4 research outputs found
Size-Controlled Functionalized Mesoporous Silica Nanoparticles for Tunable Drug Release and Enhanced Anti-Tumoral Activity
Mesoporous
silica nanoparticles (MSNs) are considered as one of
the most promising nanovectors for controlled drug delivery. For the
design of ideal drug nanocarriers, several factors have to be taken
into account, such as size and surface chemistry. Here, we report
how MSNs surface functionalization and particle size critically affect
the drug release performances and therapeutic capabilities. We illustrate
the size effect of these functionalized MSNs on in vitro, intracellular,
and in vivo drug release efficiency, as well as on nanoparticle and
drug diffusion into the targeted tissues (tumor). For this, dispersible
MSNs with different particle sizes (from 500 down to 45 nm), similar
physicochemical properties (e.g., structural and textural properties),
and high colloidal stability (even in saline conditions), were synthesized.
Their surface was specifically functionalized with a phosphonate-silane
according to a novel postgrafting strategy, for better control over
loading and release of positively charged drugs. An efficient particle-size-dependent
and pH-dependent release of the loaded drug (i.e., doxorubicin) was
achieved in physiological conditions with phosphonated-MSNs compared
to pure-MSNs. The cellular uptake efficiency is much higher with the
smallest phosphonated-nanoparticles (45 nm). Furthermore, doxorubicin
is efficiently released from the nanoparticles into the intracellular
compartments, and the drug reaches the nucleus in a time- and particle
size-dependent manner. Intratumoral diffusion of the developed nanoparticles,
as well as the drug release and its diffusion into the tumor matrix,
is clearly enhanced with the smallest phosphonated-nanoparticles (45
nm), leading ultimately to a superior cell and tumor growth inhibition
Activation of Phenyl 4ā(2-Oxo-3-alkylimidazolidin-1-yl)benzenesulfonates Prodrugs by CYP1A1 as New Antimitotics Targeting Breast Cancer Cells
Prodrug-mediated utilization of the
cytochrome P450 (CYP) 1A1 to
obtain the selective release of potent anticancer products within
cancer tissues is a promising approach in chemotherapy. We herein
report the rationale, preparation, biological evaluation, and mechanism
of action of phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)Ābenzenesulfonates
(PAIB-SOs) that are antimicrotubule prodrugs activated by CYP1A1.
Although PAIB-SOs are inert in most cells tested, they are highly
cytocidal toward several human breast cancer cells, including hormone-independent
and chemoresistant types. PAIB-SOs are <i>N</i>-dealkylated
into cytotoxic phenyl 4-(2-oxo-3-imidazolidin-1-yl)Ābenzenesulfonates
(PIB-SOs) in CYP1A1-positive cancer cells, both in vitro and in vivo.
In conclusion, PAIB-SOs are novel chemotherapeutic prodrugs with no
equivalent among current antineoplastics and whose selective action
toward breast cancer is tailored to the characteristic pattern of
CYP1A1 expression observed in a large percentage of human breast tumors
Design, Synthesis, Biological Evaluation, and StructureāActivity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4
Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2<i>H</i>)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are in the nanomolar range and unaffected in cancer cells resistant to colchicine, paclitaxel, and vinblastine or overexpressing the P-glycoprotein. None of the PPB-SOs exhibit significant antiproliferative activity. PIB-SOs block the cell cycle progression in the G<sub>2</sub>/M phase and bind to the colchicine-binding site on Ī²-tubulin leading to cytoskeleton disruption and cell death. Chick chorioallantoic membrane tumor assays show that compounds <b>36</b>, <b>44</b>, and <b>45</b> efficiently block angiogenesis and tumor growth at least at similar levels as combretastatin A-4 (CA-4) and exhibit low to very low toxicity on the chick embryos. PIB-SOs were subjected to CoMFA and CoMSIA analyses to establish quantitative structureāactivity relationships