Metabolic Intervention Liposome Boosted Lung Cancer Radio‐Immunotherapy via Hypoxia Amelioration and PD‐L1 Restraint

Abstract

At present, radiotherapy (RT) still acquires limited success in clinical due to the lessened DNA damage under hypoxia and acquired immune tolerance owing to the amplified programmed death ligand‐1 (PD‐L1) expression. Incredibly, intracellular PD‐L1 expression depression is proven to better sensitize RT by inhibiting DNA damage repair. However, the disability of the clinically used antibodies in disrupting the extracellular PD‐L1function still limits the effectiveness of radio‐immunotherapy. Therefore, better PD‐L1 regulation strategies are still urgently needed to better sensitize radio‐immunotherapy. Hence, for this purpose, TPP‐LND is synthesized by linking mitochondrial‐targeted triphenylphosphine cations (TPP+) to the antineoplastic agent lonidamine (LND), which significantly reduces the dose needed for LND to induce effective oxidative phosphorylation inhibition (2 vs 300 µM). Then, TPP‐LND is wrapped with liposomes to form TPP‐LND@Lip nanoparticles. By doing this, TPP‐LND@Lip nanoparticles can sensitize RT by reversing the hypoxic microenvironment of tumors to generate more DNA damage and reducing the expression of PD‐L1 via enhancing the adenosine 5′‐monophosphate‐activated protein kinase activation. As expected, these well‐designed economical TPP‐LND@Lip nanoparticles are more effective than conventional anti‐PD‐L1 antibodies to some extent.

Mitochondrial Disruption Nanosystem Simultaneously Depressed Programmed Death Ligand-1 and Transforming Growth Factor-β to Overcome Photodynamic Immunotherapy Resistance

“…Currently, the significant efficacy of PD-L1 monoclonal antibodies in tumor treatment has been established. , However, the lack of tumor specificity in vivo resulted in a reduction of its efficacy against tumors while also presenting potential for organ toxicity and associated immunogenicity. To illustrate this, we employed rhodamine-B-labeled IgG as a surrogate for the spatiotemporal dynamics of the PD-L1 monoclonal antibody in vivo (Figure D,E).…”

“…TMX has become the widely used adjuvant drug for the treatment of estrogen-receptor-positive breast cancer, which has usefully saved numerous lives worldwide in the past 50 years. , But, the usage of this drug in clinical situations was still seriously limited, since some of its significant functions may be neglected, especially its potent PD-L1 and TGF-β depression capacity. ,, As reported just recently, amplified AMPK phosphorylation by OXPHOS inhibitors may induce the downregulation of PD-L1 and TGF-β in tumor cells, which then could result in the conversion of cold tumors to hot ones. , Given the proven fact that TMX could effectively inhibit OXPHOS via depressing the mitochondria complex I activity to induce AMPK phosphorylation, TMX may also possess immune-regulation capacity. , To confirm this prediction, we proved in this research that TMX could inhibit PD-L1 and TGF-β expression in tumors at a dosage of 30 μM in bladder tumor cells and breast cancer cells in vitro (Figure ). Interestingly enough, as reported previously, the combination of mitochondria-targeting agents with TMX could potentially reduce the required dosage of TMX for inducing mitochondria dysfunction, which may offer an ideal TMX derivate for highly effective PD-L1 and TGF-β depression. , Based on this, we designed the MHI-TMX chemical compound by combining a mitochondria-targeted heptamethine cyanine dye called MHI with TMX, an agent that inhibited mitochondrial complex I, which was further assembled with ALB to create MHI-TMX@ALB nanoparticles (Figure ).…”

“…The synthesis of TMX@ALB involved an alternative approach for incorporating a hydrophobic drug. 47,60 The average size of particles was determined using dynamic light scattering (DLS, Zetasizer Nano ZS ZEN3600). To confirm the structure of the MHI-TMX@Alb self-assembled nanoparticles, transmission electron microscopy (TEM, FEI Talos) was conducted.…”

Antitumor and Immunotherapy Sensitizing Effects of a Thermosensitive Liposome by Increasing Autophagosome Accumulation

“…As expected, the IR780/HCQ-Lip (+L) group showed effective inhibition of primary tumor growth and more effective inhibition of distal tumor growth, indicating that IR780/HCQ-Lip could enhance the systemic antitumor ability of mice (Figure B,C,E,F). Mature DC cells can present antigens to CD8 + T cells and stimulate them to differentiate into cytotoxic T lymphocytes (CTLs), thereby specifically killing tumor cell. − Therefore, the number of CD8 + T cells reflects the strength of antitumor immunity, we measured the amount of cytotoxic T lymphocytes (CD3 + CD8 + INF-γ) in the tumor. As shown in Figure G, IR780/HCQ-Lip treatment stimulated 2.07-fold CD8 + T cells (CD3 + CD8 + IFN-γ + ) recruitment compared to that of the IR780-Lip group.…”

Dual-targeting nanotheranostics for MRI-guided enhanced chemodynamic therapy of hepatoma via regulating the tumor microenvironment

“…In addition, nanomedicine-targeted modifications provide numerous benefits for tumor therapy, such as precise delivery, improved drug solubility and stability, drug protection, and evasion of tumor defenses. 38,39 In particular, NPs modified with a homologous tumor cell membrane (TCM) can confer excellent targeting ability, longer circulation time, immune escape, and homologous adhesion. 40–42 Therefore, we hypothesized that a nanosystem modified by a TCM after compounding Fe 3 O 4 with MnO 2 would have dual targeting effects ( i.e.…”