Abstract
Naturally derived prodrugs have a wide range of pharmacological activities, including anticancer, antioxidant, and antiviral effects. However, significant barriers inhibit their use in medicine, e.g. their hydrophobicity. In this comprehensive study, we investigated simple and effective nanoformulations consisting of amine-functionalized and conjugated with folic acid (FA) mesoporous silica nanoparticles (MSNs). Two types of MSNs were studied: KCC- 1, with mean size 324 nm and mean pore diameter 3.4 nm, and MCM - 41, with mean size 197 and pore diameter 2 nm. Both types of MSNs were loaded with three anticancer prodrugs: curcumin, quercetin, and colchicine. The nanoformulations were tested to target in vitro human hepatocellular carcinoma cells (HepG2) and HeLa cancer cells. The amine-functionalized and FA-conjugated curcumin-loaded, especially KCC-1 MSNs penetrated all cells organs and steadily released curcumin. The FA-conjugated MSNs displayed higher cellular uptake, sustained intracellular release, and cytotoxicity effects in comparison to non-conjugated MSNs. The KCC-1 type MSNs carrying curcumin displayed the highest anticancer activity. Apoptosis was induced through specific signaling molecular pathways (caspase-3, H2O2, c-MET, and MCL-1). The nanoformulations displayed also an enhanced antioxidant activity compared to the pure forms of the prodrugs, and the effect depended on the time of release, type of MSN, prodrug, and assay used. FA-conjugated MSNs carrying curcumin and other safe natural prodrugs offer new possibilities for targeted cancer therapy.
Highlights
Nanomedicine is defined as nanotechnology applications in medicine and is expected to provide tremendous opportunities for novel and effective strategies in the diagnosis and therapy of several diseases [1]
Drug loaded folic acid (FA)-conjugated mesoporous silica nanoparticles (MSNs): KCC-NH2FA-CR/QR/Col, and MCM-NH2-FA-CR/QR/Col, where CR stands for curcumin, QR for quercetin, and Col for colchicine
Regarding drug type, the least antioxidant activity was found for COL, with CR yielding intermediate activity, and QR proving most effective. For both types of MSN, the antioxidant activity was most enhanced for KCC-NH2-FA loaded with CR, while both types were nearly equal for loaded QR and COL. These results demonstrate that the antioxidant activity as tested by DPPH depended on the type of MSN, type of prodrug, and timing
Summary
Nanomedicine is defined as nanotechnology applications in medicine and is expected to provide tremendous opportunities for novel and effective strategies in the diagnosis and therapy of several diseases [1]. One of the major goals of nanomedicine is to synthesize and tailor suitable drug delivery vehicles for www.oncotarget.com targeted anticancer drug delivery. Such targeted drugs may efficiently cross physiological barriers, accumulate in desirable sites, and sustainably release drugs for treatment of diseases and offer reduced negative side effects [6]. Numerous materials have been investigated in nanomedicine as drug delivery systems (DDSs), such as organic DDS-based liposomes, solid lipid nanoparticles, dendrimers, and polymeric micelles. Inorganic DDS-based nanoparticles, including magnetic nanoparticles, gold nanoparticles, carbon nanotubes, silica nanoparticles, and many other inorganic nanomaterials, have considerable potential as promising alternatives to organic systems in biomedical applications [6]. There is a high potential for silica nanoparticles as DDSs for clinical applications [13]
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