CXCR4-targeted nitric oxide nanoparticles deliver PD-L1 siRNA for immunotherapy against glioblastoma

Glioblastoma multiforme (GBM) is one of the most aggressive malignant cancers of the central nervous system (CNS), representing 14.6% of all CNS tumors [1]. The current standard of care, consisting of maximal safe surgical resection followed by concomitant radiotherapy and chemotherapy, is often associated with low therapeutic efficacy and debilitating side effects [2]. In contrast to chemotherapy, which has a systemic cytotoxic mechanism of action, immunotherapy has emerged as a promising strategy to activate immune cells against tumor cells. Over the last decade, clinical trials evaluating various immunotherapies against GBM have improved both median overall survival (mOS) and overall survival (OS) [2]. Treatment with the immunotherapeutic modality immune checkpoint blockade (ICB) has improved antitumor responses in GBM at both the local and systemic levels [3]. However, the therapeutic benefit of ICB in GBM patients is moderate and limited [4,5].

Current ICB therapies rely on antibody-based competitive inhibition of immunosuppressive molecules. The local immunosuppressive effect of the GBM microenvironment has been attributed to receptors such as programmed cell death ligand-1 (PD-L1), which, when overexpressed on tumor cell surfaces, limit the activation of cytotoxic T cells and anticancer immunity. In a recent phase II trial, exogenous antibody-induced inhibition of PD-L1 binding produced a durable response in GBM patients [6]. However, in contrast to the substantial clinical outcomes achieved, immunotherapeutic stimulation to induce a lymphocytic response often induces adverse local and systemic immune reactions [7,8]. To negate these adverse events, siRNA-mediated cancer gene therapy was developed to achieve potent gene silencing and reduce unintended uptake in normal tissues by the addition of tumor-targeting ligands to therapeutic genetic cargoes [[9], [10], [11]]. Several studies have successfully implemented targeted strategies for tumor-specific silencing with siRNAs against immune checkpoints to improve T cell infiltration and function, leading to potent anticancer effects [[12], [13], [14], [15]].

Despite the potential of siRNA-mediated cancer gene therapy, there are obstacles that limit its therapeutic efficacy, such as poor cellular uptake, rapid degradation and clearance of siRNAs, and the blood–brain barrier (BBB), which blocks penetration by genetic cargoes. Thus, there is an urgent need to identify efficient and safe BBB-penetrating agents to augment siRNA delivery across the BBB for the treatment of GBM. Nitric oxide (NO) not only plays a role in vasodilation but also disrupts the BBB, thereby increasing BBB permeability. Several approaches have been developed to increase NO signaling and thus enhance drug delivery across the BBB. Coadministration of anticancer drugs and NO donors has been found to simultaneously induce tumor-selective BBB disruption and enhance drug accumulation in tumors in GBM, demonstrating improved efficacy over current therapeutic modalities [16]. In addition, several studies reported that sustained delivery of an NO donor modulated tumor vessels and enhanced drug penetration in tumors, resulting in an increased anticancer effect [17,18]. Based on these findings, we hypothesized that the modulation of tumor vessels and the regulation of BBB permeability by NO would facilitate the tumor penetration of therapeutic siRNAs in GBM.

With this in mind, we developed a novel NO-based siRNA delivery system that produced a safe and efficient anticancer effect in GBM. Dinitrosyl iron complexes (DNICs) have emerged as a novel type of prodrug for the controlled delivery of NO and NO-related biomedical applications. In particular, encapsulation of complex [Fe2(μ-SCH2CH3)2(NO)4] in a hydrophobic poly(lactic-co-glycolic acid) (PLGA) nanosphere was explored for the potential to modulate tumor vessels and enhance the effect of anticancer therapies [17]. In this study, incorporation of a carboxylic group in complex [Fe2(μ-SCH2CH2COOH)2(NO)4] (DNIC) exhibited the potential to facilitate its coprecipitation with a calcium phosphate (CaP)-based gene delivery system to augment the efficacy of cancer gene therapy. This nanoscale NO-based siRNA therapy was shown to be a highly efficient siRNA delivery vector in GBM and was composed of several features including (i) a pH stimulus-responsive CaP core, which triggered siRNA release and endosomal escape for gene silencing; (ii) CTCE9908, a C-X-C Motif Chemokine Receptor 4 (CXCR4) antagonist peptide that enhanced the intracellular uptake of nanoparticles (NPs) by cancer cells; and (iii) DNIC, an NO donor that perpetuated sustained release of NO from NPs to open the BBB and modulate tumor vessels, leading to high bioavailability of therapeutic siRNAs in GBM.

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