Acid-Activatable Versatile Micelleplexes for PD-L1 Blockade-Enhanced Cancer Photodynamic Immunotherapy

Abstract

Photodynamic therapy (PDT) has emerged as a promising clinical modality for cancer therapy due to its ability to initiate an antitumor immune response. However, PDT-mediated cancer immunotherapy is severely impaired by tumor-cell immunosuppression of host T cell antitumor activity through the programmed cell death 1 ligand (PD-L1) and programmed cell death receptor 1 (PD-1) (PD-L1-PD-1) immune checkpoint pathway. Here, we demonstrate that PDT-mediated cancer immunotherapy can be augmented by PD-L1 knockdown (KD) in tumor cells. We rationally designed a versatile micelleplex by integrating an acid-activatable cationic micelle, photosensitizer (PS), and small interfering RNA (siRNA). The micelleplex was inert at physiological pH conditions and activated only upon internalization in the acidic endocytic vesicles of tumor cells for fluorescence imaging and PDT. Compared to PDT alone, the combination of PDT and PD-L1 KD showed significantly enhanced efficacy for inhibiting tumor growth and distant metastasis in a B16-F10 melanoma xenograft tumor model. These results suggest that acid-activatable micelleplexes utilizing PDT-induced cancer immunotherapy are more effective when combined with siRNA-mediated PD-L1 blockade. This study could provide a general strategy for enhancing the therapy efficacy of photodynamic cancer therapy.

Strategies for optimizing the delivery to tumors of macrocyclic photosensitizers used in photodynamic therapy (PDT)

“…Much more is however expected from the nanotechnology side for the possibility of exploiting passive and active mechanisms of targeting the tumors and combining more drugs in well engineered nanoplatforms for the combination of PDT with other treatment modalities. In this context, particular attention should be given to combinations including immunotherapeutics able to potentiate the immunological response elicited by PDT producing systemic antitumor effects impacting also in metastasis located far from the primary tumor treated with PDT [161,163].…”

Advanced Nanotechnology Leading the Way to Multimodal Imaging‐Guided Precision Surgical Therapy

“…[263] Platforms designed for combinations of cancer immunotherapy and nonsurgical treatment were reviewed in detail by Nam and colleagues. [271][272][273][274][275][276][277][278] A recent study reported that the combination of PDT and autophagy inhibitor after resection of orthotopic xenograft osteosarcoma observed an enhanced antitumor effect by suppressing PD-L1 expression, which indicated the potential surgical application of photodynamic-immunotherapy to improve outcomes and longterm survivals. [264][265][266][267][268][269][270] The cascaded synergistic effects of photodynamic-immunotherapy can provide a promising strategy to inhibit both primary lesions and distant metastases, which can be hardly achieved by conventional PDT with limited immunologic effects.…”

Nanomedicine‐Based Immunotherapy for the Treatment of Cancer Metastasis

“…In order to elevate the intratumoral level of IL-12, Gou and co-workers designed a biodegradable nanoparticle composed of heparin-polyethyleneimine conjugate for tumor-targeted delivery of two plasmids encoding vesicular stomatitis virus matrix protein (VSVMP) and IL-12 ( Figure 3A). [121] Copyright 2016, American Chemical Society. In this case, the nanoparticle was dosed 3 d after intraperitoneal injection of CT-26 cancer cells, when immunosuppressive TME had not been fully established to inhibit the activity of recruited CTLs and NK cells.…”