Co-delivery of gemcitabine and paclitaxel plus NanoCpG empowers chemoimmunotherapy of postoperative“cold”triple-negative breast cancer

Triple-negative breast cancer(TNBC)due to lack of clear target and notorious“cold”tumor microenvironment(TME)is one of the most intractable and lethal malignancies.Tuning“cold”TME into“hot”becomes an emerging therapeutic strategy to TNBC.Herewith,we report that integrin-targeting micellar gemcitabine and paclitaxel(ATN-mG/P,ATN sequence:Ac-PhScNK-NH2)cooperating with polymersomal CpG(NanoCpG)effectively“heated up”and treated TNBC.ATN-mG/P exhibited greatly boosted apoptotic activity in 4T1 cells,induced potent immunogenic cell death(ICD),and efficiently stimulated maturation of bone marrow-derived dendritic cells(BMDCs).Remarkably,in a postoperative TNBC model,ATN-mG/P combining with NanoCpG promoted strong anti-cancer immune responses,showing a greatly augmented proportion of mature DCs and CD8^(+)T cells while reduced immune-suppressive myeloid-derived suppressor cells(MDSCs)and regulatory T cells(T_(reg)),which led to complete inhibition of lung metastasis and 60%mice tumor-free.The co-delivery of gemcitabine and paclitaxel at desired ratio in combination with NanoCpG provides a unique platform for potent chemoimmunotherapy of“cold”tumors like TNBC.

Transferrin-guided intelligent nanovesicles augment the targetability and potency of clinical PLK1 inhibitor to acute myeloid leukemia

Acute myeloid leukemia(AML)remains a most lethal hematological malignancy,partly because of its slow development of targeted therapies compared with other cancers.PLK1 inhibitor,volasertib(Vol),is among the few molecular targeted drugs granted breakthrough therapy status for AML;however,its fast clearance and dose-limiting toxicity greatly restrain its clinical benefits.Here,we report that transferrin-guided polymersomes(TPs)markedly augment the targetability,potency and safety of Vol to AML.Vol-loaded TPs(TPVol)with 4%trans-ferrin exhibited best cellular uptake,effective down-regulation of p-PLK1,p-PTEN and p-AKT and superior apoptotic activity to free Vol in MV-4-11 leukemic cells.Intravenous injection of TPVol gave 6-fold higher AUC than free Vol and notable accumulation in AML-residing bone marrow.The efficacy studies in orthotopic MV-4-11 leukemic model demonstrated that TPVol significantly reduced leukemic cell proportions in periphery blood,bone marrow,liver and spleen,effectively enhanced mouse survival rate,and impeded bone loss.This transferrin-guided nano-delivery of molecular targeted drugs appears to be an interesting strategy towards the development of novel treatments for AML.