# pH‐Responsive Isoprenoid‐Antitumoral Polymer Conjugates for Superior Drug Loading via Self‐Assembly and Endosomal‐Targeted Anticancer Activity

## TL;DR

A new pH-sensitive polymer-drug conjugate delivers anticancer drugs more effectively while reducing toxicity to healthy cells.

## Contribution

A novel polymer-drug conjugate combining farnesal and poly-L-lysine with pH-responsive drug release and self-assembly into nanoparticles.

## Key findings

- The Far-PL conjugate showed enhanced cytotoxicity against A549 lung cancer cells.
- Far-PL self-assembled into nanoparticles with 100% drug content and a positive surface charge.
- The conjugate released drugs under acidic tumor and endosomal conditions but remained stable at physiological pH.

## Abstract

Polymer‐drug conjugates (PDCs) are a promising strategy to enhance the delivery of poorly soluble drugs, particularly in cancer therapy. By improving solubility and enabling site‐specific accumulation, PDCs minimize systemic toxicity while maximizing therapeutic efficacy. PDCs often employ stimuli‐responsive linkers, such as Schiff's bases, to achieve controlled drug release in tumor microenvironments or acidic intracellular compartments. In this study, we designed a novel PDC by conjugating the anticancer agent farnesal (Far) to ∈‐Poly‐L‐Lysine (PL) via an imine bond, without using additional linkers. PL is a natural, biodegradable, water‐soluble polymer with inherent anticancer properties, while Far is a hydrophobic isoprenoid with potent antitumor activity. The conjugate (Far‐PL) displayed pH‐responsive behavior, remaining stable at physiological pH but releasing drugs under acidic tumor (pH 6.5) and endosomal (pH 5.5) conditions. Far‐PL exhibited enhanced cytotoxicity against A549 lung cancer cells compared to its components alone, while showing reduced toxicity towards noncancerous cells (Arlo cells). The amphiphilicity allows the conjugate to self‐assemble into stable nanoparticles with a positive surface charge, narrow size distribution, and 100% drug content—clearly exceeding conventional nanoparticles (5–10 wt%). This effective PDC design demonstrates strong potential to maximize tumor‐selective activity while minimizing off‐target effects, offering a promising platform for future cancer therapeutics.

Polymer‐drug conjugate (PDC) entirely composed of active compounds with pH‐responsive properties. The PDC can self‐assemble into nanoparticles for intracellular delivery and endosome‐targeted efficacy.© 2026 WILEY‐VCH GmbH