MOFs-Based Nanoagents Enable Sequential Damage to Cancer-Associated Fibroblast and Tumor Cells for Phototriggered Tumor Microenvironment Regulation.

A composite nanoagent capable of phototriggered tumor microenvironment (TME) regulation is developed based on copper (II) metal-organic frameworks (MOFs) with encapsulation of blebbistatin (Bb) and surface modification of fibroblast activation protein-αtargeted peptide (Tp). Tp enables active targeting of the nanoagents to cancer-associated fibroblast (CAF) while near-infrared light triggers Cu2+ -to-Cu+ photoreduction in MOFs, which brings about the collapse of MOFs and the release of Bb and Cu+ . Bb mediates photogeneration of hydroxyl radicals (•OH) and therefore inhibits extracellular matrix production by inducing CAF apoptosis, which facilitates the penetration of nanoagent to deep tumor tissue. The dual-channel generation of •OH based on Bb and the Cu+ species, via distinct mechanisms, synergistically reinforces oxidative stress in TME capable of inducing immunogenic cell death, which activates the antitumor immune response and therefore reverses the immunosuppressive TME. The synergistic antitumor phototherapy efficacy of such a type of nanoagent based on the abovementioned TME remodeling is unequivocally verified in a cell-derived tumor xenograft model.

Generation of whole tumor cell vaccine for on-demand manipulation of immune responses against cancer under near-infrared laser irradiation.

The therapeutic efficacy of whole tumor cell vaccines (TCVs) is modest, which has delayed their translation into personalized immunotherapies in the clinic. Here, we develop a TCV platform based on photothermal nanoparticle-loaded tumor cells, which can be rationally applied to diverse tumor types to achieve on-demand boost of anti-tumor immune responses for inhibiting tumor growth. During the fabrication process, mild photothermal heating by near-infrared (NIR) laser irradiation induces the nanoparticle-bearing tumor cells to express heat shock proteins as endogenous adjuvants. After a single vaccination at the back of tumor-bearing mice, non-invasive NIR laser irradiation further induces mild hyperthermia at vaccination site, which promotes the recruitment, activation, and antigen presentation by dendritic cells. Using an indicator we term fluctuation of tumor growth rate, we determine appropriate irradiation regimens (including optimized irradiation intervals and times). This TCV platform enables on-demand NIR manipulation of immune responses, and we demonstrate potent therapeutic efficacy against six murine models that mimick a range of clinical scenarios, including a model based on humanized mice and patient-derived tumor xenografts.

Polymeric micelle-based nanoagents enable phototriggering combined chemotherapy and photothermal therapy with high sensitivity.

A new type of polymeric nanomicelle-based nanoagent (denoted as PT@MFH hereafter) capable of the highly sensitive release of the chemotherapeutic drug paclitaxel (PTX) upon exposure to a near-infrared (NIR) laser trigger was developed. Specifically, PTX and a photothermal polymer (T-DPPT) were encapsulated in the cavity of nanomicelles, which were constructed from an amphiphilic block copolymer (PCL-PEEP) with a lower critical solution temperature (LCST) of ∼54 °C. Owing to the unprecedented ability of the T-DPPT moiety to harvest near-infrared light, with a mass extinction coefficient at 808 nm of up to ∼80.8 L g-1 cm-1, and convert NIR light to heat, with a photothermal conversion efficiency (η) of up to ∼70%, local hyperthermia was promptly realized via irradiation from an 808 nm laser with extraordinarily low output power. This enabled remarkable contrast in the local temperature and drug release between the "silent" state (prior to phototriggering) and the "activated" state (after phototriggering). This NIR-light-activated local hyperthermia and drug release presented the basis for combined chemotherapy and photothermal therapy (PTT) in antitumor treatment and displayed superb therapeutic efficacy. This pattern together with the high spatial precision imparted by laser triggering jointly contributed to the maximum combined antitumor efficacy to the tumor, while exhibiting minimal side effects on the normal tissues, as preliminarily verified in the in vivo experiment regarding the ability of PT@MFH to efficiently inhibit tumor growth in tumor-bearing model mice.

Cell Membrane Camouflaged Hydrophobic Drug Nanoflake Sandwiched with Photosensitizer for Orchestration of Chemo-Photothermal Combination Therapy.

Many candidate anticancer drugs have suffered from their intrinsic hydrophobicity, which poses several obstacles for clinical application. To overcome this challenge and further improve the performance, herein a nanocrystal-based biomimetic formulation with a sandwich structure is developed. As the core, flake shaped nanocrystals (NCs) with high loading of the hydrophobic drug hydroxycamptothecin (HCPT) are synthesized via a mild nanoprecipitation process by exploring the template effect of serum albumin. Meanwhile, the camouflaged cancer cell membrane (CM) composed of plentiful membrane proteins endows the NCs with homotypic targeting capacity at tumor sites. In addition, the photosensitizer indocyanine green sandwiched between NCs and CM not only converts near infrared light to heat for photothermal treatment but also improves the dissolution of HCPT NCs for chemotherapy. These features corporately achieve the orchestration of chemo-photothermal combination therapy and completely inhibit tumor growth with few adverse effects, showing promise as a new modality for the utilization of hydrophobic drugs to treat cancer.

Bioinspired peptosomes with programmed stimuli-responses for sequential drug release and high-performance anticancer therapy.

Combination therapy with enhanced therapeutic and antimetastatic efficacy has become promising for cancer treatment. There is an urgent need to design a co-delivery system to sequentially release the drug pair at desired locations that can increase the intra-tumoral drug concentration and reduce the side effects. Inspired by virus architecture and function, herein, we developed a peptosome (PS)-based co-delivery system, PePm/PS/Curcumin (Cur), for the sequential release of the therapeutic peptide Pe and chemodrug Cur. PS was formed by the self-assembly of amphiphilic α-lactalbumin peptides obtained from enzymatic partial hydrolysis. Then, PS was self-cross-linked with disulfide bonds utilizing their endogenous thiol groups. The system is responsive to multiple tumor microenvironments and releases the drugs at specific tumor locations. First, after PS accumulation in tumor tissue via the EPR effect, the linkage peptide Pm in PS can be cleaved by matrix metalloproteinases (MMP) enzymatic hydrolysis. Pe can stay on the cell surface and antagonize the ErbB-2 receptor expression on the tumor cells. Moreover, the positively charged nature of remaining Mal-PS/Cur facilitates tumor cell internalization and induces a subsequent proton-sponge effect for lysosomal escape. Finally, Cur is released in the cytoplasm via a reduction-induced PS disassembly due to the high level of intracellular GSH. Both the in vitro and in vivo results exhibited an enhanced antitumor and antimetastatic efficacy of this system.