Application of Nano-Delivery Systems in Lymph Nodes for Tumor Immunotherapy

Immunotherapy has become a promising research“hotspot”in cancer treatment.“Soldier”immune cells are not uniform throughout the body;they accumulate mostly in the immune organs such as the spleen and lymph nodes(LNs),etc.The unique structure of LNs provides the microenvironment suitable for the survival,activation,and proliferation of multiple types of immune cells.LNs play an important role in both the initiation of adaptive immunity and the generation of durable anti-tumor responses.Antigens taken up by antigen-presenting cells in peripheral tissues need to migrate with lymphatic fluid to LNs to activate the lymphocytes therein.Meanwhile,the accumulation and retaining of many immune functional compounds in LNs enhance their efficacy significantly.Therefore,LNs have become a key target for tumor immunotherapy.Unfortunately,the nonspecific distribution of the immune drugs in vivo greatly limits the activation and proliferation of immune cells,which leads to unsatisfactory anti-tumor effects.The efficient nano-delivery system to LNs is an effective strategy to maximize the efficacy of immune drugs.Nano-delivery systems have shown beneficial in improving biodistribution and enhancing accumulation in lymphoid tissues,exhibiting powerful and promising prospects for achieving effective delivery to LNs.Herein,the physiological structure and the delivery barriers of LNs were summarized and the factors affecting LNs accumulation were discussed thoroughly.Moreover,developments in nano-delivery systems were reviewed and the transformation prospects of LNs targeting nanocarriers were summarized and discussed.

Nanoparticle‑Loaded Polarized‑Macrophages for Enhanced Tumor Targeting and Cell‑Chemotherapy

Cell therapy is a promising strategy for cancer therapy.However,its therapeutic efficiency remains limited due to the complex and immunosuppressive nature of tumor microenvironments.In this study,the“cell-chemotherapy”strategy was presented to enhance antitumor efficacy.M1-type macrophages,which are therapeutic immune cells with both of immunotherapeutic ability and targeting ability,carried sorafenib(SF)-loaded lipid nanoparticles(M1/SLNPs)were developed.M1-type macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver SF to tumor tissues for chemotherapy simultaneously.M1-type macrophages were obtained by polarizing macrophages using lipopolysaccharide,and M1/SLNPs were obtained by incubating M1-type macrophages with SLNP.Tumor accumulation of M1/SLNP was increased compared with SLNP(p<0.01),which proved M1/SLNP could enhance tumor targeting of SF.An increased ratio of M1-type macrophages to M2-type macrophages,and the CD3^+CD4^+T cells and CD3^+CD8^+T cell quantities in tumor tissues after treatment with M1/SLNP indicated M1/SLNP could relieve the immunosuppressive tumor microenvironments.The tumor volumes in the M1/SLNP group were significantly smaller than those in the SLNP group(p<0.01),indicating M1/SLNP exhibited enhanced antitumor efficacy.Consequently,M1/SLNP showed great potential as a novel cellchemotherapeutic strategy combining both cell therapy and targeting chemotherapy.

Gas-blasting nanocapsules to accelerate carboplatin lysosome release and nucleus delivery for prostate cancer treatment

To improve therapeutic effect and reduce severely side effects of carboplatin(CBP),the gas-generating nanocapsules were developed to accelerate CBP lysosome release and nucleus delivery.CBP/SB-NC was prepared by co-loading CBP and NaHCO 3(SB)in nanocapsules using w/o/w emulsification solvent evaporation.They exhibited vesicle-like spherical morphology,uniform particle size and negative zeta potential.Reaching the tumor site with a relatively high concentration is the first step for CBP delivery and the results showed that CBP/SB-NC could effectively increase drug accumulation at tumor site.After that,the drug delivery carriers need to be internalized into tumor cells and the in vitro cellular uptake ability results showed CBP/SB-NC could be internalized into RM-1 cells more efficient than CBP solution.After internalized by RM-1 cells,the gas-blasting release process was tested in acid environment.It was demonstrated that 5 mg/ml NaHCO 3 was optimal to achieve pH-responsive gas-blasting release.In vitro release results showed that CBP significantly rapid release in acid environment(pH 5.0)compared to neutral pH(pH 7.4)(P<0.05).Meanwhile,TEM and the change of the concentration of H+results exhibited that the explosion of CBP/SB 5-NC was more easily happened in lysosome acid environment(pH 5.0).The blasting release can accelerate CBP lysosome release to cytoplasm.Furthermore,the nucleus delivery results showed CBP/SB 5-NC can promote pH-triggered rapid nucleus delivery.And the results of Pt-DNA adduct assay showed that the binding efficiency between CBP and DNA of CBP/SB 5-NC was higher than CBP solution.At last,in vitro and in vivo anti-tumor efficacy proved that CBP/SB 5-NC could enhance anti-tumor activity for prostate cancer therapy.CBP/SB 5-NC also showed superior safety in vitro and in vivo by hemolysis assay and histopathological study.All of the results demonstrate that CBP/SB 5-NC would be an efficient gas-blasting release formulation to enhance prostate cancer treatment.

On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition

Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cells priming.Herein,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via"increased DNA damage and dual immune checkpoint inhibition"strategy.JOT-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive linker.JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral infiltration.In addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells priming.It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects.Collectively,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy.

Micro/nanomotor: A promising drug delivery system for cancer therapy

Micro/nanomotors(MNMs)are small-scale devices that can effectively convert various forms of energy into mechanical motion.Their controllable motility and good permeability have attracted the interest of researchers as promising drug carriers in cancer therapy.Compared with traditional formulations,micro/nanomotor drug delivery systems can greatly improve therapeutic efficiency and reduce the side effects of antitumor drugs.This review mainly discusses the advantages of micro/nanomotor drug delivery systems and the applications of MNMs propelled by exogenous,endogenous,and biohybrid power in cancer therapy.Finally,the main challenges of the applications of micro/nanomotor drug delivery systems,as well as future development trends and opportunities are discussed.