Encouraging results are emerging from systems that exploit Toll like receptor (TLR) signaling, nanotechnology, checkpoint inhibition and molecular imaging for cancer immunotherapy. A major remaining challenge is developing effective, durable and tumour-specific immune responses without systemic toxicity. Here, we report a simple and versatile system based on synergistic activation of immune responses and direct cancer cell killing by combined TLR ligation using polyIC as TLR3 and imiquimod (R837) as TLR7 agonist, in combination with the model antigen ovalbumin (OVA) and phospholipid micelles loaded with zinc-doped iron oxide magnetic nanoparticles (MNPs). The combination of TLR agonists triggered a strong innate immune response in the lymph nodes (LNs) without systemic release of pro-inflammatory cytokines. The vaccines showed excellent efficacy against aggressive B16-F10 melanoma cells expressing OVA, which was improved with immune checkpoint abrogation of the immunosuppressive programmed death-ligand 1 (PD-L1) at the level of the cancer cells. By magnetic resonance (MR) and nuclear imaging we could track the vaccine migration from the site of injection to LNs and tumour. Overall, we show this synergistic TLR agonists and their combination with MNPs and immune checkpoint blockade to have considerable potential for preclinical and clinical development of vaccines for cancer immunotherapy.
Irradiation of CdSe-ZnS quantum dots (QDs) with visible light in the presence of [PtCl(4)(bpy)] (1) (bpy = 2,2'-bipyridine) produced with high efficiency [PtCl(2)(bpy)] (2) by photoinduced electron transfer; a reaction and strategy which opens up new opportunities for cancer therapy.
Herein
we elucidate the mechanism of photoreduction of the Pt(IV)
complex cis,cis,trans-[Pt(NH3)2(Cl)2(O2CCH2CH2CO2H)2] (1) into Pt(II) species (among
which is cisplatin) by quantum dots (QDs), a process which holds potential
for photodynamic therapy. Density functional theory (DFT) and time-dependent
density functional theory (TDDFT) methodologies, integrated by selected
experiments, were employed to study the interaction and the light-induced
electron transfer (ET) process occurring between two QD models and 1. Direct adsorption
of the complex on the nanomaterial surface results in large electronic
coupling between the LUMO (lowest unoccupied molecular orbital) of
the excited QD* and the LUMO+1 of 1, providing the driving
force to the light-induced release of the succinate ligands from the
Pt derivative. As confirmed by photolysis experiments performed a
posteriori, DFT highlights that QD photoactivation of 1 can favor the formation of preferred Pt(II) photoproducts, paving
the way for the design of novel hybrid Pt(IV)–semiconductor
systems where photochemical processes can be finely tuned.
The cisplatin prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2)2](2-) (1) forms outer-sphere coordination interactions with non-toxic low MW PEI, which results in enhanced cancer cell killing, also achieved using PEI-coated AuNPs.
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