Pancreatic cancer stroma plays a critical role in tumor progression, invasion, metastasis and resistance.Targeting tumor cell alone could not meet the demand for prolonging patients'' survival.Growing studies have laid emphasis on developing combined regimens between targeting pancreatic cancer stroma and chemotherapy, radiotherapy and immunotherapy.We are faced with some new opportunities in spite of the great challenges brought to the research and development of targeting drugs owing to the complicated stroma components, crosstalking signal pathways and abnormal angiogenesis of pancreatic cancer.In this article, recent advances in therapeutic strategies of targeting pancreatic cancer stroma are reviewed and analyzed from the aspects of extracellular matrix (ECM), cancer associated fibroblasts (CAFs) and vessels, in the hope of providing some novel ideas for targeting therapy against pancreatic cancer.

Recent advances in nanotechnology have greatly facilitated the development of nanoparticle drug delivery system. The present work reviews recent literature on nanotechnology-based applications and developments of silymarin preparation. A variety of nanoparticle formulations have been extensively investigated to improve the absorption and bioavalability of silymarin, including: improving the drug dissolution signficantly(such as nanosuspensions, inclusion complex with β-cyclodextrins, self-emulsifying drug delivery systems, solid dispersions, micronization), promoting the permeability across cell membrane(such as complexation with phospholipids, nanostructured lipid carriers)and other methods(such as micelles, mesoporous silica nanoparticles, polyamidoamine dendrimers). The applications of nanoscience and nanotechnology can help to promote the further pharmaceutical development of silymarin.

Tumor-associated macrophages (TAMs) are the most abundant innate immune cells in tumors, which generally exhibit anti-inflammatory M2 phenotypes, and are the key inducers of tumor development, metastasis and drug resistance, and thus becoming a popular target in the field of antitumor immunotherapy.The study and application of nanocarriers optimize TAMs-targeted antitumor therapy.According to the characteristics and functions of TAMs, modulation strategies based on TAMs are elaborated, including TAMs depletion, inhibition of TAMs recruitment and TAMs repolarization.At the same time, in order to apply the above strategies more efficiently and overcome the general off-target problems in treatment, specific TAMs-targeted therapies based on nanocarriers are reviewed and analyzed, including passive targeting to TAMs, active targeting to macrophages and specifically active targeting to M2-TAMs. Finally, based on the limitations of targeting TAMs alone, new therapeutic strategies of targeting both TAMs and tumor cells via nanocarrier based delivery systems are introduced to provide new ideas for the application of these strategies in the field of tumor immunotherapy and combination therapy with other antitumor strategies.

Nanotechnology has brought new strategies in the area of pharmaceutical sciences, especially in the drug delivery system. Among them, the application of protein as drug carriers has drawn extensive attention. A wide variety of proteins that have been used fordrug delivery system including the common animal- and plant-basedproteins, as well as the recombinant protein nanoparticles, which possess many advantages such as biocompatibility, biodegradability, low antigenicity, higher stability and drug loading property. This system is of great significance in the fields of clinical treatment, especially targeted therapy of tumors. In this paper, the fabrication of nanoparticles from animal, botanical, and recombinant proteins are described. And then, trend of development in protein-based nanocarriers is also prospected.

The objectives of this study were to prepare polysaccharide modified compound liposomes loaded with paclitaxel (PTX) and doxorubicin (DOX) and characterize their phyisicochemical properties,stability and in vitro release profiles.Both PTX-DOX-Lipo and N-lauryl-O-glycol chitosan (LGC) modified liposomes (PTX-DOX-Lipo-LGC) were successfully prepared,and the morphology of the liposomes was observed by transmission electron microscope (TEM),and particle size and zeta potential were analyzed by dynamic light scattering (DLS).pH and osmotic pressure were also determined.The drug loading and encapsulation efficiency,stability and in vitro release were assayed using high-performance liquid phase.Both PTX-DOX-Lipo and PTX-DOX-Lipo-LGC exhibited spherical shape with smooth surface.The average diameter was about 150 nm.pH value and osmotic pressure were in the range of 5.3-6.1 and 820-870 mOsm/kg,respectively.Both PTX and DOX could be encapsulated in liposomes with high encapsulation efficiency (greater than 90％).Compared with PTX-DOX-Lipo,PTX-DOX-Lipo-LGC exhibited lower leakage,higher stability in serum and more sustained release profiles.Moreover,a quicker release rate was observed in pH 5.8 PBS compared with pH 7.4 PBS.PTX-DOX-Lipo-LGC with high drug loading,good stability and sustained drug release profiles has a wide prospect in future clinical application.

Solid dispersions of the insoluble compound CHMFL-KIT-110 were prepared by solvent method with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus),Poloxamer 407,PEG 6000,Copovidone (Kollidon VA64) as carriers and SLS,Tween 80,Cremophor RH40 as solubilizers. The optimal formulation was screened and obtained with dynamic solubilities and supersaturation performances as indexes. The final product was characterized by Fourier transform infrared (FT-IR),differential thermal analysis (DTA) and X-ray powder diffraction (XRPD). The stability and pharmacokinetic behavior in rats were also investigated. Results suggested that when the weight ratio of CHMFL-KIT-110/Soluplus/SLS was 1∶4∶0.5,dynamic solubility of the solid dispersions was significantly improved with no recrystallization. In the accelerated condition (40 °C,75% RH) for 30 days,CHMFL-KIT-110 in the solid dispersions was still amorphous with no crystal observed. The results of pharmacokinetics in rats showed that the cmax and AUC0→t of CHMFL-KIT-110 solid dispersions were 373.1 times and 358.7 times higher than those of free drugs,respectively. These results help to understand the formulation development and clinical practice of CHMFL-KIT-110.

In order to evaluate the consistency of the release behavior between the self-made saxagliptin and metformin hydrochloride sustained-release tablets and the reference preparations in vitro, the similarity of the dissolution curves between the self-made preparations and the reference preparations in four dissolution mediums: HCl (pH 1.0), acetate buffer saline (pH 4.5), phosphate buffer saline (pH 6.8) and pure water, and the gel morphology and strength of the self-made preparations and the reference preparations in the HCl (pH 1.0) solution medium were compared.Results showed that in four dissolution mediums, the dissolution rates of saxagliptin in the self-made preparations and the reference preparations at 15 min were greater than 85%, and the ?2 similarity factors of metformin hydrochloride were 89, 83, 80, 86, all greater than 50, so the dissolution of the self-made preparations was consistent with those of the reference preparations.The volume expansion rate, water absorption rate and erosion rate were consistent with those of the reference preparations, and the gel strength of the self-made preparations was the same as that of the reference preparations.The in vitro release behaviors of the self-made preparations and the reference preparations are consistent, which provide a good guarantee for bioequivalence.

Tumor-associated fibroblasts(TAFs),the most important stromal cells of the tumor microenvironment (TME),have been found to support tumorigenesis and tumor metastasis in a variety of ways,including paracrine, direct contact with cells,immune regulation and extracellular matrix remolding.Therefore,TAFs in the TME have been an optimal target for cancer therapy.In this review,the TAFs targeted therapies are summarized to provide the new strategy for tumor treatments based on the analysis of the location and specific biological phenotypes of TAFs in tumors.

Hypoxia,a salient feature of solid tumors,is often associated with invasiveness,metastasis and resistance to anticancer drugs.The strategies including the use of oxygen-carriers based on hyperbaric oxygen and blood substitutes to transport oxygen into tumors or in situ generation of O2from the tumor microenvironment endogenous H2O2have been explored to relieve the tumor hypoxia and to improve therapeutic efficiency.In addi-tion,it is potential to design hypoxia-responsive nanocarriers based on tumor hypoxia microenvironment to deliver anticancer drugs to the targeted tumor site,thereby improve drug concentrations in targeted site,significantly increase the antitumor efficiency and reduce the side-effects of drugs.This review gives an overview of the advances in relieving tumor hypoxia and hypoxia-responsive nanocarriers for tumor to provide a reference for the research and development of new antitumor drugs.

With the rapid development of nanotechnology and in-depth understanding of tumor microenvironment, stimuli-responsive smart drug delivery nanosystem based on tumor microenvironment(TME)has received extensive attention. TME-responsive smart delivery nanosystem can transport antitumor drug in circulation stably, after arriving in tumor tissue or targeted cells, the structure of nanocarriers changes under the stimuli of TME. Improved drug concentrations in targeted site significantly increase the antitumor efficiency and reduce the side effects of drugs. The stimulating factors in the TME include pH, redox potential, enzyme, reactive oxygen species(ROS), adenosine-5′-triphosphate(ATP)and so on. This review mainly gives a comprehensive overview in the latest research and new development in TME-responsive smart drug delivery nanosystems for efficient tumor therapy, mainly based on pH response type, enzyme response, reduction response, ROS response, and ATP response smart drug delivery nanosystems. Moreover, research directions in the future are pointed out in this review.