Combination immunotherapy of PEG-modified preladenant thermosensitive liposomes and PD-1 inhibitor effectively enhances the anti-tumor immune response and therapeutic effects.

Immunotherapy is a promising cancer treatment strategy. In contrast, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors are associated with low response rates and are only useful in a small group of cancer patients. A combination of treatments may be effective for overcoming this clinical issue. Preladenant is an adenosine (ADO) receptor inhibitor that can block the ADO pathway and improve the tumor microenvironment (TME), thereby enhancing the immunotherapeutic effect of PD-1 inhibitors. However, its poor water solubility and low targeting limit its clinical applications. We designed a PEG-modified thermosensitive-liposome (pTSL) loaded with ADO small molecule inhibitor preladenant (P-pTSL) to overcome these problems and enhance the effect of PD-1 inhibitor on breast cancer immunotherapy. The prepared P-pTSL was round and uniformly distributed with a particle size of (138.9 ± 1.22) nm, PDI: 0.134 ± 0.031, and zeta potential (-10.1 ± 1.63) mV; preladenant was released slowly at 37 °C but released fast at 42 °C from P-pTSL, which was 76.52 ± 0.44%. P-pTSL has good long-term and serum stability and excellent tumor-targeting ability in mice. Moreover, the combination with PD-1 inhibitor significantly enhanced the anti-tumor effect, and the improvement of related factors in serum and lymph was more obvious under the condition of 42 °C thermotherapy in vitro.

Novel biomimetic nanostructured lipid carriers for cancer therapy: preparation, characterization, and in vitro/in vivo evaluation.

Nanostructured lipid carriers (NLC) have become a research hotspot, wherein cancer-targeting effects are enhanced and side effects of chemotherapy are overcome. Usually, accelerated blood clearance (ABC) occurs after repeated injections, without changing the immunologic profile, despite PEGylation which prolongs the circulation function. To overcome these problems, we designed a red blood cell-membrane-coated NLC (RBCm-NLC), which was round-like, with a particle size of 60.33 ± 3.04 nm and a core-shell structure. Its stability was good, the drug paclitaxel (PTX) release from RBCm-PTX-NLC was less than 30% at pH7.4 and pH6.5, and the integrity of RBC membrane surface protein was maintained before and after preparation. Additionally, in vitro assays showed that, with the RBCm coating, the cellular uptake of the NLC by cancer cells was significantly enhanced. RBCm-NLC can avoid recognition by macrophage cells and prolong circulation time in vivo. In S180 tumor-bearing mice, the DiR-labeled RBCm-NLC group showed a stronger fluorescence signal and longer retention in tumor tissues, indicating a prompt tumor-targeting effect and extended blood circulation. Importantly, RBCm-PTX-NLC enhanced the antitumor effect and extended the survival period significantly in vivo. In summary, biomimetic NLC offered a novel strategy for drug delivery in cancer therapy.

Cancer cell membrane-coated mesoporous silica loaded with superparamagnetic ferroferric oxide and Paclitaxel for the combination of Chemo/Magnetocaloric therapy on MDA-MB-231 cells.

To effectively inhibit the growth of breast cancer cells (MDA-MB-231 cells) by the combination method of chemotherapy and magnetic hyperthermia, we fabricated a biomimetic drug delivery (CSiFePNs) system composed of mesoporous silica nanoparticles (MSNs) containing superparamagnetic ferroferric oxide and Paclitaxel (PTX) coated with MDA-MB-231 cell membranes (CMs). In the in vitro cytotoxicity tests, the MDA-MB-231 cells incubated with CSiFePNs obtained IC50 value of 0.8 µgL-1, 3.5-fold higher than that of SiFePNs. The combination method of chemotherapy and magnetic hyperthermia can effectively inhibit the growth of MDA-MB-231 cells.

Analysis of Genetic Diversity and Population Structure in Three Forest Musk Deer Captive Populations with Different Origins.

Musk deer (Moschidae), whose secretion is an expensive and irreplaceable component of traditional medicine, have become endangered in the wild due to habitat fragmentation and over-exploitation. In recent years, China has had success in the artificial breeding of forest musk deer, thus relieving the pressure on wild populations. However, many farmed populations are experiencing degradation, and little genetic information is available for conservation management. In this study, we selected 274 individuals from three typical captive populations (originated from the Ta-pa Mountains (Tp), the midrange of the Qinling Mountains (Ql) and the Western Sichuan Plateau (WS), respectively) to evaluate the genetic variations. A total of more than 3.15 billion high-quality clean reads and 4.37 million high-quality SNPs were generated by RAD sequencing. Based on the analysis, we found that captive forest musk deer populations exhibit a relatively low level of genetic diversity. Ql displayed a higher level of genetic diversity than the Tp and WS populations. Tp and WS had experienced population bottlenecks in the past as inferred from the values of Tajima's D. There were high levels of heterozygote deficiency caused by inbreeding within the three populations. Population structure analysis suggested that the three populations have evolved independently, and a moderate amount of genetic differentiation has developed, although there was a low level of gene flow between the Ql and Tp populations. Furthermore, the average quantities of musk secreted by musk deer in the Tp and WS populations were significantly higher than that in the Ql population. The present genetic information should be considered in management plans for the conservation and utilization of musk deer from captive breeding.