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.

The acidic tumor microenvironment (TME), which mainly results from the high glycolytic rate of tumor cells, has been characterized as a hallmark of solid tumors and found to be a pivotal factor participating in tumor progression. Recently, due to the increasing understanding of the acidic TME, it has been shown that the acidic TME could be utilized as a multifaceted target during the design of various pH-responsive nanoscale theranostic platforms for the precise diagnosis and effective treatment of cancers. In this article, we will give a focused overview on the latest progress in utilizing this characteristic acidic TME as the target of nano-theranostics to enable cancer-specific imaging and therapy. The future perspectives in the development of acidic TME-targeting nanomedicine strategies will be discussed afterwards.

Effective and sustained tumor oxygenation has found practical significance in benefiting the treatment of solid tumors. In this study, fluorinated covalent organic polymers (COPs) are prepared by crosslinking the photosensitizer meso-5, 10, 15, 20-tetra (4-hydroxylphenyl) porphyrin (THPP) with perfluorosebacic acid (PFSEA) and poly(ethylene glycol) (PEG) via a one-pot esterification, to enable simultaneous tumor oxygenation and photodynamic treatment. Due to the presence of PFSEA, the obtained THPP pf -PEG shows efficient loading of perfluoro-15-crown-5-ether (PFCE), a type of perfluocarbon, and thereby molecular oxygen, both of which would significantly enhance the photodynamic effect of THPP. After chelating THPP with a radio-isotope, 99m Tc, both THPP pf -PEG and PFCE-loaded THPP pf -PEG (PFCE@THPP pf -PEG) can be vividly visualized under the single-photon emission computed tomography (SPECT) imaging, which uncovers efficient tumor accumulation of those COPs' post intravenous injection. Owing to the oxygen delivery ability of PFCE, efficient tumor oxygenation is observed for mice post injection of PFCE@THPP pf -PEG, which further leads to greatly enhanced photodynamic treatment of tumors. This study presents a unique type of multifunctional fluorinated COPs with well-defined composition, long blood circulation time, and sustained tumor oxygenation ability, showing great promises for potential clinical translation in photodynamic treatment of tumors.

Up to date, a large variety of liposomal nanodrugs have been explored for cancer nanomedicine, showing encouraging results in both preclinical animal experiments and clinical treatment of cancer patients. Herein, a phospholipid conjugated with a cisplatin prodrug is used as the major structure component of liposomes together with other commercial lipids via self-assembling. By doping with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR), a lipophilic dye with strong near infrared (NIR) absorbance and fl uorescence, the obtained DiR-Pt(IV)-liposome is found to be an effective probe for in vivo NIR fl uorescence and photoacoustic bimodal imaging. Attributing to its intrinsically doped cis -Pt(IV) prodrug, effi cient photothermal conversion ability, and excellent tumor homing ability, DiR-Pt(IV)-liposome confers greatly enhanced therapeutic outcomes in the combined photothermal-chemotherapy. Moreover, Pt(IV)-liposome is also demonstrated to be an effi cient carrier for both small hydrophilic molecules and proteins, which are encapsulated inside the water-cavity of liposomes, further demonstrating the versatile functions of this nanoplatform. This study develops a unique type of liposomal nanomedicine with a prodrug conjugated phospholipid as the major structure component. Such Pt(IV)-liposome is featured with advantages including precisely defi ned/easily tunable drug compositions, stealth-like pharmacokinetics, effi cient tumor passive uptake, and the capabilities to simultaneously load with various types of imaging or therapeutic agents.

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