Immune/Hypoxic Tumor Microenvironment Regulation-Enhanced Photodynamic Treatment Realized by pH-Responsive Phase Transition-Targeting Nanobubbles

Abstract

Due to a special pathological type of triple-negative breast cancer (TNBC) and the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her 2), targeted therapies are not effective. The lack of effective treatment drugs and insensitivity to the current single-treatment methods are the biggest problems that we face with the TNBC treatment. Therefore, new strategies to achieve selective treatment and further visual efficacy evaluation will be powerful tools against TNBC. Herein, a novel tumortargeted nanosized ultrasound contrast nanobubble loaded with chlorin e6 (Ce6), metformin (MET), and perfluorohexane (PFH) and covalently connected to the anti-PD-L1 peptide ( D PPA-1) in the outer shell was fabricated. When accumulated in acidic tumor tissues, poly(ethylene glycol) (PEG) ligands detach, and D PPA-1 is exposed for programmed death-ligand 1 (PD-L1) targeting and blocking. The released metformin can relieve hypoxia by inhibiting mitochondrial complex I in the tumor microenvironment (TME) and enhance the therapeutic efficacy of Ce6 while synergizing with D PPA-1 by reducing PD-L1 expression. More significantly, photodynamic therapy (PDT) using multifunctional tumor-targeted nanosized ultrasound contrast agents (PD-L1targeted pH-sensitive chlorin e6 (Ce6) and metformin (MET) drug-loaded phase transitional nanoparticles (Ce6/MET NPs-D PPA-1)) combined with PD-L1 checkpoint blocking can not only reduce tumor-mediated immunosuppression but also produce strong antitumor immunity. This finding provides a new idea for constructing multifunctional TNBC therapeutic nanoagents.

Exploring chitosan-shelled nanobubbles to improve HER2 + immunotherapy via dendritic cell targeting

“…For example, multiple combined anticancer treatments have been developed using nanobubbles loaded with sonosensitizers and immune checkpoint inhibitors. Antitumor immunity has been markedly improved with NB formulations via the maturation of dendritic cells and the activation of CD8 + cytotoxic T cells both in vitro and in vivo [ 51 – 53 ]. In this work, chitosan-shelled perfluoropentane-cored NBs that are functionalized with either anti-CD11c or anti-CD1a monoclonal antibodies have been purposely designed for targeted cancer vaccination.…”

“…Nanobubbles have recently been investigated as a means to activate immune systems [ 51 – 53 ]. For example, multiple combined anticancer treatments have been developed using nanobubbles loaded with sonosensitizers and immune checkpoint inhibitors.…”

Recent Advances in Strategies for Addressing Hypoxia in Tumor Photodynamic Therapy

“…Although tumors acquire energy predominantly via the “Warburg effect” [ 59 ], seriously accelerated OXPHOS was still observed in considerable malignant cell lines during tumorigenesis, development, and metastasis [ 60 , 61 ]. Consequently, diverse mitochondria respiratory chain inhibitors, including α-tocopherol succinate [ 62 ], papaverine [ 63 ], atovaquone [ 64 , 65 , 66 , 67 , 68 ], tamoxifen [ 69 , 70 ], metformin [ 71 , 72 , 73 , 74 , 75 , 76 , 77 ], and nitric oxide (NO) [ 78 , 79 , 80 , 81 ], have been used for reducing oxygen consumption and increasing PDT efficiency. For example, a nanoplatform was prepared through incorporating L-Arginine and a photosensitizer chlorin e6 with poly-lactic-co-glycolic acid (PLGA) ( Figure 6 ) [ 79 ].…”

Recent advances in the targeted delivery of paclitaxel nanomedicine for cancer therapy

“…The results showed that in contrast mode and fluorescence imaging, the nanobubbles had high gray-scale intensity and their ability to aggregate also increased. 124 To conclude their findings, an A10-3.2 aptamer and loaded PTX-PLGA multifunctional theranostic agent was synthesized for the ultrasound imaging of cancer, which was also used as therapy. 125 D. Le Broc-Ryckewaert et al formulated nanoparticles loaded with paclitaxel with a size in the range of 49–95 nm together with charged surfaces, which were synthesized without the use of any surfactant or detergent.…”