Polymeric nanoparticles (NPs) are widely employed as cancer nanomedicines due to their ability to more effectively deliver cytotoxic chemotherapeutics such as paclitaxel (PTX). PTX is commonly used to treat a variety of solid organ malignancies, but suffers from poor solubility, rapid clearance, and low target tissue concentrations. NPs can be utilized to control drug release kinetics and increase drug delivery efficiency. Interestingly, particle stiffness modulates cellular internalization and nanocarrier efficacy, warranting further study and optimization of nanomechanical properties. In particular, softer structures generally exhibit more rapid cellular internalization and enhanced potency. However, despite the potential impact of nanoscale mechanics, relatively few studies modulate nanoparticle core composition in order to decrease stiffness and optimize therapeutic efficacy. We have previously demonstrated sustained and efficient PTX delivery using poly(1,2-glycerol carbonate)-graft-succinic acid-paclitaxel (PGC-PTX) conjugate NPs. Encapsulation of free PTX within the PGC-PTX NP core increases core interactions and, consequently, particle stiffness. In contrast, the incorporation of a more hydrophilic polymer, such as poly(lactide-co-glycolide) (PLGA) or polypropylene glycol (PPG), can potentially disrupt compact aggregation in the hydrophobic polymer core and reduce particle stiffness. We herein evaluate the modulation of nanocarrier mechanical properties as well as efficacy through the incorporation of additional polymers such as PLGA and PPG. Specifically, we report the preparation, characterization, and evaluation of the in vitro cytotoxic activity of PGC-PTX/PLGA and PGC-PTX/PPG polymer blend nanocarriers.