Anti-PD-L1 checkpoint inhibitor combined with nanocarrier-mediated cisplatin codelivery system for effective treatment of pancreatic cancer.

Immune checkpoint inhibitor-based cancer immunotherapy has shown promise as a potential treatment in the clinic. It has been reported that anti-PD-L1 combined with cisplatin treatment can improve the antitumor effect. However, the therapeutic outcome is limited due to the abundance of tumor stroma in pancreatic cancer (PC), which prevented the penetration of cisplatin and anti-PD-L1 into tumor regions, thus impeding the effectiveness in the treatment of PC. In this study, a nanocarrier-mediated codelivery system of hyaluronidase and cisplatin was constructed, which can degrade the stroma and promote cisplatin and anti-PD-L1 to penetrate the tumor stroma into the deep tumor, so as to suppress PC effectively. When combined the cisplatin nanocarrier system BPEI-SS-Pt/HAase@CaP (BSP/H@CaP) with an immune checkpoint inhibitor to overcome the poor therapeutic outcome of PC, the results indicated that the therapeutic effect of BSP/H@CaP combined with anti-PD-L1 was better than that of BSP/H@CaP and single anti-PD-L1 group. Because the stroma is degrading, a higher amount of BPEI-SS-Pt and anti-PD-L1 can enter the tumor stroma and reach the inner depths of the tumor for immune stimulation, leading to a synergistically augmented chemotherapy and immunotherapy for PC. The above combination therapy is useful for clinical translation to overcome the treatment resistance of matrix-rich PC.

Construction of GSH-responsive polyethyleneimine-based delivery vector for effective gene transfection.

The rise of gene therapy has solved many diseases that cannot be effectively treated by conventional methods. Gene vectors is very important to protect and deliver the therapeutic genes to the target site. Polyethyleneimine (PEI) modified with mannitol could enhance the gene transfection efficiency reported by our group previously. In order to further control and improve the effective gene release to action site, disulfide bonds were introduced into mannitol-modified PEI to construct new non-viral gene vectors PeiSM. The degrees of mannitol linking with disulfide bonds were screened. Among them, moderate mannitol-modified PEI with disulfide bonds showed the best transfection efficiency, and significantly enhanced long-term systemic transgene expression for 72 hin vivoeven at a single dose administration, and could promote caveolae-mediated uptake through up-regulating the phosphorylation of caveolin-1 and increase the loaded gene release from the nanocomplexes in high glutathione intracellular environment. This functionalized gene delivery system can be used as an potential and safe non-viral nanovector for further gene therapy.

Injectable hybrid hydrogels enable enhanced combination chemotherapy and roused anti-tumor immunity in the synergistic treatment of pancreatic ductal adenocarcinoma.

Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and KrasG12D-engineered primary PDAC mice and synergistically promotes the infiltration of CD8+ cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC.

Glioma-targeted oxaliplatin/ferritin clathrate reversing the immunosuppressive microenvironment through hijacking Fe2+ and boosting Fenton reaction.

Glioma is easy to develop resistance to temozolomide (TMZ). TMZ-resistant glioma secretes interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß), recruiting regulatory T cell (Treg) and inhibiting the activity of T cells and natural killer cell (NK cell), subsequently forming an immunosuppressive microenvironment. Oxaliplatin (OXA) greatly inhibits the proliferation of TMZ-resistant glioma cells, but the ability of OXA to cross blood-brain barrier (BBB) is weak. Thus, the therapeutic effect of OXA on glioma is not satisfactory. Transferrin receptor 1 (TfR1) is highly expressed in brain capillary endothelial cells and TMZ-resistant glioma cells. In this study, OXA was loaded into ferritin (Fn) to prepare glioma-targeted oxaliplatin/ferritin clathrate OXA@Fn. OXA@Fn efficiently crossed BBB and was actively taken up by TMZ-resistant glioma cells via TfR1. Then, OXA increased the intracellular H2O2 level and induced the apoptosis of TMZ-resistant glioma cells. Meanwhile, Fn increased Fe2+ level in TMZ-resistant glioma cells. In addition, the expression of ferroportin 1 was significantly reduced, resulting in Fe2+ to be locked up inside the TMZ-resistant glioma cells. This subsequently enhanced the Fenton reaction and boosted the ferroptosis of TMZ-resistant glioma cells. Consequently, T cell mediated anti-tumor immune response was strongly induced, and the immunosuppressive microenvironment was significantly reversed in TMZ-resistant glioma tissue. Ultimately, the growth and invasion of TMZ-resistant glioma was inhibited by OXA@Fn. OXA@Fn shows great potential in the treatment of TMZ-resistant glioma and prospect in clinical transformation.

Polymer-Initiating Caveolae-Mediated Endocytosis and GSH-Responsive MiR-34a Gene Delivery System for Enhanced Orthotopic Triple Negative Breast Cancer Therapy.

Gene therapy based on miRNAs has broad application prospects in the treatment of tumors. However, due to degradation and ineffective release during intracellular transport, current gene delivery vectors used for miRNAs limited their actual transfection efficiency. This study develops a novel nonviral vector PEI-SPDP-Man (PSM) that can simultaneously target cellular uptake pathways and intracellular responsive release for miR-34a. PSM is synthesized by connected mannitol (Man) to branched polyethylenimine (PEI) using a disulfide bond. The prepared PSM/miR-34a gene delivery system can induce and enter to tumor cells through caveolae-mediated endocytosis to reduce the degradation of miR-34a in lysosomes. The disulfide bond is sensed at high concentration of glutathione (GSH) in the tumor cells and miR-34a is released, thereby reducing the expression of Bcl-2 and CD44 to suppress the proliferation and invasion of tumor cells. In vitro and in vivo experiments show that through the targeted cellular uptake and the efficient release of miR-34a, an effective antitumor and antimetastasis profiles for the treatment of orthotopic triple negative breast cancer (TNBC) are achieved. This strategy of controlling intracellular transport pathways by targeting cellular uptake pathways in the gene therapy is an approach that could be developed for highly effective cancer therapy.

Calcium phosphate hybrid micelles inhibit orthotopic bone metastasis from triple negative breast cancer by simultaneously killing cancer cells and reprogramming the microenvironment of bone resorption and immunosuppression.

Triple negative breast cancer (TNBC) is prone to develop drug resistance and metastasis. Bone is the most common distant metastasis site of breast cancer cell. Patients with bone metastasis from TNBC suffer from unbearable pain due to the growth of bone metastasis and bone destruction. Simultaneously blocking the growth of bone metastasis and reprogramming the microenvironment of bone resorption and immunosuppression is a promising strategy to treat bone metastasis from TNBC. Herein, we prepared a pH and redox responsive drug delivery system, named DZ@CPH, by encapsulating docetaxel (DTX) with hyaluronic acid-polylactic acid micelle then reinforcing with calcium phosphate and zoledronate for targeting to bone metastasis from TNBC. DZ@CPH reduced the activation of osteoclast and inhibited bone resorption by decreasing the expression of nuclear factor κB receptor ligand and increasing the expression of osteoprotegerin in drug-resistant bone metastasis tissue. At the same time, DZ@CPH inhibited the invasion of bone metastatic TNBC cells by regulating the apoptosis-related and invasion-related protein expression. It also increased the sensitivity of orthotopic drug-resistant bone metastasis to DTX by inhibiting the expression of P-glycoprotein, Bcl-2 and transforming growth factor-ß in tissue of drug-resistant bone metastasis. Moreover, the ratio between M1 type macrophage to M2 type macrophage in bone metastasis tissue was increased by DZ@CPH. In a word, DZ@CPH blocked the growth of bone metastasis from drug-resistant TNBC through inducing the apoptosis of drug-resistant TNBC cells and reprogramming the microenvironment of bone resorption and immunosuppression. DZ@CPH has a great potential in clinical application for the treatment of bone metastasis from drug-resistant TNBC. STATEMENT OF SIGNIFICANCE: Triple negative breast cancer (TNBC) is prone to develop bone metastasis. Now bone metastasis is still an intractable disease. In this study, docetaxel and zoledronate co-loaded calcium phosphate hybrid micelles (DZ@CPH) were prepared. DZ@CPH reduced the activation of osteoclasts and inhibited bone resorption. At the same time, DZ@CPH inhibited the invasion of bone metastatic TNBC cells by regulating the expression of apoptosis and invasion related protein in bone metastasis tissue. Moreover, the ratio between M1 type macrophages to M2 type macrophages in bone metastases tissue was increased by DZ@CPH. In a word, DZ@CPH blocked vicious cycle between the growth of bone metastasis and bone resorption, which greatly improved the therapeutic effect on bone metastasis from drug-resistant TNBC.

New steroidal saponins from the roots of Paris verticillata.

Four new polyhydroxylated steroidal saponins, parisverticillatosides A-D (1-4), together with four known spirostanol saponins (5-8) were isolated from the roots of Paris verticillata. Their structures were elucidated on the basis of extensive spectroscopic analysis and chemical evidences. The discovery of the new compounds 1-4 extended the diversity and complexity of this spirostanol saponin family. The saponins 5 and 6 exhibited cytotoxicities against two human glioma cell lines.

Tumor targeted combination therapeutic system for the effective treatment of drug resistant triple negative breast cancer.

Breast cancer has become the malignant tumor with the largest incidence, especially the drug resistant triple negative breast cancer (TNBC). The combination therapeutic system can play a better role in resisting drug resistant TNBC. In this study, dopamine and tumor targeted folic acid modified dopamine were synthesized as carrier materials to construct melanin-like tumor targeted combination therapeutic system. The optimized nanoparticles of CPT/Fe@PDA-FA10 with efficient loading of camptothecin and iron was achieved, which showed tumor targeted delivery ability, pH sensitive controlled release, effective photothermal conversion performance and excellent anti-tumor efficacy in vitro and in vivo. CPT/Fe@PDA-FA10 plus laser could significantly kill the drug resistant tumor cells, inhibit the growth of the orthotopic drug resistant triple negative breast cancer through apoptosis/ferroptosis/photothermal treatment, and had no significant side effects on the main tissues and organs. This strategy provided a new idea for the construction and clinical application of triple-combination therapeutic system as effective treatment for drug resistant triple negative breast cancer.

Bone targeted miRNA delivery system for miR-34a with enhanced anti-tumor efficacy to bone-associated metastatic breast cancer.

Bone metastatic cancer is the most common occurrence in breast cancer, and the treatment is also facing great challenges. MicroRNA-34a (miRNA-34a) is a promising anti-cancer miRNA for gene therapy to bone metastatic cancer patients. However, the lack of specificity to bone and low accumulation at the site of bone tumor remains the major challenge when used bone-associated tumor. To solve this problem, a bone-targeted vector for delivery of miR-34a to bone metastatic breast cancer was constructed by using the commonly used gene vector branched polyethylenimine 25 k (BPEI 25 k) as the skeleton and linking with alendronate (ALN) moieties for bone targeting group. The constructed gene delivery system PCA/miR-34a can efficiently prevent miR-34a from degradation during blood circulation and enhance the specific bone delivery and distribution. PCA/miR-34a nanoparticles can be uptake into tumor cells through clathrin and caveolae-mediated endocytosis, and directly regulate the expression of oncogenes, thus promoting tumor cell apoptosis and relieving bone tissue erosion. The results of experiments in vitro and in vivo confirmed that the constructed bone-targeted miRNA delivery system PCA/miR-34a can enhance the anti-tumor efficacy in bone metastatic cancer, and provide a potential strategy for gene therapy in bone metastatic cancer.

Cytotoxic steroidal glycosides from the rhizomes of Paris polyphylla var. yunnanensis.

Paris polyphylla var. yunnanensis (Franch.) Hand.-Mazz. (Melanthiaceae), an important specie of the genus Paris, has long been in a traditional Chinese medicine (TCM) for a long time. This study aimed to isolate and identify the structures of bioactive saponins from the rhizomes of P. polyphylla var. yunnanensis and evaluate their cytotoxicity against BxPC-3, HepG2, U373 and SGC-7901 carcinoma cell lines. Seven previously undescribed and seven known saponins were identified, and Paris saponins VII (PSVII) showed significant cytotoxicity against the BxPC-3 cell line with IC50 values of 3.59 µM. Furthermore, flow cytometry, transmission electron microscopy and western-bolt analysis revealed that PSVII inhibited the proliferation of BxPC-3 cells and might be involved in inducing apoptosis and pyroptosis by activating caspase-3, -7 and caspase-1, respectively.

Tumor microenvironment and redox dual stimuli-responsive polymeric nanoparticles for the effective cisplatin-based cancer chemotherapy.

The serious side effects of cisplatin hindered its clinical application and the nanotechnology might be the potential strategy to address the limitation. However, rapid clearance in the blood circulation and ineffective controlled drug release from nanocarriers hamper the therapeutic efficacy of the nano-delivery system. We constructed a tumor microenvironment and redox dual stimuli-responsive nano-delivery system PEG-c-(BPEI-SS-Pt) by cross-linking the disulfide-containing polymeric conjugate BPEI-SS-Pt with the dialdehyde group-modified PEG2000via Schiff base. After optimized the cross-linking time, 72 h was selected to get the nano-delivery system.1H NMR and drug release assays showed that under the acidic tumor microenvironment (pH 6.5-6.8), the Schiff base can be broken and detached the PEG cross-linked outer shells, displaying the capability to release the drugs with a sequential pH- and redox-responsive manner. Moreover, PEG-c-(BPEI-SS-Pt) showed more effective anti-tumor therapeutic efficacyin vivowith no significant side effects when compared with the drug of cisplatin used in the clinic. This strategy highlights a promising platform with the dual stimuli-responsive profile to achieve better therapeutic efficacy and minor side effects for platinum-based chemotherapy.

Nano-Codelivery of Temozolomide and siPD-L1 to Reprogram the Drug-Resistant and Immunosuppressive Microenvironment in Orthotopic Glioblastoma.

Glioblastoma (GBM) is an invasive cancer with high mortality in central nervous system. Resistance to temozolomide (TMZ) and immunosuppressive microenvironment lead to low outcome of the standardized treatment for GBM. In this study, a 2-deoxy-d-glucose modified lipid polymer nanoparticle loaded with TMZ and siPD-L1 (TMZ/siPD-L1@GLPN/dsb) was prepared to reprogram the TMZ-resistant and immunosuppressive microenvironment in orthotopic GBM. TMZ/siPD-L1@GLPN/dsb simultaneously delivered a large amount of TMZ and siPD-L1 to the deep area of the orthotopic TMZ-resistant GBM tissue. By inhibiting PD-L1 protein expression, TMZ/siPD-L1@GLPN/dsb markedly augmented the percentage of CD3+CD8+IFN-γ+ cells (Teff cells) and reduced the percentage of CD4+CD25+FoxP3+ cells (Treg cells) in orthotopic TMZ-resistant GBM tissue, which enhanced T-cell mediated cytotoxicity on orthotopic TMZ-resistant GBM. Moreover, TMZ/siPD-L1@GLPN/dsb obviously augmented the sensitivity of orthotopic TMZ-resistant GBM to TMZ through decreasing the protein expression of O6-methyl-guanine-DNA methyltransferase (MGMT) in TMZ-resistant GBM cells. Thus, TMZ/siPD-L1@GLPN/dsb markedly restrained the growth of orthotopic TMZ-resistant GBM and extended the survival time of orthotopic GBM rats through reversing a TMZ-resistant and immunosuppressive microenvironment. TMZ/siPD-L1@GLPN/dsb shows potential application to treat orthotopic TMZ-resistant GBM.

Biomimetic GBM-targeted drug delivery system boosting ferroptosis for immunotherapy of orthotopic drug-resistant GBM.

BACKGROUND: Clinical studies have shown that the efficacy of programmed cell death receptor-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors on glioblastoma (GBM) is much lower than what is expected because of the low immunogenicity of GBM. Ferroptosis of cancer cells can induce the maturation of dendritic cells (DC cells) and increase the activity of T cell. The activated T cells release IFN-γ, which subsequently induces the ferroptosis of cancer cells. Thus, the aim of this paper is to set up a new GBM-targeted drug delivery system (Fe3O4-siPD-L1@M-BV2) to boost ferroptosis for immunotherapy of drug-resistant GBM. RESULTS: Fe3O4-siPD-L1@M-BV2 significantly increased the accumulation of siPD-L1 and Fe2+ in orthotopic drug-resistant GBM tissue in mice. Fe3O4-siPD-L1@M-BV2 markedly decreased the protein expression of PD-L1 and increased the ratio between effector T cells and regulatory T cells in orthotopic drug-resistant GBM tissue. Moreover, Fe3O4-siPD-L1@M-BV2 induced ferroptosis of GBM cells and maturation of DC cell, and it also increased the ratio between M1-type microglia and M2-type microglia in orthotopic drug-resistant GBM tissue. Finally, the growth of orthotopic drug-resistant GBM in mice was significantly inhibited by Fe3O4-siPD-L1@M-BV2. CONCLUSION: The mutual cascade amplification effect between ferroptosis and immune reactivation induced by Fe3O4-siPD-L1@M-BV2 significantly inhibited the growth of orthotopic drug-resistant GBM and prolonged the survival time of orthotopic drug-resistant GBM mice.

The regulatory role and mechanism of autophagy in energy metabolism-related hepatic fibrosis.

Hepatic fibrosis is a key pathological process of chronic liver diseases, caused by alcohol, toxic and aberrant energy metabolism. It progresses to cirrhosis or even hepatic carcinoma without effective treatment. Studies have shown that autophagy has important regulatory effects on hepatic stellate cells (HSCs) energy metabolism, and then affect the activation state of HSCs. Autophagy maintains hepatic energy homeostasis, and the dysregulation of autophagy can lead to the activation of HSCs and the occurrence and development of hepatic fibrosis. It is necessary to explore the mechanism of autophagy in energy metabolism-related hepatic fibrosis. Herein, the current study summarizes the regulating mechanisms of autophagy through different targets and signal pathways in energy metabolism-related hepatic fibrosis, and discusses the regulatory effect of autophagy by natural plant-derived, endogenous and synthetic compounds for the treatment of hepatic fibrosis. A better comprehension of autophagy in hepatic stellate cells energy metabolism-related hepatic fibrosis may provide effective intervention of hepatic fibrosis, explore the potential clinical strategies and promote the drug treatment of hepatic fibrosis.

MCP mediated active targeting calcium phosphate hybrid nanoparticles for the treatment of orthotopic drug-resistant colon cancer.

BACKGROUND: Colon cancer is a most common malignant cancer in digestive system, and it is prone to develop resistance to the commonly used chemotherapy drugs, leading to local recurrence and metastasis. Paris saponin VII (PSVII) could not only inhibit the proliferation of colon cancer cells but also effectively induce apoptosis of drug-resistant colon cancer cells and reduce the metastasis of drug-resistant colon cancer cells as well. However, PSVII was insoluble in water and fat. It displayed no selective distribution in body and could cause severe hemolysis. Herein, colon cancer targeting calcium phosphate nanoparticles were developed to carry PSVII to treat drug-resistant colon cancer. RESULTS: PSVII carboxymethyl-ß-cyclodextrin inclusion compound was successfully encapsulated in colon cancer targeting calcium phosphate nanoparticles (PSVII@MCP-CaP) by using modified citrus pectin as stabilizer agent and colon cancer cell targeting moiety. PSVII@MCP-CaP significantly reduced the hemolysis of PSVII. Moreover, by specific accumulating in orthotopic drug-resistant colon cancer tissue, PSVII@MCP-CaP markedly inhibited the growth of orthotopic drug-resistant colon cancer in nude mice. PSVII@MCP-CaP promoted the apoptosis of drug-resistant colon cancer cells through mitochondria-mediated apoptosis pathway. Moreover, PSVII@MCP-CaP significantly inhibited the invasion and migration of drug-resistant colon cancer cells by increasing E-cadherin protein expression and reducing N-cadherin and MMP-9 protein expression. CONCLUSION: PSVII@MCP-CaP has great potential in the treatment of drug-resistant colon cancer. This study also explores a new method to prepare active targeting calcium phosphate nanoparticles loaded with a fat and water insoluble compound in water.

New Steroidal Saponins Isolated from the Rhizomes of Paris mairei.

The genus Paris is an excellent source of steroidal saponins that exhibit various bioactivities. Paris mairei is a unique species and has been widely used as folk medicine in Southwest China for a long time. With the help of chemical methods and modern spectra analysis, five new steroidal saponins, pamaiosides A-E (1-5), along with five known steroidal saponins 6-10, were isolated from the rhizomes of Paris mairei. The cytotoxicity of all the new saponins was evaluated against human pancreatic adenocarcinoma PANC-1 and BxPC3 cell lines.

Chemoattractants driven and microglia based biomimetic nanoparticle treating TMZ-resistant glioblastoma multiforme.

Currently, clinical treatment for temozolomide (TMZ)-resistant glioblastoma multiforme (GBM) is still a difficult problem. The aim of this paper is to set up a new GBM-targeted drug delivery system to treat TMZ-resistant GBM. Zoledronate (ZOL) not only induces apoptosis of TMZ-resistant GBM cells by down-regulation of farnesyl pyrophosphate synthetase (FPPS) but also increases the proportion of M1-type GBM associated macrophages (GAM). Based on chemoattractants secreted by GBM cells, a ZOL loaded nanoparticle coated with microglia cell membrane (ZOL@CNPs) was prepared to deliver ZOL to central nervous system to treat TMZ-resistant GBM. ZOL@CNPs was actively recruited to TMZ-resistant GBM region by CX3CL1/CX3CR1 and CSF-1/CSF-1R signal axis, and the release of ZOL from ZOL@CNPs was triggered by glutathione in GBM cells. ZOL@CNPs inhibited the growth of TMZ-resistant GBM through inducing apoptosis and inhibiting the migration and invasion of TMZ-resistant GBM cells. Besides, the immunosuppressive and hypoxic microenvironment, playing an important role in the growth of TMZ-resistant GBM, was significantly improved by ZOL@CNPs through increasing the proportion of M1-type GAM and blocking the expression of HIF-1α. ZOL@CNPs has a great potential application in the treatment for TMZ-resistant GBM.

Bone-targeted PAMAM nanoparticle to treat bone metastases of lung cancer.

Aim: To prepare pH-sensitive nanoparticle composed of alendronate (ALN) and poly(amidoamine) (PAMAM) to treat bone metastases of lung cancer. Methods: The solvent evaporation method was used to prepare docetaxel (DTX)-loaded ALN-PAMAM nanoparticles (DTX@ALN-PAMAM). Results: The in vitro results showed DTX@ALN-PAMAM significantly enhanced the anticancer activity of DTX and inhibited the formation of osteoclasts. DTX@ALN-PAMAM concentrated at bone metastasis site in mice, which resulted in the suppression of bone resorption, pain response and growth of bone metastases. Eventually, the therapeutic effect of DTX on bone metastases of lung cancer was obviously improved. Conclusion: ALN modified PAMAM nanoparticle could be an effective platform for the treatment of bone metastases of lung cancer.

Construction of redox-responsive tumor targeted cisplatin nano-delivery system for effective cancer chemotherapy.

Cisplatin is one of the most widely used platinum-based anticancer chemotherapeutic drugs. However, its low solubility, serious side effects and the development of cisplatin resistance limit its further use in the clinic. Controlling the delivery and release of cisplatin at the targeted site efficiently is a meaningful way to overcome these undesirable side effects of cisplatin. Herein, a tumor targeted and stimuli responsive nano-delivery system for cisplatin was constructed using branched polyethyleneimine (BPEI) as the backbone, disulfide bond as the redox-responsive covalent linker and hyaluronic acid (HA) as targeting recognition unit which can bind selectively to the receptor of CD44, which is highly expressed on the A549 tumor cells. The cisplatin-polyethyleneimine conjugate BPEI-SS-Pt was prepared and the drug loading of cisplatin was up to 32.66 ± 0.06%. After optimized the coating weight ratio of HA and BPEI-SS-Pt, the nanoparticle delivery system HA-(BPEI-SS-Pt)-1/4 outperformed with smaller particle size of 159.0 ± 21.0 nm, narrow polydispersity index (PDI) of 0.069 ± 0.022 and higher cisplatin loading of 29.23 ± 0.18%, showing specific tumor-targeting ability and redox-responsive drug release manner. Moreover, for the treatment of cancer in vivo, it achieved more effective antitumor performance along with minor side effects and systemic toxicity compared with cisplatin which is of great significance for the chemotherapeutic drug in the clinic.

Osteoclasts and tumor cells dual targeting nanoparticle to treat bone metastases of lung cancer.

Bone is one of the prone metastatic sites of lung cancer. Osteoclast plays an important role in bone resorption and the growth of bone metastases of lung cancer. In order to treat bone metastases of lung cancer, we reported a docetaxel (DTX)-loaded nanoparticle, DTX@AHP, which could target dually at osteoclasts and bone metastatic tumor cells. The in vitro drug release from DTX@AHP exhibited pH and redox responsive characteristics. DTX@AHP displayed high binding affinity with bone matrix. In addition, DTX@AHP significantly inhibited the differentiation of RAW264.7 into osteoclast and effectively inhibited the proliferation of osteoclasts and tumor cells in in-vitro 3D bone metastases model of lung cancer. DTX@AHP could accumulate in bone metastases sites in vivo. Consequently, DTX@AHP not only markedly inhibited the growth of bone metastases of lung cancer but also reduced osteolysis in tumor-bearing mice. DTX@AHP exhibited great potential in the treatment of bone metastases of lung cancer.