. The tumor acidity-triggered polymersome membrane permeability allows the entrance of tumoral glucose and oxygen for H2O2 production by GOD, which is further transformed into hydroxyl radicals (•OH) under the catalysis of ferrocene moieties. Chemodynamic therapy (CDT) based on •OH can induce efficient cellular apoptosis and release of fragmented DNA and tumor-associated antigens to promote endogenous STING activation and reverse immunosuppressive tumor microenvironment. Simultaneously, pH-responsive release of DiABZI activates STING pathway to elicit antitumor immune responses. Therefore, DiABZI and CDT synergistically enhance the antitumor immunity via combination chemodynamic-immunotherapy. The primary tumors are completely ablated and the growth of distant tumors that are established after treatment is also suppressed efficiently. The polymersome nanoreactor-mediated chemodynamic-immunotherapy represents a promising treatment strategy toward primary solid and metastatic tumors.

Polymersome Nanoreactor-Mediated Combination Chemodynamic-Immunotherapy via ROS Production and Enhanced STING Activation

Hypoxia-Responsive Polyprodrug Nanocarriers for Near-Infrared Light-Boosted Photodynamic Chemotherapy.

Photodynamic therapy (PDT) of cancers is seriously restricted by tumor hypoxia. In addition to the intrinsic hypoxic microenvironment, continuous photoirradiation further aggravates intratumoral hypoxia, thereby reducing the PDT effect significantly. Oxygen-independent PDT is recognized as an efficient approach to overcome this issue. Herein, singlet oxygen (1 O2 )-stored covalent organic framework (COF) nanoparticles loading the near-infrared (NIR) dye cypate, which realize oxygen-independent 1 O2 production for concurrent photothermal therapy (PTT) and PDT under NIR irradiation, are presented. The cypate-loading COF nanoparticles are prepared by using the photosensitizers and 1 O2 -stored molecules via formation of Schiff base bonds, followed by coverage of poly(vinyl pyrrolidone). The COF nanoparticles significantly improve the photostability and photothermal conversion efficiency of cypate by protecting them from photodegradation under NIR irradiation. Upon 660 nm laser irradiation, 1 O2 is produced by the photosensitizer motifs and is successfully stored by the 1 O2 -stored moieties. After intravenous injection and tumor accumulation, the COF nanoparticles can generate heat quickly upon 808 nm irradiation which induces the efficient release of the stored 1 O2 to ablate tumors via O2 -independent concurrent PTT/PDT. Accordingly, the COF nanocarriers of 1 O2 provide a paradigm to develop O2 -independent concurrent PTT/PDT for precise cancer treatment upon NIR irradiation.

Covalent Organic Framework Nanocarriers of Singlet Oxygen for Oxygen-Independent Concurrent Photothermal/Photodynamic Therapy to Ablate Hypoxic Tumors.

Drug resistance of cisplatin significantly limits its therapeutic efficacy in clinical applications against different cancers. Herein, we develop a novel strategy to overcome cisplatin drug resistance through sensitizing cisplatin-resistant human lung cancer cells (A549R) under amplified oxidative stress using a vesicular nanoreactor for simultaneous cisplatin delivery and H2O2 generation. We engineer the nanoreactor by the self-assembly of the amphiphilic diblock copolymers to co-deliver glucose oxidase (GOD) and cisplatin (Cis) (Cis/GOD@Bz-V). Cis/GOD@Bz-V was rationally designed to stay impermeable during blood circulation while mild acidity (pH 6.5-6.8) can activate its molecular-weight selective membrane permeability and release cisplatin locally. Diffusion of small molecules such as oxygen and glucose across the membranes can induce the in situ generation of superfluous H2O2 to promote cellular oxidative stress and sensitize A549R cells via activation of pro-apoptotic pathways. Cis/GOD@Bz-V nanoreactors could effectively kill A549R at pH 6.8 in the presence of glucose by the combination of H2O2 generation and cisplatin release. Growth of A549R xenograft tumors can be inhibited efficiently without the obvious toxic side effects via the systemic administration of Cis/GOD@Bz-V. Accordingly, the tumor acidity-activable cisplatin-loaded nanoreactors show great potential to enhance the therapeutic efficacy against cisplatin-resistant cancers.

Qinghao Zhou

Papers

Polymersome Nanoreactor-Mediated Combination Chemodynamic-Immunotherapy via ROS Production and Enhanced STING Activation

Hypoxia-Responsive Polyprodrug Nanocarriers for Near-Infrared Light-Boosted Photodynamic Chemotherapy.

Covalent Organic Framework Nanocarriers of Singlet Oxygen for Oxygen-Independent Concurrent Photothermal/Photodynamic Therapy to Ablate Hypoxic Tumors.

Cisplatin resistance reversal in lung cancer by tumor acidity-activable vesicular nanoreactors via tumor oxidative stress amplification

Tumor-dilated polymersome nanofactories for enhanced enzyme prodrug chemo-immunotherapy