Sugar-Coated Carbon Nanotubes Unleash Chemotherapy on Demand in Tumor-Like Acidity

Chemotherapy has always been a blunt instrument: powerful drugs that kill cancer cells also ravage healthy tissue on their way through the body. A new study published in the Journal of Saudi Chemical Society offers a strikingly engineered alternative. Researchers have built a multifunctional nanocarrier from single-walled carbon nanotubes, wrapping them in a cationic polymer and capping them with a sugar-derived ligand, so that the anticancer drug 5-fluorouracil is loaded efficiently and then released preferentially under the acidic conditions that characterize tumor tissue. The platform, known as OXSWCNT–PEI–GlcA, achieved a drug loading efficiency of 88 percent and released 88 percent of its payload within 48 hours at pH 5.6, compared with only 52 percent at the physiological pH of 7.4 — a differential that could, in principle, concentrate cytotoxic activity where it is needed most while sparing healthy cells during circulation.

The construction of the nanocarrier is a three-step chemical campaign. The team began with pristine single-walled carbon nanotubes and oxidized them in a sulfuric and nitric acid mixture, sonicating and refluxing the material for 24 hours to decorate the graphitic surface with carboxyl and hydroxyl groups. These oxygenated sites served as chemical handles for the next stage: grafting branched polyethyleneimine, or PEI, a polymer rich in amine groups, using epichlorohydrin under alkaline conditions. Finally, glucuronic acid — a glucose-derived molecule — was activated with EDC and NHS coupling chemistry and conjugated to the amine-bearing scaffold. The result is a nanotube wrapped in a layered corona that is simultaneously amine-rich, hydrophilic, and decorated with sugar moieties chosen for a very specific biological reason.

That reason lies in cancer metabolism. Tumor cells are famously addicted to glucose, a phenomenon known as the Warburg effect, and they satisfy their enormous metabolic appetite by overexpressing glucose transporters on their surfaces — most notably GLUT1, which is induced by hypoxia-driven signaling and correlates with aggressive tumor behavior and poor prognosis. Glucuronic acid, as a glucose analog, is a plausible ligand for these transporters, and glucose–drug conjugates such as glufosfamide have already exploited this route to smuggle cytotoxic payloads into cancer cells. By conjugating GlcA to the nanotube surface, the researchers aimed to combine this potential targeting capability with the pH-responsive behavior that PEI naturally confers, creating a carrier whose outer layer could interact with transporter-rich tumor cells while its polymer shell responds to acidity.

Characterization confirmed that the elaborate surface chemistry had worked without destroying the underlying nanotubes. Fourier-transform infrared spectroscopy showed the disappearance of the GlcA carbonyl peak after conjugation, alongside the amide signatures of PEI grafting. X-ray diffraction revealed only minor shifts in the graphitic planes, indicating that the crystalline carbon framework remained intact beneath the organic coating. Electron microscopy told a consistent story: scanning images showed a compact polymeric layer coating the interwoven nanotube network, while transmission electron microscopy captured the preserved tubular architecture with added surface roughness from the deposited polymer. Energy-dispersive X-ray analysis quantified the transformation dramatically — carbon content fell from 90.8 to 65.6 weight percent, while oxygen rose to 30.3 percent and nitrogen appeared at 4.1 percent, the unmistakable fingerprint of an amine-rich PEI layer and oxygenated sugar residues spread uniformly across the surface.

The adsorption experiments revealed how the drug binds and what governs the process. Loading was optimal at pH 4, where 5-fluorouracil — a weakly acidic drug with a pKa of 7.93 — exists predominantly in its neutral form and the protonated PEI chains expand to expose more binding sites. Under these conditions the carrier achieved an adsorption capacity of 17.6 milligrams per gram with 88 percent loading efficiency. Kinetic analysis showed the data fit a pseudo-second-order model with correlation coefficients exceeding 0.9999, indicating that the rate is controlled by the chemistry of bond formation rather than simple diffusion. The Freundlich isotherm best described the equilibrium, pointing to adsorption on a heterogeneous surface with multilayer coverage — a picture consistent with the continuous polymeric coating seen microscopically. Notably, the modification boosted the maximum adsorption capacity more than fivefold compared with unmodified oxidized nanotubes, from 17.65 to 90.61 milligrams per gram at 298 kelvin.

Thermodynamics added a crucial layer of insight. The negative enthalpy change of −22.6 kilojoules per mole confirmed the process is exothermic, which explains why adsorption weakened at elevated temperatures, and the negative Gibbs free energy values at all tested temperatures confirmed spontaneous binding. Perhaps most interesting was the negative entropy change of −40.5 joules per mole per kelvin, indicating that drug molecules adopt a more ordered, constrained arrangement on the modified surface. The authors suggest this molecular confinement could help stabilize drug–carrier interactions under physiological conditions, limiting premature release during circulation — precisely the failure mode that makes conventional chemotherapy so toxic to healthy tissue.

The release experiments are where the design truly earns its keep. Placed in a dialysis system at 37 degrees Celsius, the drug-loaded carrier released roughly 10.5 percent of its 5-fluorouracil within the first 30 minutes at pH 5.6, versus 6.5 percent at pH 7.4. The gap widened relentlessly: 52 percent versus 34 percent after six hours, 80 percent versus 47 percent after 24 hours, and finally 88 percent versus 52 percent at the 48-hour mark. The mechanism is electrostatic. In acidic conditions, PEI amine groups become protonated, the chains repel one another and expand, and the matrix swells — loosening the network, weakening drug–carrier interactions, and opening the enlarged mesopores, which BET measurements showed had grown from 18.2 to 41.1 nanometers after functionalization. At physiological pH, reduced protonation keeps the polymer compact, trapping the drug inside a denser network.

Mathematical modeling of the release kinetics revealed a non-Fickian, or anomalous, transport mechanism. The Peppas–Sahlin equation gave the best fit with correlation coefficients of 0.999, and the diffusional exponent from the Korsmeyer–Peppas model fell between 0.5 and 1 under both pH conditions. This means release is governed not by diffusion alone but by a combination of drug diffusion through the matrix and simultaneous polymer relaxation and swelling — a dual mechanism that gives the carrier its tunable, sustained profile. The Higuchi release constant was markedly higher at acidic pH, confirming that the tumor-like environment accelerates delivery exactly when and where it matters therapeutically.

Biological testing on human colorectal cancer cells, HT-29, provided the first evidence that the chemistry translates into cellular effects. Using the MTT viability assay, the unloaded carrier showed acceptable cytocompatibility at low concentrations, with viability near untreated controls at 0.5 to 5 micrograms per milliliter, declining gradually to about 52 to 54 percent at the highest doses. The drug-loaded formulation diverged clearly from 50 micrograms per milliliter onward, reducing viability to approximately 60 percent compared with 77 percent for the bare carrier — a difference attributable to the biological activity of the delivered 5-fluorouracil. Importantly, the decline was progressive and concentration-dependent rather than abrupt, consistent with a moderated drug-availability profile rather than the sudden cytotoxic burst typical of free chemotherapeutics.

The study stops short of clinical claims, and appropriately so. The authors emphasize that further work on cellular uptake and in vivo evaluation is needed before the platform’s transporter-targeting potential and therapeutic efficacy can be established. Carbon nanotubes also carry well-known baggage — poor aqueous solubility and slow systemic clearance — that functionalization strategies like this one are designed to mitigate but not necessarily eliminate. Still, the convergence of results is compelling: a fivefold boost in drug capacity, thermodynamically stabilized binding, an 88-versus-52 percent release differential between tumor-like and physiological pH, and dose-dependent killing of colorectal cancer cells in vitro. Together they sketch a nanocarrier that loads like a sponge, travels like a locked vault, and opens like a key in the acidic lock of the tumor microenvironment — a design philosophy that may shape the next generation of stimulus-responsive cancer therapies.

Subject of Research: pH-responsive carbon nanotube-based nanocarriers for controlled delivery of the chemotherapy drug 5-fluorouracil

Article Title: Polyethyleneimine/Glucuronic acid-grafted carbon nanotubes for 5-fluorouracil delivery: adsorption optimization, pH-responsive release, and in-vitro cytotoxicity

Article References: badiee, N., Miralinaghi, P., Miralinaghi, M., & Serri, A. (2026). Polyethyleneimine/Glucuronic acid-grafted carbon nanotubes for 5-fluorouracil delivery: adsorption optimization, pH-responsive release, and in-vitro cytotoxicity. Journal of Saudi Chemical Society, 30(2), Article 15. https://doi.org/10.1007/s44442-026-00058-w

Image Credits: AI Generated

DOI: 10.1007/s44442-026-00058-w

Keywords: carbon nanotubes, drug delivery, 5-fluorouracil, polyethyleneimine, glucuronic acid, pH-responsive release, nanomedicine, chemotherapy, HT-29 cells, adsorption kinetics, cancer therapy, nanocarriers