New molecular motifs that can act as pH-regulating triggers for amphiphilic, pH-sensitive block copolymers are investigated. Inspired by the mechanism of action of pH-indicators, such as methyl orange, and natural amino acids, we designed these copolymers where either 4-Amino-4'-dimethylaminoazobenzene, AZB (pKa 3.4, an amine derivative of methyl orange), isoleucine, Ile (pKa 2.37 for carboxylic acid), or a statistical mixture of both were appended as side chains to the hydrophobic block to act as pH-triggers. These new side chain motifs were identified with an aim to enhance the self-assembling properties of the block copolymers in terms of particle size and stability, drug encapsulation, and release. As the parent polymer, poly (ethylene) glycol-block- poly (carbonate) (PEG-b-PC) of number average molecular weight 12.1 kDa was used. We observed that PEG-b-PC block copolymers, when engineered with AZB or Ile-type of pH-regulators appended as side chains to PC blocks, formed self-assembled, spherical nanoparticles with hydrodynamic diameters ranging from 114 to 137 nm depending on copolymer composition. Critical aggregation concentrations (CAC) of the block copolymers were found to be governed by the type and content of side chains. We explored the use of these newly designed block copolymer assemblies as drug carriers using gemcitabine (GEM) as a model cytotoxic drug generally used for pancreatic ductal adenocarcinoma (PDAC). We showed that AZB and Ile decorated copolymeric nanocarriers were able to encapsulate GEM at 13.8-28.8 % loading content and release the drug in a pH-dependent pattern. Drug-loaded nanocarriers showed cellular entry into PDAC cells in vitro and were found to exert cytotoxicity against these cells. Neither the block copolymers bearing AZB or Ile-type pH-responsive triggers, nor their self-assembled nanoparticles showed any cytotoxicity at usable concentrations, thereby reflecting the potentials of these molecular motifs for designing stimuli-responsive drug delivery nanosystems. Copyright © 2021 Elsevier B.V. All rights reserved.