The synthesis of well-defined functional nanoparticles for the encapsulation of hydrophobic and hydrophilic drugs is described. Nanoparticles were built from amphiphilic copolymers consisting of P(OEG-A) homopolymers chain extended with vinyl benzyl chloride (VBC) and pentafluorophenyl acrylate (PFP-A) comonomers. Subsequently, the pendant chlorine atoms, introduced into the chains by VBC units, were substituted using sodium methanethiosulfonate, yielding copolymer chains with methanethiosulfonate (MTS) pendant functionality. The thiol/MTS exchange chemistry afforded by the MTS groups was then used to introduce different functional groups by reacting with a range of thiols. These copolymers were self-assembled in water yielding nanoparticles with sizes of 20 nm. The activated esters in the copolymer were used to cross-link the nanoparticles with difunctional amino compounds (cross-linkers). A cross-linker bearing an acid cleavable bond (ketal) was used to generate pH-sensitive core-shell nanoparticles. Drug encapsulation and release was modeled using hydrophobic (Nile Red) and hydrophilic (thiol-modified fluorescein isothiocyanate, FITC) dye molecules. The release of each dye was monitored using UV-vis spectroscopy, demonstrating the possibility of selective release of single dye or the simultaneous release of both dyes depending on the experimental stimuli. An in vitro study confirmed that the nanoparticles were nontoxic to the NIH-3T3 cell line. Cell uptake analysis by flow cytometry and fluorescence microscopy indicated a higher uptake for cross-linked nanoparticles than for non-cross-linked nanoparticles.