RESUMO
Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy.
Assuntos
Antígeno B7-H1 , Neoplasias do Colo , Imunoterapia , Neoplasias Hepáticas , Microambiente Tumoral , Animais , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Humanos , Imunoterapia/métodos , Neoplasias do Colo/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/terapia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Camundongos , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Feminino , Nanopartículas/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Using a solvent-free radical grafting technique, glycidyl methacrylate (GMA) and maleic anhydride (MAH) were used as functionalized graft monomers, styrene (St) as a copolymer monomer, and grafted onto polylactic acid (PLA). A series of PLA-g-(GMA/MAH-co-St) graft copolymers were prepared by adjusting the GMA/MAH ratio. Subsequently, the prepared graft copolymers were used as a compatibilizer with PLA and polypropylene carbonate (PPC) for melt blending to prepare PLA/PPC/PLA-g-(GMA/MAH-co-St) blends. The effects of changes in the GMA/MAH ratio in the graft copolymer on the thermodynamics, rheology, optics, degradation performance, mechanical properties, and microstructure of the blend were studied. The results found that GMA, MAH, and St were successfully grafted onto PLA, and the PLA-g-(GMA/MAH-co-St) graft copolymer obtained from the reaction had a good toughening effect on the PLA/PPC blend system, which significantly improved the mechanical properties of the PLA/PPC/PLA-g-(GMA/MAH-co-St) blend without reducing its degradation performance, resulting in a biodegradable blend material with excellent comprehensive performance. In the PLA-g-(GMA/MAH-co-St) grafting reaction system, when GMA/MAH = 1.5/1.5 (w/w), the grafting degree of the graft copolymer increased most significantly, from 0.83 phr to 1.51 phr. This composition of graft copolymer can effectively improve the compatibility between PLA and PPC. The resulting PLA/PPC blend can maintain good melt flow properties (MFR of 14.51 g/10 min), high transparency, and low haze (light transmittance of 91.56 %, haze of 20.5 %), while significantly improving its thermal stability (T95%, Tmax, and Et increased by 12.87 °C, 20.33 °C, and 32.00 kJ/mol, respectively). Moreover, when introducing PLA-g-(GMA/MAH-co-St) (GMA/MAH = 1.5/1.5 (wt/wt)) graft copolymer into the system, the toughness of the PLA/PPC/PLA-g-(GMA/MAH-co-St) blend system is optimal, with the notch impact strength and fracture elongation increasing to 184.6 % and 535.4 % of the PLA/PPC blend, respectively, at which point the fracture surface of the impact sample shows a wrinkled fracture feature indicative of toughness.
Assuntos
Compostos de Epóxi , Metacrilatos , Poliésteres , Polímeros , Poliésteres/química , Polímeros/química , Polipropilenos , Anidridos Maleicos , EstirenoRESUMO
Cardanol (CD) is used as a reactive compatibilizer, and blended with polylactic acid (PLA) and polypropylene carbonate (PPC) resin (70/30(w/w)) to obtain a series of PLA/PPC/CD blends. The systematic study was conducted on the thermal properties, optical properties, rheological properties, mechanical properties, and microscopic morphology of the blend, by varying amounts of CD added to the blends. A detailed explanation and comprehensive analysis of the reaction mechanism between CD and PLA/PPC have been made. The study found that CD acts as a "bridge" between the PLA and PPC, forming the structure of a block copolymer (PLA-b-CD-b-PPC), and the copolymer can greatly improve the compatibility of PLA and PPC. When the amount of CD reaches 8 wt%, only one Tg is observed in the blend, simultaneously, PLA/PPC has already transitioned from a partially compatible system to a completely compatible system. At the same time, the addition of CD does not have any negative impact on the thermal stability of the PLA/PPC blend under processing temperature conditions, and the thermal stability of the PLA/PPC/CD blends can even be improved under extreme conditions. In addition, the addition of CD allows the PLA/PPC/CD blends to maintain a high light transmittance while reducing the opacity of the blend (the light transmittance remains above 92 %, and the opacity is reduced from 37 % to about 24 %), demonstrating excellent optical properties. Moreover, the elongation at break and impact strength of the PLA/PPC/CD blend both show a trend of first increasing and then decreasing with the increase of CD amount. When the CD amount varies within the range of 6- 8 wt%, the blends undergoes a brittle-ductile transition, and its toughness is greatly improved while the rigidity can also meet practical needs. When the amount of CD in the system increases to 12 wt%, the toughness of the blend reaches its peak, and its elongation at break and impact strength reach 513.24 % and 9211.5 J/m2 respectively (increased to 2442.84 % and 270.73 % of the PLA/PPC blend). Concurrently, the fracture surface of the blend exhibits large-scale plastic flow in the direction of the applied force, with marked shear yield phenomena, showing obvious characteristics of tough fracture.