RESUMEN
Immune checkpoint blockade (ICB) therapies have had a tremendous impact on cancer therapy. However, most patients harbor a poorly immunogenic tumor microenvironment (TME), presenting overwhelming de novo refractoriness to ICB inhibitors. To address these challenges, combinatorial regimens that employ chemotherapies and immunostimulatory agents are urgently needed. Here, a combination chemoimmunotherapeutic nanosystem consisting of a polymeric monoconjugated gemcitabine (GEM) prodrug nanoparticle decorated with an anti-programmed cell death-ligand 1 (PD-L1) antibody (αPD-L1) on the surface and a stimulator of interferon genes (STING) agonist encapsulated inside is developed. Treatment with GEM nanoparticles upregulates PD-L1 expression in ICB-refractory tumors, resulting in augmented intratumor drug delivery in vivo and synergistic antitumor efficacy via activation of intratumor CD8+ T cell responses. Integration of a STING agonist into the αPD-L1-decorated GEM nanoparticles further improves response rates by transforming low-immunogenic tumors into inflamed tumors. Systemically administered triple-combination nanovesicles induce robust antitumor immunity, resulting in durable regression of established large tumors and a reduction in the metastatic burden, coincident with immunological memory against tumor rechallenge in multiple murine tumor models. These findings provide a design rationale for synchronizing STING agonists, PD-L1 antibodies, and chemotherapeutic prodrugs to generate a chemoimmunotherapeutic effect in treating ICB-nonresponsive tumors.
Asunto(s)
Neoplasias , Microambiente Tumoral , Humanos , Ratones , Animales , Antígeno B7-H1/metabolismo , Neoplasias/tratamiento farmacológico , Linfocitos T CD8-positivos , Inmunoterapia/métodos , GemcitabinaRESUMEN
Nanomedicines have achieved several successful clinical applications for cancer therapy over the past decades. To date, numerous nanomedicine formats and design rationales have been proposed to improve pharmaceutical delivery and treatment efficacy. Despite these advances, the achievement of high drug loading and loading efficiencies of drug payloads in nanocarriers remains a technical challenge. In addition, study of the correlation between therapeutic potential and drug loading has been ignored. Here, using a self-assembling dimeric cabazitaxel prodrug, we show that the prodrug can be quantitatively entrapped within clinically approved polymer matrices for intravenous injection and that the drug loading in the nanoparticles (NPs) is tunable. The engineered NPs (NPs1-4) with different drug loading values exhibit dissimilar morphologies, release kinetics, in vitro cytotoxic activity, pharmacokinetic properties, tissue distribution, and in vivo anticancer efficacy and safety profiles. Furthermore, the effect of drug loading on the treatment outcomes was explored through detailed in vitro and in vivo studies. Intriguingly, among the constructed NPs, those comprising poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-PLA) copolymers showed substantially prolonged pharmacokinetic properties in the blood circulation, which further promoted their intratumoral delivery and accumulation. Furthermore, the PEG-PLA-composed NPs with high drug loading (~50%) demonstrated favorable efficacy and safety profile in animal models. These data provide convincing evidence that the in vivo performance of a given self-assembling drug is not compromised by high drug loading in nanoplatforms, which may potentially reduce concerns over excipient-associated side effects and immunotoxicities. Overall, our study provides new insight into the rationale for designing more effective and less toxic delivery systems.
Asunto(s)
Nanopartículas , Profármacos , Animales , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Polietilenglicoles , PolímerosRESUMEN
In this study, we newly designed and synthesized a small library of ten structurally related C,N-cyclometalated ruthenium(II) complexes containing various pyridine-functionalized NHC ligand and chelating bipyridyl ligands (e.g., 2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, and 1,10-phenanthroline (phen)). The complexes were well characterized by NMR, electrospray ionization-mass spectrometry, and single-crystal X-ray structure analyses. Among the new ruthenium(II) derivatives, we identified that the complex Ru8 bearing bulky moieties (i.e., phen and pentamethyl benzene) had the most potent cytotoxicity against all tested cancer cell lines, generating dose- and cell line-dependent IC50 values at the range of 3.3-15.0â µm. More significantly, Ru8 not only efficiently inhibited the metastasis process against invasion and migration of tumor cells but also exhibited potent antivascular effects by suppressing HUVEC cells migration and tube formation in vitro and blocking vessel generation in vivo (chicken chorioallantoic membrane model). In a metastatic A2780 tumor xenograft-bearing mouse model, administration of Ru8 outperformed antimetastatic agent NAMI-A and clinically approved cisplatin in terms of antitumor efficacy and inhibition of metastases to other organs. Overall, these data provided compelling evidence that the new cyclometalated ruthenium complex Ru8 is an attractive agent because of synergistically suppressing bulky tumors and metastasized tumor nudes. Therefore, the complex Ru8 deserves further investigations.
Asunto(s)
Antineoplásicos , Cisplatino/química , Compuestos Organometálicos , Neoplasias Ováricas , Rutenio , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Femenino , Humanos , Ratones , Compuestos Organometálicos/metabolismo , Rutenio/farmacologíaRESUMEN
Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes (PtRu 1-4) have been synthesized and evaluated for their antitumor performance. Using the optimal complex, PtRu-1, we show that this water-soluble chimeric prodrug not only potently inhibits the metastasis and proliferation of tumor cells but also has an unexpectedly higher safety margin in animals compared with the traditionally-used, clinically approved drug cisplatin.