Hemoglobin-mediated biomimetic synthesis of paramagnetic O₂-evolving theranostic nanoprobes for MR imaging-guided enhanced photodynamic therapy of tumor

Abstract

The hypoxic microenvironment in solid tumors severely limits the efficacy of photodynamic therapy (PDT). Therefore, the development of nanocarriers co-loaded with photosensitizers and oxygen, together with imaging guidance ability, is of great significance in cancer therapy. However, previously reported synthetic methods for these multi-functional probes are complicated, and the raw materials used are toxic. Methods: Herein, the human endogenous protein, hemoglobin (Hb), was used for the simultaneous biomimetic synthesis of Gd-based nanostructures and co-loading of Chlorine e6 (Ce6) and oxygen for alleviating the hypoxic environment of tumors and accomplishing magnetic resonance imaging (MRI)-guided enhanced PDT. The Gd@Hb Ce6-PEG nanoprobes were synthesized via a green and protein biomimetic approach. The physicochemical properties, including relaxivity, oxygen-carrying/release capability, and PDT efficacy of Gd@Hb Ce6-PEG , were measured in vitro and in vivo on tumor-bearing mice after intravenous injection. Morphologic and functional MRI were carried out to evaluate the efficacy of PDT. Results: The results demonstrated the successful synthesis of compact Gd@Hb Ce6-PEG nanostructures with desired multi-functionalities. Following treatment with the nanoparticles, the embedded MR moiety was effective in lighting tumor lesions and guiding therapy. The oxygen-carrying capability of Hb after biomimetic synthesis was confirmed by spectroscopic analysis and oxygen detector in vitro . Further, tumor oxygenation for alleviating tumor hypoxia in vivo after intravenous injection of Gd@Hb Ce6-PEG was verified by photoacoustic imaging and immunofluorescence staining. The potent treatment efficacy of PDT on early-stage was observed by the morphologic and functional MR imaging. Importantly, rapid renal clearance of the particles was observed after treatment. Conclusion: In this study, by using a human endogenous protein, we demonstrated the biomimetic synthesis of multi-functional nanoprobes for simultaneous tumor oxygenation and imaging-guided enhanced PDT. The therapeutic efficacy could be quantitatively confirmed at 6 h post PDT with diffusion-weighted imaging (DWI).

Detection of Hypoxia in Cancer Models: Significance, Challenges, and Advances

“…The nanoprobes have been designed to respond to tumor acidosis, a common result of hypoxia, by triggering the release of incorporated contrast agents. Tumors derived from 4T1 breast cancer cells [ 97 ] and BxPC3 pancreatic cells [ 98 ] have been used to confirm the efficacy of MR-CA nanoprobes at detecting hypoxic regions. Although these methods require access to advanced and costly equipment, intratumoral hypoxia has been successfully detected and visualized in 3D.…”

Recent Advances in Strategies for Addressing Hypoxia in Tumor Photodynamic Therapy

“…For example, recently a paramagnetic nanostructure consisting of hemoglobin, Gd, and PEGylated chlorin e6, was prepared using a non-toxic hemoglobin-mediated biomimetic synthesis method [ 168 ]. Interestingly, hemoglobin functioned as a biological template, stabilizer for the nanoparticle formation, and substrate for the loading of chlorin e6 in the synthesis process, and maintained its ability to bind and carry oxygen.…”

Biomimetic phototherapy in cancer treatment: from synthesis to application

“…Notably, the surface modification of the cell membrane can endow NPs with the ability to actively target diseased tissues. So far, enormous efforts have been devoted to applying membrane materials for delivering phototherapy agents for enhanced anti-tumor treatment, such as RBC membrane (Pei et al, 2018 ; Liu et al, 2018a , b ; Shi et al, 2020 ), cancer cell membrane (Li et al, 2017 ; Wang et al, 2020a , b ), PLTM (Ma et al, 2021 ), macrophage membrane (Liu et al, 2021 ), phagocyte membrane (Hu et al, 2020 ), MDSC membrane (Zhang et al, 2020a , b ), and fused membranes (Xu et al, 2021 ).…”