Hydrogels synthesized from poly(l-lysine isophthalamide) (PLP) crosslinked with l-lysine methyl ester were investigated as drug delivery systems for a wide size range of molecules (0.3-2000kDa). PLP is an anionic, pseudo-peptidic polymer that is an ideal hydrogel backbone due to its pH-responsiveness and amphiphilicity. Drug loading and release were evaluated for various model drugs: hydrophobic fluorescein (Mw=332Da) and hydrophilic fluorescein isothiocyanate-dextran (FITC-Dex Mw=10kDa, 150kDa, 500kDa, and 2000kDa). Weight incorporation was high, up to 22.8±3.1%. Release after 24h in pH 7.4 was in the range from 70.4±1.2% to 91.6±0.8% for all model drugs. In contrast, drug release after 24h in pH 3.0 was significantly lower, less than 8% for fluorescein, 500kDa, and 2000kDa FITC-Dex. Thus, the adaptability of these novel hydrogels to both hydrophobic and hydrophilic molecules, spanning a wide size range, suggests their use as a platform delivery system. This is also the first known hydrogel system for the oral delivery of payloads larger than 70kDa, which, combined with triggered release in response to pH changes along the gastrointestinal tract, indicates that these hydrogels have promising applications in oral drug delivery.