Synthesis of Peptoid-Conjugated PLGA Nanoparticles for Enhanced Intracellular Drug Delivery

Abstract

The clinical utility of conventional anticancer drugs is often compromised by poor aqueous solubility and non-specific systemic toxicity. To mitigate these limitations, poly(lactic-co-glycolide) (PLGA) nanoparticles (NPs) have been widely explored as drug delivery systems. However, cellular uptake efficiency of PLGA NPs remains suboptimal because of electrostatic repulsion between the negatively charged particle surface and the anionic components of the cell membrane. To overcome this challenge, we introduce surface functionalized PLGA NPs with cationic cell-penetrating peptoids (CPPs). Covalent conjugation of CPPs to surface of PLGA NPs was confirmed by a shift in zeta potential (ζ) from negative to positive values and the appearance of N1s peak in X- ray photoelectron spectroscopy (XPS). The drug delivery potential of the CPP-functionalized nanoparticles (CPP- NPs) was evaluated using doxorubicin (Dox) and camptothecin (CPT) as model cargos. 3-day in vitro release profiles of Dox were characterized, demonstrating that CPP-NPs provide a pH-responsive, sustained-release platform suitable for anticancer drug delivery. Cellular uptake of the CPP-NP platform was enhanced in HeLa cells compared to unfunctionalized PLGA nanoparticles, as evaluated by confocal laser scanning microscopy and flow cytometry. Cytotoxicity evaluation indicated that blank carriers showed no appreciable effect on cell viability over the tested period, whereas drug-loaded CPP-NPs resulted in time-dependent cytotoxicity consistent with sustained intracellular drug release from CPP-NPs. This work establishes a versatile CPP-PLGA nanocarrier with potential to accommodate both hydrophilic and hydrophobic therapeutic payloads and offers a promising strategy for intracellular drug delivery.