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Chemotherapeutic agents can trigger the immune response via inducing immunogenic cell death (ICD), but the weak ICD effect induced by chemotherapy alone limits its lasting antitumor immunotherapy effect. A Cro polymerized prodrug carriers (POEG-b-PCro) with immunostimulatory by ICD induction was developed and co-delivered DOX to generate synergistic ICD induction for chemo-immunotherapy on breast cancer. DOX/POEG-b-PCro micelles displayed prolonged circulation in blood, efficient accumulation in tumors, internalization and then co-released DOXCro in tumor cells. Moreover, the DOX/POEG-b-PCro micelles synergistically triggered ICD induction by releasing the nuclear high mobility group box 1 (HMGB1) and down-regulation of c-Met level for generating chemo-immune anti-tumor actions. Importantly, the DOX/POEG-b-PCro micelles synergistically enhanced the tumor cytotoxic T lymphocytes infiltration, concomitant decreasing the immunosuppressive regulatory T (Treg) cells, accompanied with the increased cytokines secretion of IFN-γ and TNF-α, consequently displaying an improved anti-tumor activity in 4 T1 breast cancer mice. Overall, POEG-b-PCro prodrug micelles co-delivered DOX could be served as a promising nano drug delivery system for synergistic ICD induction on breast cancer chemo-immunotherapy.

Nowadays, breast cancer has become a major killer threatening women's health. MET is a receptor tyrosine kinase that upon binding of its ligand, hepatocyte growth factor, activates downstream pathways with diverse cellular functions which are important in the occurrence and development of breast cancer. Crizotinib (Cro) is a multi-target tyrosine kinase inhibitor targeting ALK gene recombination, MET gene amplification and ROS gene. Although Cro has the ideal treatment for breast cancer, Cro has stronger hepatotoxicity and lacks targeting capacity to the tumor cell, which limited Cro to effectively therapy breast cancer. In this study, we develop a novel prodrug micelle through polymerization reaction polymerizing Cro onto the chain to form POEG-b-PCro prodrug micelles, in which the drug loading capacity of Cro was significantly increased to improve the cumulant of the tumor. Pharmacokinetic and biodistribution studies illustrated that POEG-b-PCro prodrug micelles had a significant effect by improving Cro content in the tumor. Meanwhile, the antitumor mechanism of POEG-b-PCro prodrug micelles proved that POEG-b-PCro prodrug micelles had a stronger effect by reducing negative regulatory proteins. POEG-b-PCro prodrug micelles had splendid safety through safety study

Liver fibrosis is a pathological process of multiple chronic liver diseases progressing to cirrhosis for which there are currently no effective treatment options. During fibrosis progression, the overproduction of extracellular matrix (ECM) collagen secreted by hepatic stellate cells (HSCs) greatly impedes drug delivery and reduces drug therapeutic effects. In this study, a glycyrrhetinic acid (GA)-conjugated prodrug micellar system with collagenase I (COL) decoration (COL-HA-GA, abbreviated as CHG) was designed to codelivery sorafenib (Sora/CHG, abbreviated as S/CHG) for potentiating ECM degradation and HSCs targeting on liver fibrosis therapy. In ECM barrier models established in vitro or in vivo, CHG micelles efficiently degraded pericellular collagen and demonstrated enormous ECM penetration abilities as well as superior HSCs internalization. Moreover, CHG micelles exhibited more SoraGA accumulations and activated HSCs targeting efficiencies in the fibrotic livers than those in the normal livers. More importantly, S/CHG micelles were more effective in anti-liver fibrosis by lowering the collagen content, inhibiting the HSCs activation, as well as down-regulating the fibrosis-related factors, leading to reverse the fibrotic liver to normal liver through the multi-mechanisms including angiogenesis reduction, liver fibrosis microenvironment regulation, and epithelial-mesenchymal transition inhibition. In conclusion, the developed COL decorated nano-codelivery system with fibrotic ECM collagen degradation and activated HSCs targeting dual-functions exhibited great potential for liver fibrosis therapy. STATEMENT OF SIGNIFICANCE: A glycyrrhetinic acid (GA)-conjugated prodrug with collagenase I (COL) decoration (CHG) was designed for codelivery with sorafenib (S/CHG), potentiating extracellular matrix (ECM) degradation-penetration and hepatic stellate cells (HSCs) targeting on liver fibrosis therapy. In ECM barrier models, CHG micelles efficiently degraded pericellular collagen and demonstrated ECM penetration abilities, as well as displayed superior HSCs internalization. Moreover, S/CHG micelles were more effective in anti-liver fibrosis by lowering the collagen content, inhibiting the HSCs activation, as well as down-regulating cytokines, reversing the fibrotic liver to normal through various mechanisms. In conclusion, the developed fibrotic ECM degradation and HSCs targeting dual-functional nano-codelivery system provided a prospective potentiality in liver fibrosis therapy.

Cancer metastasis is the leading cause of high mortality and disease recurrence in breast cancer. In this study, a novel tumor microenvironment charge reversal polymetformin (PMet)-based nanosystem co-delivering doxorubicin (DOX) and plasmid encoding IL-12 gene (pIL-12) was developed for chemo-gene combination therapy on metastatic breast cancer. Cationic PMet was readily self-assembled into micelles for DOX physical encapsulation and pIL-12 complexation, and a hyaluronidase-sensitive thiolated hyaluronic acid (HA-SH) was then collaboratively assembled to the pIL-12/DOX-PMet micelleplexes, abbreviated as HA/pIL-12/DOX-PMet. DOX/pIL-12 loaded in HA/pIL-12/DOX-PMet micelleplexes presented prolonged circulation in blood, efficient accumulation in tumors, and internalization in tumor cells via CD44 receptor-mediated tumor specific-targeting, and DOX/pIL-12 was co-released in endo/lysosomes tumor microenvironment followed by HAase-triggered HA-SH deshielding from HA/pIL-12/DOX-PMet micelleplexes. Moreover, HA/PMet micelleplexes displayed excellent pIL-12 transfection and IL-12 expression in tumors of 4T1 tumor-bearing mice. Importantly, HA/pIL-12/DOX-PMet micelleplexes synergistically enhanced the NK cells and tumor infiltrated cytotoxic T lymphocytes and modulated the polarization from protumor M2 macrophages to activated antitumor M1 macrophages, with concomitant decreasing of the immunosuppressive regulatory T (Treg) cells, accompanied by an increase in the cytokines expression of IL-12, IFN-γ and TNF-α, consequently showing an improved antitumor and antimetastasis activity in 4T1 breast cancer lung metastasis mice model. In conclusion, the tumor microenvironment charge reversal HA/PMet nanosystem holds great promise for DOX/pIL-12 co-delivery and exploitation in chemo-gene combination therapy on metastatic breast cancer.

Immunochemotherapy is viewed as a promising approach for cancer therapy via combination treatment with immune-modulating drugs and chemotherapeutic drugs. A novel dual-functional immunostimulatory polymeric prodrug carrier PEG2k-Fmoc-1-MT was developed for simultaneously delivering 1-methyl tryptophan (1-MT) of an indoleamine 2,3-dioxygenase (IDO) inhibitor and chemotherapeutic doxorubicin (DOX) for breast cancer immunochemotherapy. DOX/PEG2k-Fmoc-1-MT micelles were more effective in cell proliferation inhibition and apoptosis induction in 4T1 cells. PEG2k-Fmoc-1-MT prodrug micelles presented enhanced inhibition ability of IDO with decreased kynurenine production and increased the proliferation in dose-dependent manners of effector CD4+ and CD8+ T cells. DOX/PEG2k-Fmoc-1-MT micelles exhibited prolonged blood circulation time and superior accumulation of DOX and 1-MT in tumors compared to that of DOX and 1-MT solutions. A significantly enhanced immune response of the DOX/PEG2k-Fmoc-1-MT micelles was observed with the decreasing tryptophan/kynurenine ratio in blood and tumor tissue, promoting effector CD4+ and CD8+ T cells while reducing regulatory T cell (Tregs) expression. Meanwhile, the coreleased DOX-triggered immunogenic cell death action combined with the cleaved 1-MT promoted the related cytokine secretion of tumor necrosis factor-α, interleukin-2, and interferon-γ, further facilitating the T cell-mediated immune responses. More importantly, the DOX-loaded micelles led to a significantly improved inhibition on tumor growth and prolonged animal survival rate in a 4T1 murine breast cancer model. In conclusion, DOX codelivered by a PEG2k-Fmoc-1-MT immunostimulatory polymeric prodrug showed a maximum immunochemotherapy efficacy against breast cancer.

The abnormal structure and function of blood vessels in the TME are obvious characteristics of the tumour. Abnormal blood vessels with high leakage support the occurrence of malignant tumours and increase the possibility of tumour cell invasion and metastasis. The formation of abnormal vascular also enhances immunosuppression and prevents the delivery of chemotherapy drugs to deeper tumours. Therefore, the normalisation of tumour blood vessels is a very promising approach to improve anti-tumour efficacy, aiming to restore the structural integrity of vessels and improve drug delivery efficiency and anti-tumour immunity. In this review, we have summarised strategies to improve cancer treatment that via nano drug delivery technology regulates the normalisation of tumour blood vessels. The treatment strategies related to the structure and function of tumour blood vessels such as angiogenesis factors, tumour-associated macrophages, tumour vascular endothelial cells, tumour-associated fibroblasts and immune checkpoints in the TME were mainly discussed. The normalisation of tumour blood vessels presents new opportunities and challenges for the more efficient delivery of nanoparticles to tumour tissues and cells and an innovative combination of treatments for cancer.

Immunochemotherapy is viewed as a promising approach for cancer therapy