title: Dual-drug delivery by porous silicon nanoparticles for improved cellular uptake, sustained release, and combination therapy.
abstract: Dual-drug delivery of antiangiogenic and chemotherapeutic drugs can enhance the therapeutic effect for cancer therapy. Conjugation of methotrexate (MTX) to porous silicon (PSi) nanoparticles (MTX-PSi) with positively charged surface can improve the cellular uptake of MTX and inhibit the proliferation of cancer cells. Herein, MTX-PSi conjugates sustained the release of MTX up to 96 h, and the released fragments including MTX were confirmed by mass spectrometry. The intracellular distribution of the MTX-PSi nanoparticles was confirmed by transmission electron microscopy. Compared to pure MTX, the MTX-PSi achieved similar inhibition of cell proliferation in folate receptor (FR) over-expressing U87 MG cancer cells, and a higher effect in low FR-expressing EA.hy926 cells. Nuclear fragmentation analysis demonstrated programmed cell apoptosis of MTX-PSi in the high/low FR-expressing cancer cells, whereas PSi alone at the same dose had a minor effect on cell apoptosis. Finally, the porous structure of MTX-PSi enabled a successful concomitant loading of another anti-angiogenic hydrophobic drug, sorafenib, and considerably enhanced the dissolution rate of sorafenib. Overall, the MTX-PSi nanoparticles can be used as a platform for combination chemotherapy by simultaneously enhancing the dissolution rate of a hydrophobic drug and sustaining the release of a conjugated chemotherapeutic drug.
authors: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland. Electronic address: chang-fang.wang@helsinki.fi.
authors: Chang-Fang
authors: CF
authors: Wang
authors: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland; Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku, FI-20014 Turku, Finland.
authors: Ermei M
authors: EM
authors: Mäkilä
authors: Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku, FI-20014 Turku, Finland.
authors: Martti H
authors: MH
authors: Kaasalainen
authors: Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
authors: Marja V
authors: MV
authors: Hagström
authors: Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku, FI-20014 Turku, Finland.
authors: Jarno J
authors: JJ
authors: Salonen
authors: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
authors: Jouni T
authors: JT
authors: Hirvonen
authors: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland. Electronic address: helder.santos@helsinki.fi.
authors: Hélder A
authors: HA
authors: Santos
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D008727:Methotrexate / Q000737:chemistry / Q000494:pharmacology; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010316:Particle Size; D010671:Phenylurea Compounds / Q000494:pharmacology; D016062:Porosity; D012825:Silicon / Q000737:chemistry*; D000077157:Sorafenib; D017550:Spectroscopy, Fourier Transform Infrared; D055672:Static Electricity
chemical_list: D003692:Delayed-Action Preparations; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D008727:Methotrexate; D012825:Silicon
keywords: Combination therapy; Intracellular uptake; Methotrexate/Sorafenib; Porous silicon nanoparticles; Sustained drug release