Photothermal therapy (PTT) is a highly effective anti-tumor method. However, when laser radiation was used to ablate tumors, it usually triggers a series of inflammatory reactions, promoting the further development of tumors and affecting the effect of anti-tumor therapy. Therefore, it is an effective method to improve the anti-tumor effect by suppressing the inflammatory response through the precise targeted delivery of anti-inflammatory drug while realizing the photothermal treatment of tumors. To this end, the redox-responsive linker 3, 3'-dithiodipropionic acid was used to bond the classic hydrophobic anti-inflammatory drug 18β-glycyrrhetinic acid (18β-GA) and the hydrophilic fragment methoxy-polyethylene glycol (mPEG-NH₂) to obtain redox-responsive amphiphilic polymer PEG-DA-GA in this study. Then, photothermal agent IR-780 was encapsulated to prepare redox-responsive polymer micelle PDG/IR-780 NPs. The PDG/IR-780 NPs exhibited uniform particle size of 80.2±5.3 nm and the polydispersity index (PDI) was 0.215±0.079. All animal experiments followed the ethical requirements formulated by the Ethics Committee of Sichuan University. The results showed that PDG/IR-780 NPs could respond to the abundant glutathione (GSH) in tumor cells to promote the disintegration of nanoparticle and the release of 18β-GA, thus significantly improved the killing efficiency on 4T1 cells, when compared with the non-redox-responsive control PSG/IR-780 NPs. When the concentration of 18β-GA was 50 μg·mL^-1, the cell viability of 4T1 cells in the PDG/IR-780 NPs group was only (19.29±1.80)%, which was significantly lower than the result of in PSG/IR-780 NPs group (29.30±1.37)%. The results of frozen sections of tumor tissues showed that the designed PDG NPs can promote the tumor-targeted distribution of drugs compared with the free drug group. Eventually, PDG/IR-780 NPs achieved wonderful anti-tumor efficacy on 4T1 triple-negative breast cancer model, revealing the new possibility of the combined therapy strategy of photothermal and anti-inflammatory therapy.

Tumor microenvironment (TME) is composed of abnormal tumor vasculature, extracellular matrix components, endothelial cells, pericytes, tumor associated fibroblasts, smooth muscle cells and immune cells, which is characterized by hypoxia, acidosis and high interstitial fluid pressure. Hypoxia and acidosis within the TME trigger an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e.g., fibroblasts) and immune cells (lymphocytes and macrophages), inducing tumor growth, angiogenesis, and ultimately, resulting in metastasis. What's more, the components of TME including abnormal tumor vasculature, rich composition of the ECM, and abundant stroma cells impair tumoral distribution and penetration of the drugs. At the same time, this stromal microenvironment plays a vital role in creating an immunosuppressive environment.Over the past years, more and more researches focus on targeting and remolding TME to improve therapeutic effects against tumors. Herein, we reviewed current strategies developed to target and remodel TME, including modulating tumor hypoxia, tumor vasculature, tumor associated fibroblasts, extracellular matrix components, tumor associated macrophage phenotypes and dendritic cells. Also, potential problems and future directions are pointed out in this review.

There are two serious obstacles to tumor immunotherapy. Firstly, the immune response of the tumor is seriously reduced due to immunosuppressive tumor microenvironment (ITM) and low immunogenicity of tumor. The second obstacle is the dense and complex heterogeneous structures, which seriously prevent the nanoparticles (NPs) from penetrating deeper into tumor tissue. Immunogenic cell death (ICD) induced by doxorubicin (DOX) is an effective method to enhance tumor immune activity. However, interferon-γ (IFN-γ) secreted by cytotoxic T lymphocytes (CTL) after ICD induction would increase the expression of indoleamine 2, 3-dioxygenase 1 (IDO1) and enhance ITM. IDO1 siRNA would reduce the expression of IDO1 protein, regulate the tumor immunosuppressive microenvironment and regulate ITM, so as to enhance the ICD effect of DOX. In this paper, a novel charge conversional, particle size reduction and highly penetrable NPs based on a pH sensitive copolymer poly(ethylene glycol)-poly-L-lysine-2, 3-dimethylmaleic anhydride (mPEG-PLL-DMA, PLD) and polyamidoamine (PAMAM) dendrimers to achieve deep delivery of tumor tissue. DOX and IDO1 siRNA were encapsulated to achieve efficient tumor immunotherapy. Preparation and cell level experiments showed that PLD material had significant pH sensitivity. Results of 3D tumor penetrable experiment in vitro showed that adding the pH sensitive material PLD significantly improved the permeability of the preparation. In addition, 4T1 tumor model was established for BALB/c mice and all animal experiments were displayed in according with the requirements of the Animal Experiment Ethics Committee of Shenyang Pharmaceutical University. The results of in vivo efficacy experiments and tissue experiments evaluated that IDO1 siRNA significantly improved the ICD effect owing to DOX, so as to significantly inhibit tumor growth.

Exosomes are one of the most important ways of cell-to-cell communication in living lives. They are involved in major physiological and pathological processes, including drug resistance, infection propagation, cancer development and cardiovascular diseases. The biological functions of exosomes made it possess characteristics of low immunogenicity, high delivery efficiency, ability to cross multiple biological barriers and targeting capacity, which also encourage people to try to use it as a drug carrier to overcome the disadvantages of poor stability, low solubility, low bioavailability and high toxicity of some drugs. In this paper, the latest progress of exosomes in the delivery of antitumor drugs, including small chemotherapeutic drugs, biological macromolecules and nucleic acid drugs, is reviewed. In addition, the isolation, drug loading, and modification method and the application prospect of exosomes are also discussed.

Cancer is considered as one of the major diseases endangering human health in the world, it is urgent to find a safer and more efficient treatment for cancer therapy. Gene therapy with ribonucleic acid (RNA) drugs could regulate the expression of tumor related genes, and exhibit good anti-tumor therapeutic potential in preclinical and clinical trials. Based on the differences between tumor tissues and normal tissues in microenvironment signal characteristics such as pH, specific enzyme concentration or redox gradient, various microenvironment responsive nanocarriers had been studied and developed to deliver RNA drugs to tumor tissues and cells, improving the anti-tumor efficacy of RNA drugs and reducing toxic and side effects. This paper reviews the pathophysiological characteristics of tumor microenvironment and various strategies of tumor microenvironment responsive nanocarriers, in order to provide reference for the design of safe and efficient RNA drug delivery system for cancer therapy.

The non-specific accumulation and release of drugs are the main factors affecting the therapeutic effect as well as causing toxic side effects of chemotherapeutic drugs. Nowadays, the application of nanotechnology and responsive drug release is an important strategy to improve the tumor-specific accumulation of drugs and reduce their side effects. In this study, an α-enolase targeted peptide (ETP)-modified polyethylene glycol poly-lysine block copolymer loaded with oxaliplatin prodrug was synthesized first, and then, polymer-coating Fe₃O₄ nanoparticles were prepared by phase transfer dialysis method to improve the blood circulation stability and tumor targeting of oxaliplatin. At the same time, the physicochemical properties, reductant-responsive drug release, cellular uptake, tumor targeting and other biological functions of ETP modified oxaliplatin-loaded Fe₃O₄ nanoparticles were studied in vitro and in vivo. First, the results of reductant-triggered drug release study showed that the drug-loaded nanoparticles could achieve rapid release of more than 80% of the prototype oxaliplatin within 3 h under the reduction conditions simulating the tumor cytoplasmic microenvironment. Secondly, the results of flow cytometry showed that the modification of ETP could increase the ratio of cellular uptake of drug-loaded nanoparticles in tumor cells, and the way that drug-loaded nanoparticles endocytosed by tumor cells were mainly through the energy-dependent and receptor protein and fossin-mediated endocytosis pathway. The animal procedures were approved by the Institutional Animal Care and Use Committee of School of Pharmacy of Fudan University. Moreover, the results of pharmacokinetic experiment showed that the area under the curve (AUC_0-∞) of oxaliplatin could be significantly increased by nano-formulation which was about 5 times than that of free oxaliplatin. Besides, the pharmacokinetic results also showed that the drug-loaded Fe₃O₄ nanoparticles constructed by covalent linkage and chelation had good overall stability in vivo. Finally, the in vivo imaging results showed that ETP modification could increase tumor accumulation of drug-loaded nanoparticles, which would be conducive to the efficacy of oxaliplatin in tumor lesions. In summary, the oxaliplatin-loaded Fe₃O₄ nanoparticles with the capability of reductant-responsive drug release have good drug release characteristics, blood circulation stability and tumor targeting ability, and have the potential to improve the anti-tumor therapeutic effect of oxaliplatin.

Borneol (Bo) and Arg-Gly-Asp (RGD) co-modified docetaxel (DTX) loaded MPEG-PLGA nanoparticles (DTX-Bo-RGD-NPs) were prepared to improve the therapeutic effect of DTX against glioma after intranasal administration. DTX-Bo-RGD-NPs were prepared by emulsification-solvent evaporation method, and their morphology, particle size, zeta potential, drug loading capacity (DLC), stability, and in vitro release properties were investigated. The fluorescence probe coumarin-6 loaded NPs were prepared for investigating the NPs' uptake property on C6 and 16HBE cell models to evaluate in vitro targeting ability. The DiR loaded NPs were prepared for observing the fluorescence intensity at the brain tumor site after intranasal administration through in vivo imaging system in a C6 rat orthotropic model, evaluating the targeting ability in vivo. The anti-tumor effects of DTX-Bo-RGD-NPs were also investigated in such C6 rat orthotropic model in vivo. Animal welfare and experimental procedures are in compliance with the regulations of the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine. The results showed that DTX-Bo-RGD-NPs were spherical and uniformly distributed, with a particle size of about 140 nm and a zeta potential of -20 to -30 mV. The drug delivery system showed good stability and sustained release property in vitro, and favorable brain tumor targeting effect in vitro and in vivo. Such novel drug delivery system significantly improved the accumulation of DTX-Bo-RGD-NPs in tumor sites and displayed a higher brain tumor targeting efficiency, providing promising therapeutics of DTX for the treatment of glioma after intranasal administration.

Cryptotanshinone (CPT), an active ingredient with the inhibitory effect on brain glioma cells, is trapped with poor solubility and low tumor permeability. Therefore, it is urgent to design nano drug delivery systems characterized with deep penetration and accurate targeting. In the present study, tLyp-1 modified liposomes loaded with CPT (tLipo/CPT) was prepared by emulsion solvent evaporation method. Peptide tLyp-1 which targeting tumor angiogenesis and neuropilin receptors (NRP) was modified on surface of CPT liposomes, with the aim of active targeting brain glioma cells and further release CPT precisely. The size and polymer dispersity index (PDI) of tLipo/CPT were (162.2 ± 14.6) nm and 0.24 ± 0.03. The optimal molar ratio of tLyp-1 modified on CPT liposomes was 0.5% determined by intracellular fluorescence parameters. The morphology displayed a smooth sphericity structure as determined by transmission electron microscope. Efficiency of CPT encapsulated in tLipo/CPT was detected by high performance liquid chromatography. The encapsulation efficiency of CPT was (70.06 ± 7.22) %. Liposomes modified with tLyp-1 peptide (tLipo) were internalized more than liposomes not modified with tLyp-1 (Lipo) by GL261 cells. Fluorescence intensity of tLipo in GL261 cells increased 40% than that of Lipo. Furthermore, we proved that the intake of tLipo/CPT in GL261 cells was mediated by NRP-1 receptor. MTT analysis indicated that tLipo/CPT significantly inhibit the proliferation of GL261 cells. The half maximal inhibitory concentration (IC₅₀) was 5.70 μmol·L^-1. In vitro blood-brain barrier (BBB) model experiment indicated that tLipo/CPT could penetration across BBB. Moreover, in vivo fluorescence biodistribution study indicated tail vein injection of DiR labeled tLipo after 0.5 h, DiR fluorescence could be observed in the brain of mice. Even after 24 h, DiR fluorescence still was observed in the brain. Our research certified that tLipo/CPT can penetrate the BBB and show effect of anti-glioma by inhibiting the proliferation of GL261 cells. The animal experiment was carried out in accordance with protocol evaluated and approved by the Ethics Committee of Nanjing University of Chinese Medicine.

To explore the effect of tanshinone IIA (TanIIA) on the occurrence and development of breast cancer, we employed the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) transgenic mice as a spontaneous breast cancer mouse model. Animal welfare and experimental procedures were in accordance with the regulations of the Animal Ethics Committee of Nanjing University of Chinese Medicine. The animals were divided into control group, low-dose TanIIA treatment group (30 mg·kg^-1·day^-1), and high-dose TanIIA treatment group (60 mg·kg^-1·day^-1). The treatment was administered orally and daily for 5 weeks. The mice were sacrificed after final treatment. Mammary gland and lung were collected for histopathology studies. We evaluated the chemoprophylaxis effect of TanIIA on breast cancer in mice according to the pathological characteristics of breast cancer at different stages of development. Immunofluorescence staining were employed for blood vessel analysis. The expression levels of E-cadherin, proliferating nuclear antigen (PCNA), and oncogene c-Myc were detected by immunohistochemistry. Flow cytometry was used to analyze cell cycle and Cytoscape was used to construct drug-disease protein-protein interaction (PPI) network. Our results showed that TanIIA inhibits breast tumor progression by delaying malignancy from adenoma to early carcinoma, and inhibits blood vessel formation during tumor development. TanIIA (60 mg·kg^-1·day^-1) inhibits the expression levels of PCNA and c-Myc, upregulates the expression of E-cadherin. In addition, cell cycle experiments showed that the cell cycle of PyMT primary mammary cells in the high-dose TanIIA group was arrested in the G0/G1 phase. Our study demonstrated that TanIIA can significantly inhibit breast tumor progression in MMTV-PyMT mouse model, which may be related to the inhibition of angiogenic switch and cell cycle arrest.

In order to solve the problems of erratic drug absorption and low bioavailability after oral administration for poorly-water soluble drugs due to low solubility, a series of novel pharmaceutical dosage forms as solid dispersion, liposome, microemulsion, vesicle, cyclodextrin inclusion complexes and drug nanocrystal have been developed in recent years. Among which drug nanocrystal attracts more attentions for its simpler preparation method, higher drug loading and easier manufacturing technology in the design of dosage forms suitable for different administration routes. In this paper, the nanocrystals of the poorly-water soluble drugs prepared based on bottom-up and top-down technologies were introduced. The characteristics and applications of the nanocrystal-based dosage forms as suspension, tablet and capsule were also introduced and carefully evaluated with the focus on their pharmacokinetics, pharmacodynamics and tissue targeted drug distribution after delivery by oral administration, intravenous injection and pulmonary inhalation. The advantages of drug nanocrystals in their therapeutics effects over the bulk drugs were discussed together with the inherent mechanism. Finally, the problems existing in basic research and scaled-up manufacture of drug nanocrystal as well as the possible ways of solution were listed out so as to make the nanocrystal-based preparations exert their maximum therapeutic effect after clinical application.