3 research outputs found
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 polyÂ(ethylenimine)
(PEI)<sub>600</sub>-grafted α-cyclodextrin rings linearized
on polyethylene glycol to form FA-terminated PR-PEI<sub>600</sub> (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 <sup>1</sup>H nuclear magnetic resonance (<sup>1</sup>H 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 tetrahydropyridoÂ[4,3-<i>d</i>]Âpyrimidine 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, tetrahydropyridoÂ[4,3-<i>d</i>]Âpyrimidine 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