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.

Efficient and targeted drug/siRNA co-delivery mediated by reversibly crosslinked polymersomes toward anti-inflammatory treatment of ulcerative colitis (UC)

Co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical challenge against their utilization. We herein developed macrophage-targeting, reversibly crossli nked polymersomes (TKPR-RCP) based on the TKPR-modified, poly(ethyle ne glycol)-b-poly(trimethylene carbonate-codithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) triblock copolymer, which could efficiently encapsulate TNF-α siRNA and dexamethasone sodium phosphate (DSP) in their hydrophilic core. The cationic PEI segments provided additional electrostatic interactions with cargo molecules to promote the encapsulatiion, and disulfide crosslinking of the polymersome membrane endowed the TKPR-RCP with high colloidal stability. Because the cationic PEI was embedded in the hydrophilic core, the polymersomes displayed neutral surface charge and thus possessed high serum stability. The TKPR-RCP co-encapsulating TNF-α siRNA and DSP could be efficiently internalized by macrophages (~98%) and undergo redox-responsive membrane de-crosslinking to accelerate cargo release in the cytoplasm, thus inducing efficient gene silencing and anti-inflammatory effect .Intravenous injectio n of the co-delivery TKPR-RCP mediated pote nt and cooperative anti-inflammatory effect in inflamed colons of UC mice, and significantly prevented animals from colonic injury. This study therefore provides a promising approach for the co-delivery of hydrophilic drug/siRNA toward the treatment of inflammatory bowel diseases.

Polymersome-mediated cytosolic delivery of cyclic dinucleotide STING agonist enhances tumor immunotherapy

Cyclic dinucleotides(CDNs)as stimulator of interferon genes(STING)agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy.The efficacy of these CDNs is,however,reduced greatly by their fast clearance,poor cell uptake and inefficient cytosolic transportation.Here,we report that reduction-responsive biodegradable chimaeric polymersomes(CPs)markedly enhance tumor retention and cytosolic delivery of a synthetic CDN,ADU-S100,and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes,giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control.The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation,which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge.The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.

Targeted chemotherapy for subcutaneous and orthotopic non-small cell lung tumors with cyclic RGD-functionalized and disulfide-crosslinked polymersomal doxorubicin

Lung cancer, with its high mortality and increasing morbidity, has become one of the most lethal malignancies worldwide. Here, we developed cyclic RGD peptide-directed and disulfide-crosslinked polymersomal doxorubicin (cRGD-PS-Dox) as a targeted chemotherapy for human non-small cell lung cancer (NSCLC). Notably, cRGD-PS-Dox exhibited a high Dox loading (15.2 wt.%), small hydrodynamic diameter (96 nm), superb stability, prominent targetability to αvβ3 integrin overexpressing A549 human lung cancer cells, and rapid release of the drug into nuclei, leading to a significantly improved antitumor activity compared with the control groups, i.e., PS-Dox and Lipo-Dox (a liposome injection employed in clinical settings). The pharmacokinetic and biodistribution results for cRGD-PS-Dox revealed similar elimination half-lives but two-fold enhanced tumor accumulation compared with PS-Dox and Lipo-Dox. Intriguingly, cRGD-PS-Dox effectively suppressed the growth of A549 lung tumors in both subcutaneous and orthotopic models with minimal adverse effects at a Dox dose of 12 mg/kg, leading to significant survival benefits compared with PS-Dox and Lipo-Dox. This αvβ3 integrin-targeting multifunctional polymersomal doxorubicin is highly promising for targeted chemotherapy of human NSCLC.

Poly(ethylene oxide)-graft-methotrexate Macromolecular Drugs Conjugating via Aminopteridine Ring Exhibit Potent Anticancer Activity

Water soluble poly(ethylene oxide)-graft-methotrexate (PEO-g-MTX) conjugates with a robust amide linkage via the amine or carboxylic acid groups of MTX were designed,prepared and investigated for in vitro anti-tumor effects.MTX was conjugated to multi-functional PEO containing multiple pendant carboxylic acid (PEO-g-COOH)or amine groups (PEO-g-NH2) via the carbodiimide chemistry,which afforded PEO-g-MTX conjugates with an amide bond to the aminopteridine ring or carboxylic acid groups of MTX (denoted as PEO-g-MTX(COOH) and PEO-g-MTX(NH2),respectively).Dynamic light scattering (DLS) revealed that all PEO-g-MTX conjugates,with MTX contents varying from 4.8 to 19.6 wt％,existed as unimers in phosphate buffer (PB,pH 7.4,20 mmol·L-1).Interestingly,MTT assays showed that PEO-g-MTX(COOH) exhibited potent anti-tumor activity in HeLa,A549,KB and NIH3T3 cells with cytotoxicity profiles comparable to that of free MTX.In contrast,PEO-g-MTX(NH2)revealed diminishing cytostatic effect with IC50 (half maximal inhibitory concentration) ten to hundred times higher than that of PEO-g-MTX(COOH).Moreover,PEO-g-MTX(COOH) conjugates allowed facile conjugation with targeting ligands.Notably,folate-decorated PEO-g-MTX(COOH) macromolecular drugs showed apparent targetability to folate receptor-overexpressing KB cells with an IC50 over 12-fold lower than non-targeting PEO-g-MTX-(COOH) control and about 2-fold lower than free MTX under otherwise the same conditions.