Dual-drug delivery of antiangiogenic drug and chemotherapeutic drug can enhance the therapeutic effect for cancer therapy. Conjugation of methotrexate (MTX) to PSi nanoparticles (MTX−PSi) with positively charged surfaces 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 electronic 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 the 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 successful concomitant loading of another anti-angiogenic hydrophobic drug, sorafenib, and considerably enhanced the dissolution rate of sorafenib. Overall, the MTX−PSi nanoparticle system can be used as a platform for combination chemotherapy by enhancing the dissolution rate of the hydrophobic drug and sustaining the release of the conjugated chemotherapeutic drug.