Receptor-Mediated, Tumor-Targeted Gene Delivery Using Folate-Terminated Polyrotaxanes

Safe and effective gene delivery is essential to the success of gene therapy. We synthesized and characterized a novel nonviral gene delivery system in which folate (FA) molecules were functioned as blockers on cationic polyrotaxanes (PR) composed of poly­(ethylenimine) (PEI)₆₀₀-grafted α-cyclodextrin rings linearized on polyethylene glycol to form FA-terminated PR-PEI₆₀₀ (FPP). The FA terminal caps of FPP target cell surfaces abundant in FA receptor (FR), a common feature of tumor cells. The structure of FPP was characterized by using ¹H nuclear magnetic resonance (¹H NMR). The delivery particle was composed of chemically bonded PEG (4000), α-cyclodextrins (CD), and PEI (600 Da) at a molar ratio of 1:17:86.7, and the particle size and zeta potential of FPP/pDNA polyplexes were measured using dynamic light scattering. FPP/pDNA exhibited a lower cytotoxicity, strong specificity to FR, and high efficiency of delivering DNA to target cells in vitro and in vivo with the reporter genes. Furthermore, the FPP/DNA complex showed an enhanced antitumor effect in the nude mice compared with other delivery systems, such as PEI-25K. Together, these results suggest that FPP may be useful for gene therapy

Design, Synthesis, and Structure–Activity Relationship of Tetrahydropyrido[4,3‑<i>d</i>]pyrimidine Derivatives as Potent Smoothened Antagonists with <i>in Vivo</i> Activity

Medulloblastoma is one of the most prevalent brain tumors in children. Aberrant hedgehog (Hh) pathway signaling is thought to be involved in the initiation and development of medulloblastoma. Vismodegib, the first FDA-approved cancer therapy based on inhibition of aberrant hedgehog signaling, targets smoothened (Smo), a G-protein coupled receptor (GPCR) central to the Hh pathway. Although vismodegib exhibits promising therapeutic efficacy in tumor treatment, concerns have been raised from its nonlinear pharmacokinetic (PK) profiles at high doses partly due to low aqueous solubility. Many patients experience adverse events such as muscle spasms and weight loss. In addition, drug resistance often arises among tumor cells during treatment with vismodegib. There is clearly an urgent need to explore novel Smo antagonists with improved potency and efficacy. Through a scaffold hopping strategy, we have identified a series of novel tetrahydropyrido­[4,3-<i>d</i>]­pyrimidine derivatives, which exhibited effective inhibition of Hh signaling. Among them, compound <b>24</b> is three times more potent than vismodegib in the NIH3T3-GRE-Luc reporter gene assay. Compound <b>24</b> has a lower melting point and much greater solubility compared with vismodegib, resulting in linear PK profiles when dosed orally at 10, 30, and 100 mg/kg in rats. Furthermore, compound <b>24</b> showed excellent PK profiles with a 72% oral bioavailability in beagle dogs. Compound <b>24</b> demonstrated overall favorable <i>in vitro</i> safety profiles with respect to CYP isoform and hERG inhibition. Finally, compound <b>24</b> led to significant regression of subcutaneous tumor generated by primary Ptch1-deficient medulloblastoma cells in SCID mouse. In conclusion, tetrahydropyrido­[4,3-<i>d</i>]­pyrimidine derivatives represent a novel set of Smo inhibitors that could potentially be utilized to treat medulloblastoma and other Hh pathway related malignancies

Evidence of Microplastics in Bronchoalveolar Lavage Fluid among Never-Smokers: A Prospective Case Series

Microplastics (MPs) are abundant in air, but evidence of their deposition in the respiratory tract is limited. We conducted a prospective case series to investigate the deposition of microplastics in bronchoalveolar lavage fluid (BALF) and determine the internal dose of MPs via inhalation. Eighteen never-smokers aged 32–74 years who underwent fiberoptic bronchoscopy with BALF were recruited from Zhuhai, China. Control samples were obtained by performing the same procedure using isotonic saline instead of BALF. Laser direct infrared spectroscopy combined with scanning electron microscopy detected the presence and characteristics of MPs and quantitatively analyzed the microplastic in BALF and control samples. Concentrations of total and specific MPs in BALF and control samples were compared using the Wilcox test. Thirteen types of MPs were observed in 18 BALF samples. Polyethylene (PE, 86.1%) was the most abundant in BALF, followed by poly(ethylene terephthalate) (PET, 7.5%) and polypropylene (PP, 1.9%). Compared with the control samples, BALF had significantly higher concentrations of PE (median [IQR] of BALF: 0.38 [8.05] N/g), PET (0.26 [0.54] N/g), polyurethane (0.16 [0.24] N/g), PP (0.16 [0.11] N/g), and total MPs (0.91 [6.58] N/g). The presence of MPs in BALF provides novel evidence that MPs penetrate deep into the respiratory tract