Multifunctional Nanoplatform-Mediated Chemo-Photothermal Therapy Combines Immunogenic Cell Death with Checkpoint Blockade to Combat Triple-Negative Breast Cancer and Distant Metastasis

Abstract

Background Breast cancer has become the most common cancer in women. Compare with other subtypes of breast cancer, triple-negative breast cancer (TNBC) is more likely to relapse and metastasize. Highly effective therapeutic strategies are desperately needed to be explored. In this study, a multifunctional nanoplatform is expected to mediate chemo-photothermal therapy, which can combine immunogenic cell death with checkpoint blockade to combat TNBC and distant metastasis. Methods Poly (lactic acid-glycolic acid)-Poly (ethylene glycol) (PLGA-PEG) nanoparticles (NPs), a type of polymeric NPs, loaded with IR780, a near-infrared (NIR) dye, and doxorubicin (DOX) as the chemotherapeutic drug, were assembled by an improved double emulsification method (designated as IDNPs). The characterization, intracellular uptake, biosafety, photoacoustic (PA) imaging performance, and biodistribution of IDNPs were studied. Chemo-photothermal therapeutic effect and immunogenic cell death (ICD) were evaluated both in vitro and in vivo. The potency of chemo-photothermal therapy-triggered ICD in combination with anti-PD-1 immune checkpoint blockade (ICB) immunotherapy in eliciting immune response and treating distant tumors was further investigated. Results IR780 and DOX were successfully loaded into PLGA-PEG to form the IDNPs, with size of 243.87nm and Zeta potential of −6.25mV. The encapsulation efficiency of IR780 and DOX was 83.44% and 5.98%, respectively. IDNPs demonstrated remarkable on-site accumulation and PA imaging capability toward 4T1 TNBC models. Chemo-photothermal therapy demonstrated satisfactory therapeutic effects both in vitro and in vivo, and triggered ICD efficiently. ICD, in combination with anti-PD-1, provoked a systemic antitumor immune response against distant tumors. Conclusion Multifunctional IDNPs were successfully synthesized to mediate chemo-photothermal therapy, which combines immunogenic cell death with checkpoint blockade to combat TNBC and distant metastasis, showing great promise preclinically and clinically.

Clinical application of immunogenic cell death inducers in cancer immunotherapy: turning cold tumors hot

“…Researchers used nanotechnology to assemble DOX with near-infrared dyes to combine chemotherapy and photo-thermal therapy. This combination method significantly prolongs the median survival of breast cancer mouse models when compared to immunotherapy and ICD inducer alone, suggesting that this nanoparticle enhances antitumor immunotherapy ( Zhu et al, 2023 ). Therefore, they provide further nanotechnology application references for combination therapies to improve immunotherapy.…”

Nanoparticle-Mediated Immunotherapy in Triple-Negative Breast Cancer

“…47 Similarly, in the study of Wang et al, poly(lactic acid)−glycol−poly(ethylene glycol) nanoparticles were assembled by a modified double emulsification method using IR780 as the carrier and DOX as a chemotherapeutic drug. 52 Besides chemotherapy, nanoparticles combined with PTT and immune adjuvants can enhance PTT-induced ICD. For instance, Revuri et al synthesized an injectable multimanganese dioxide F127/hyaluronic acid (HA)-based hydrogel containing melamine nanoparticles and the TLR7 agonist resiquimod (R848).…”

“…105 Zhu et al designed PLGA−PEG NPs. 52 Poly(b-amino esters) (PBAEs) are applied to facilitate the gene delivery. Deng et al designed CRISPR-Cas9 plasmid to target Cdk5 gene.…”

“…For example, Liu et al designed magnetic nanosystems loaded with the NIR photothermal agents IR780 and DOX . Similarly, in the study of Wang et al, poly­(lactic acid)–glycol–poly­(ethylene glycol) nanoparticles were assembled by a modified double emulsification method using IR780 as the carrier and DOX as a chemotherapeutic drug …”

“…Liu et al designed two NPs encapsulated with imiquimod and paclitaxel, respectively modified by tannic acid in order to actively target lymph node conduits . Zhu et al designed PLGA–PEG NPs …”