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Engineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer.

ABSTRACT: Patients with primary and bone metastatic breast cancer have significantly reduced survival and life quality. Due to the poor drug delivery efficiency of anti-metastasis therapy and the limited response rate of immunotherapy for breast cancer, effective treatment remains a formidable challenge. In this work, engineered macrophages (Oxa(IV)@ZnPc@M) carrying nanomedicine containing oxaliplatin prodrug and photosensitizer are designed as near-infrared (NIR) light-activated drug vectors, aiming to achieve enhanced chemo/photo/immunotherapy of primary and bone metastatic tumors. Oxa(IV)@ZnPc@M exhibits an anti-tumor M1 phenotype polarization and can efficiently home to primary and bone metastatic tumors. Additionally, therapeutics inside Oxa(IV)@ZnPc@M undergo NIR triggered release, which can kill primary tumors via combined chemo-photodynamic therapy and induce immunogenic cell death simultaneously. Oxa(IV)@ZnPc@M combined with anti-PD-L1 can eliminate primary and bone metastatic tumors, activate tumor-specific antitumor immune response, and improve overall survival with limited systemic toxicity. Therefore, this all-in-one macrophage provides a treatment platform for effective therapy of primary and bone metastatic tumors.

SUBMITTER: Huang Y

PROVIDER: S-EPMC8280231 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Photodynamic therapy (PDT) is a treatment in which photoactive compounds delivered to cancerous tissues are excited with light and then transfer the absorbed energy to adjacent tissue oxygen molecules to generate toxic singlet oxygen (1O2). As 1O2 is produced only where light and photosensitizers (PSs) are combined, PDT holds promise as a minimally invasive, highly selective treatment for certain cancers. The practical application of PDT requires easily synthesized, water-soluble PSs that have low dark toxicities, high 1O2 quantum yields, and efficient absorption of 650-850 nm near-infrared (NIR) light, which deeply penetrates tissue. We recently developed a linear tetrapyrrole metal complex, Pd[DMBil1]-PEG750, that meets most of these criteria. This complex is remarkably effective as a PS for PDT against triple-negative breast cancer (TNBC) cells but, critically, it does not absorb NIR light, which is necessary to treat deeper tumors. To enable NIR activation, we synthesized a new derivative, Pd[DMBil1]-PEG5000-SH, which bears a thiol functionality that facilitates conjugation to NIR-absorbing gold nanoshells (NSs). Upon excitation with pulsed 800 nm light, NSs emit two-photon-induced photoluminescence spanning 500-700 nm, which can sensitize the attached PSs to initiate PDT. Additionally, NSs produce heat upon 800 nm irradiation, endowing the NS-PS conjugates with an auxiliary photothermal therapeutic (PTT) capability. Here, we demonstrate that NS-PS conjugates are potent mediators of NIR-activated tandem PDT/PTT against TNBC cells in vitro. We show that Pd[DMBil1]-PEG5000-SH retains the photophysical properties of the parent Pd[DMBil1] complex, and that NS-PS generate 1O2 under pulsed 800 nm irradiation, confirming activation of the PSs by photoluminescence emitted from NSs. TNBC cells readily internalize NS PS conjugates, which generate reactive oxygen species in the cells upon pulsed NIR irradiation to damage DNA and induce apoptosis. Together, these findings demonstrate that exploiting photoluminescent NSs as carriers of efficient Pd[DMBil1] PSs is an effective strategy to enable NIR light-activated tandem PDT/PTT.

Project description:The spatiotemporal stimulation of liposome-liposome or liposome-membrane fusion processes attracts growing interest as a means to mimic cell-cell interactions in nature and for using these processes for biomedical applications. We report the use of o-nitrobenzyl phosphate functionalized-cholesterol tethered nucleic acid-modified liposomes as functional photoresponsive units for inducing, by NIR-irradiation, spatiotemporal liposome-liposome or liposome-membrane fusion processes. The liposomes are loaded with upconversion nanoparticles (UCNPs) and their NIR irradiation (? = 980 nm) yields luminescence at ? = 365 nm, providing a localized light-source to deprotect the o-nitrobenzyl phosphate groups and resulting in the fragmentation of the nucleic acid structures. In one system, the NIR-triggered fusion of two liposomes, L1 and L2, is exemplified. Liposome L1 is loaded with UCNPs and Tb3+ ions, and the liposome boundary is functionalized with a cholesterol-tethered, o-nitrobenzyl phosphate caged hairpin nucleic acid structure. Liposome L2 is loaded with 2,6-pyridinedicarboxylic acid, DPA, and its boundary is modified with a cholesterol-tethered nucleic acid, complementary to a part of the caged hairpin, associated with L1. NIR-irradiation of the L1/L2 mixture resulted in the photocleavage of the hairpin structure, associated with L1, and the resulting fragmented nucleic acid associated with L1 hybridized with the nucleic acid linked to L2, leading to the fusion of the two liposomes. The fusion process was followed by dynamic light scattering, and by monitoring the fluorescence of the Tb3+-DPA complex generated upon the fusion of the liposomes and their exchange of contents (fusion efficiency 30%). In a second system, the fusion of the liposomes L1, loaded with UCNPs and doxorubicin (DOX), with HeLa cancer cells functionalized with nucleic acid tethers, complementary to the hairpin units associated with the boundary of L1, and linked to the MUC-1 receptor sites associated with the HeLa cells, through a MUC-1 aptamer unit is exemplified. The effect of DOX-loaded L1/HeLa cell fusion on the cytotoxicity towards HeLa cells is addressed. The NIR UCNP-stimulated cleavage of the o-nitrobenzyl phosphate caged hairpin units associated with L1 leads to the fragmentation of the hairpin units and the resulting nucleic acid tethers hybridize with the nucleic acid-modified HeLa cells, resulting in the liposome-HeLa cell fusion and the release of DOX into the HeLa cells. Selective spatiotemporal cytotoxicity towards HeLa cells is demonstrated (ca. 40% cell killing within two days). The study presents a comprehensive stepwise set of experiments directed towards the development of NIR-driven liposome-liposome or liposome-membrane fusion processes.

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Engineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer.

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