Pyrano[2,3-c]pyrazole derivatives have been reported as exerting various biological activities. One compound with potential anti-tumor activity was screened out by MTT assay from series of dihydropyrazopyrazole derivatives we had synthesized before using a one-pot, four-component reaction, and was named as 6-amino-4-(2-hydroxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (hereinafter abbreviated as AMDPC). The IC50 of AMDPC against Bcap-37 breast cancer cells was 46.52 μg/mL. Then the hydrophobic AMDPC was encapsulated in PEG-PLGA block copolymers, and then self-assembled as polymeric micelle (mPEG-PLGA/AMDPC) to improve both physiochemical and release profiles. The effect of mPEG-PLGA/AMDPC on BCAP-37 cancer cells showed similar anti-tumor effects as AMDPC. Furthermore, the anti-tumor mechanism of mPEG-PLGA/AMDPC was investigated, which can probably be attributed to stimulating the expression of P21 gene and therefore protein production on BCAP-37 cells, and then blocked the cell cycle through the P53-independent pathway both in S phase and G2 phase. Thus, mPEG-PLGA/AMDPC is a promising therapeutic agent for cancer treatment, and further in vivo studies will be developed.

The purpose of this study was to overcome the clinical defects of 7-ethyl-10-hydroxycamptothecin (SN-38) and explore its characteristics and antitumor effects. Materials and methods: An amorphous solid dispersion of SN-38 with disodium glycyrrhizin (Na 2 GA) was prepared by mechanical ball milling (Na 2 GA/SN-38-BM). Moreover, an untreated mixture of Na 2 GA and SN-38 (Na 2 GA/SN-38-UM), a pure drug SN-38, was prepared for comparison with Na 2 GA/SN-38-BM. The samples were characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), dynamic light scattering, and transmission electron microscopy. Then, further in vitro and in vivo studies were performed including cell uptake, cytotoxicity, antitumor efficacy, tissue distribution, and histopathological evaluation (H&E staining). Results: SN-38 loaded in Na 2 GA was self-formed as nano-micelles in water. The particle size of nano-micelle was 69.41 nm and ζ-potential was-42.01 mV. XRD and SEM analyses showed that the ball milling transformed SN-38 crystals into amorphous form and that solubility increased by 189 times. Compared with SN-38 and Na 2 GA/SN-38-UM, Na 2 GA/SN-38-BM has a stronger cytotoxicity to tumor cells and exhibited a significant inhibition of tumor growth. Then, pharmacokinetic studies showed that the bioavailability of Na 2 GA/SN-38-BM was about four times that of SN-38 suspension. Conclusion: Na 2 GA/SN-38-BM (69 nm,-42 mV) nanoparticles which had excellent pharmacokinetic and distribution properties can dramatically enhance the anticancer efficacy of SN-38 in vitro and in vivo, suggesting a promising formulation for efficient anticancer therapy.

We developed a tumor-targeted contrast agent based on linear polylysine (PLL) by conjugating a small molecular imaging agent, fluorescent molecule and targeting agent amino phenylboronic acid onto the amino groups of polylysine, which can specifically target monosaccharide sialic acid residues overexpressing on the surface of tumor cell membranes. Further, 3,4,5,6-Tetrahydrophthalic anhydride (DCA) was attached to the free amino groups of the polylysine to change to a negative charge at physiology pH to lower the cytotoxicity, but it soon regenerated to a positive charge again once reaching the acidic intratumoral environment and therefore increased cell uptake. Laser confocal microscopy images showed that most of the polymeric contrast agents were bound to the cancer cell membrane. Moreover, the tumor targeting contrast agent showed the same magnetic resonance imaging (MRI) contrasting performance in vitro as the small molecule contrast agent used in clinic, which made it a promising tumor-targeting polymeric contrast agent for cancer diagnosis.

Triptolide (TP), a compound isolated from a Chinese medicinal herb, possesses potent anti-tumor, immunosuppressive, and anti-inflammatory properties, but was clinically limited due to its poor solubility, bioavailability, and toxicity. Considering the environment-friendly, low-cost mechanochemical techniques and potential dissolution enhancement ability of Na 2 GA, an amorphous solid dispersion (Na 2 GA&TP-BM) consisting of TP and Na 2 GA were well-prepared to address these issues. The performance of Na 2 GA&TP-BM was improved through ball milling, such as from crystalline state to an amorphous solid dispersion, suitable nano micelle size and surface potential, and increased solubility. This change had a significant improvement of pharmacokinetic behavior in mice and could be able to extend the blood circulation time of the antitumor drug. Moreover, in vitro and in vivo anti-tumor study showed that Na 2 GA&TP-BM displayed more potent cytotoxicity to tumor cells. The work illustrated an environment-friendly and safe preparation of the TP formulation, which was promising to enhance the oral bioavailability and antitumor ability of TP, might be considered for efficient anticancer therapy.

Taking advantage of their enhanced permeability and retention (EPR) effect, nanomedicines have been extensively studied for targeted drug delivery to tumor tissues. However, tumor heterogeneity restricts the EPR effect and drug penetration into tumors, and nano-formulations only generate a limited therapeutic improvement in clinical settings. Macrophages have the inherent ability of tumor homing, stealth in blood circulation, and phagocytosis of particles. In this short review, we categorize and discuss in-depth recent works using macrophages as carriers for delivery in this growing field of bioinspired research.