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It is our goal in this review not only to protect the array of ligand-targeted siRNA NPs, but also to indicate possible flaws in the particular study and alert the reader to the potential of the ligand, independent of the efficacy of the NP. tumors is due to the enhanced permeation and retention (EPR) effect. The EPR effect is usually thought to result from a combination of leakiness of tumor blood vessels resulting in flux of NPs from your blood into the tumor tissue and reduced numbers of lymphatic vessels in tumors associated with decreased drainage of NPs and occurs despite a higher interstitial pressure within the tumor. Notably, several rarely used therapies, such as nitroglycerin, may enhance the EPR effect and augment accumulation of NPs within tumors [2, 3]. When NPs Rifaximin (Xifaxan) have diameters less than ~10?nm, they are rapidly secreted by the kidneys and the effect of EPR is greatly reduced [4]. Moreover, NPs with very short half-life and/or with their nonspecific binding may accumulate within the tumor to a greater extent, if the Rifaximin (Xifaxan) EPR effect is usually enhanced by pegylation of particles. By prolonging blood circulation (plasma half-life) of the NP and reducing nonspecific binding, pegylation may also enable accumulation of ligand-nanoparticle conjugates in tumors above the EPR effect. Building on accumulation of NPs in tumors from the EPR effect, researchers have sought to increase their tumor delivery by coating the particles with tumor-localizing ligands. The mechanism by which ligands increase the antitumor efficacy of their cargo (in our case siRNA) is usually somewhat controversial. Most investigators have decided that increased efficacy of targeted ligand-siRNA NPs is due to enhanced binding to the tumor surface marker and accumulation of NPs in the tumor compared to that in nontargeted tissues. Some investigators, however, have found that accumulation of targeted and nontargeted NPs within tumors was comparable and found that increased efficacy of the targeted NP was due to enhanced receptor-mediated endocytosis and increased intracellular localization of the siRNA therapeutic [5]. Most likely, both mechanisms have important functions in ligand- targeted therapy, improving efficacy, and depend around Rabbit Polyclonal to SLC6A8 the delivery vehicle, the target of the ligand, and strategy used in making the ligand (i.e., aptamer, peptide, or antibody). In this review, we describe various strategies that have been developed for ligand-siRNA therapeutics to increase their selectivity toward tumors (Physique 1). Decorating the NP with Rifaximin (Xifaxan) the ligand together with PEG shell, however, does not adequately describe how ligand molecules may affect stability of the core particle. As investigators have reported, ligand molecules and their specific linkages to the NP may significantly influence release of siRNA and their efficacy [6]. Open in a separate windows Physique 1 Schematic overview of the different ligands and core particles that target tumors. An array of core particles and ligands has been used to carry siRNA which inhibit oncogenes or induce apoptosis of tumor cells. In addition, the efficacy (or lack thereof) of the siRNA-NP may interfere with the impartial evaluation of ligand-directed therapies. It is our goal in this review not only to cover the array of ligand-targeted siRNA NPs, but also to indicate possible flaws in the particular study and alert the reader to the potential of the ligand, independent of the efficacy of the NP. This determination will be particularly important in cases in which there has been Rifaximin (Xifaxan) reduced antitumor efficacy with the nanoparticle. 2. Ligands Targeting Tumor Cells and Vessels Ligands targeting tumor cells and their angiogenic vessels have primarily been peptides isolated by the phage display method (Table 1) (Physique 2) Rifaximin (Xifaxan) [7C15] (see review by [16]). Since tumor cells and angiogenic blood vessels often have comparable cell surface receptors, ligands can have dual targeting capabilities for both tumor vasculature and tumor cells. When this is the case, siRNA therapeutic agents.

chemotherapy alone.Govindan et al [146]NivolumabCisplatin and gemcitabine or pemetrexed; paclitaxel and carboplatinAdvanced NSCLCNivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies) Q3W for 4 cycles, followed by nivolumab monotherapy every 3 weeksThe combination regimen, especially the paclitaxel-carboplatin plus nivolumab 5 mg/kg, showed encouraging activity (2-year OS rate: 62%). not yet determined. Future studies should focus on these issues and WS3 help to develop the optimal combination regimen for each cancer. mutant CT26 colon cancer [62]. Despite its positive immunomodulatory effect in murine WS3 tumors, whether teniposide acts as an ICD inducer in human cancers remains elusive. Poly (ADP-ribose) polymerase inhibitors (PARPi), including olaparib and niraparib, inhibit DNA repair in homologous-recombination-deficient malignant cells, leading to synthetic lethality [96]. Such retention and accumulation of DNA damage can activate the cGAS-STING pathway and the subsequent type-I IFN response, as mentioned above. In line with this notion, the administration of olaparib to murine (encoding breast cancer type 1 susceptibility protein) -deficient TNBCs increased the CD8+ T cell abundance and activated antitumor immunity [72]. Despite PARPis generally eliciting antitumor efficacy in mutation status. Such increasing CTL abundance and intra-tumoral PD-L1 level potentiate the combined therapy of PARPi and ICBs [99]. As expected, a combination of niraparib plus pembrolizumab therapy showed promising synergistic antitumor activity in patients with TNBC or ovarian cancer [100, 101], despite the best treatment efficacy still being observed in patients with is silenced in most cancer cells, but is expressed in many normal cells, including lymphocytes; therefore, these medications were traditionally supposed to impair, rather than promote, antitumor immunity [106, 107]. Intriguingly, a recent study showed that GSDME-mediated pyroptosis acts as a form of ICD and effectively activated antitumor CD8+ T-cell immunity in murine melanoma [108]. The combination of B-Raf proto-oncogene, serine/threonine kinase (BRAF) and MAPK/ERK kinase (MEK) inhibitors, the frontline care for sunitinib in patients with advanced RCC (median PFS: 13.8 em vs /em . 8.4 months). Grade 3 treatment-related adverse events were comparable between the two groups.Motzer et al [10]CamrelizumabDecitabineRelapsed or refractory classic Hodgkin LymphomaCamrelizumab 200 mg monotherapy Q3W or decitabine 10 mg/d, days 1 to 5 plus camrelizumab 200 mg, day 8 Q3WThe addition of decitabine to camrelizumab significantly improved the tumor response in patients who were clinically na?ve to the PD-1 blockade.Nie et al [140]Gemcitabine and cisplatinRecurrent or metastatic nasopharyngeal carcinomaCamrelizumab 200 mg (day 1), gemcitabine 1 g/m2 (days 1 and 8), and cisplatin 80 mg/m2 (day 1) every 3 weeks followed by camrelizumab 200 mg maintenance once every 3 weeksThe combination of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile and promising preliminary antitumor activity in treatment-naive patients.Fang et al [141]DurvalumabPlatinum and etoposideExtensive-stage SCLCEtoposide 80C100 mg/m2 on days 1 to 3 + carboplatin AUC=5/6 or 75C80 mg/m2 + durvalumab 1500 mg, Q3W for 4 cycles + maintenance durvalumab 1500 mg Q4W vs. platinum Akap7 and etoposide for 6 cyclesDurvalumab plus platinum-etoposide significantly improved OS in patients with ES-SCLC em vs /em . chemotherapy alone (median OS: 13.0 em vs /em . 10.3 months). The safety of the two regimens was similar.Paz-Ares et al [142]IpilimumabCarboplatin and etoposideExtensive-stage SCLCCarboplatin AUC=6 + etoposide 120 mg/m2 day 1 and 100 mg day 2 and 3, Q3W up to 6 cycles + ipilimumab 10 mg/kg day 1 of chemotherapy cycles 3-6 and then once every 12-weeks from week 30The combination therapy showed a beneficial effect in extensive-stage SCLC; however, the toxicity was also significant. Sequential immunotherapy after chemotherapy might be a more feasible approach.Arriola WS3 et al [143]Platinum and etoposideExtensive-stage SCLCInduction: etoposide 100 mg/m2 on days 1 to 3 + carboplatin AUC=5 or cisplatin 75 mg/m2 day 1 Q3W for 4 cycles + 4 cycles of ipilimumab or placebo 10 mg/kg Q3W from cycle 3 of chemotherapy; Maintenance: ipilimumab or placebo 10 mg/kg Q12W The combination of ipilimumab and chemotherapy did not prolong the OS of patients with extensive-stage SCLC.Reck et al [144]Paclitaxel and carboplatinextensive-disease SCLCInduction (Q3W for a maximum of WS3 18 weeks): carboplatin AUC=6 + paclitaxel 175 mg/m2 vs. concurrent ipilimumab (4 cycles of ipilimumab 10 mg/kg + paclitaxel + carboplatin followed by 2 cycles of placebo + paclitaxel + carboplatin) vs. phased ipilimumab (4 cycles of placebo + paclitaxel + carboplatin followed by 2 cycles of ipilimumab + paclitaxel + carboplatin); Maintenance: ipilimumab for phased- and concurrent-ipilimumab arms) or placebo (control arm) Q12W Phased ipilimumab, but not concurrent ipilimumab, significantly prolonged immune-related PFS em vs /em . chemotherapy alone. A numerical, but not significant, improvement of OS was also observed.Reck et al [145]Advanced squamous NSCLCInduction: carboplatin.