Parkinson’s disease (PD) is the world’s second most common neurodegenerative disorder, affecting over 8 million people globally.
Levodopa has been the mainstay of treatment since the 1960s because it crosses the blood-brain barrier and is converted to dopamine, helping patients regain motor function.
But levodopa has a short half-life and a narrow therapeutic window. Over time, many patients develop disabling dyskinesias and “off” episodes as blood levels rise and fall.
Continuous, real-time pharmacokinetic data could help clinicians individualise dose, timing, and delivery mode, and is a key step towards feedback-guided therapy.
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Limitations Of Current Levodopa Monitoring
Today, levodopa levels are measured mainly by high-performance liquid chromatography (HPLC) or liquid chromatography–mass spectrometry (LC–MS) on plasma samples.
These methods are accurate but slow, labour-intensive, and rely on bulky lab equipment. Levodopa also degrades rapidly during sample transport, and intermittent blood draws cannot capture full pharmacokinetic (PK) profiles.
Electrochemical sensors can, in principle, offer continuous monitoring, but most existing levodopa sensors work at point-of-care using blood or sweat and still require intermittent sampling.
Implantable sensors promise true on-site, real-time monitoring but face several hurdles: low drug concentrations in interstitial fluid, biofouling, and levodopa’s tendency to oxidise and self-polymerise on electrode surfaces.
Few devices have been rigorously benchmarked against plasma HPLC, leaving the relationship between interstitial fluid and blood levels poorly defined.
How The NanoMIP Sensor Works
The new system uses a spindle-shaped carbon nanotube fibre (SSCNTF) as the core electrode, coated with a nanoscale molecularly imprinted polymer that selectively recognises levodopa.
The sensor is implanted subcutaneously and connected to a flexible printed circuit board patch, which performs differential pulse voltammetry (DPV) and sends data wirelessly via Bluetooth.
To make the electrode, the team electrochemically expanded a commercial CNT fibre in sulfuric acid, creating a spindle-shaped region with a large accessible CNT surface. They then electropolymerised a molecularly imprinted layer onto this SSCNTF using cyclic voltammetry.
Finally, they removed the levodopa template by chronoamperometry, followed by a water rinse, leaving behind binding cavities complementary to the drug.
In phosphate-buffered saline, the nanoMIP fibre showed a detection limit of 0.5 μM and a high sensitivity of 6.45 μA μM-1 over the physiologically relevant 0-30 μM range.
It discriminated levodopa from a wide panel of species (glucose, urea, lactate, creatinine, uric acid, cortisol, ascorbic acid, carbidopa, acetaminophen, and several amino acids), maintained reversible responses over dozens of concentration-switching cycles, and remained stable after at least seven days in water at 4 °C.
Crucially, the nanoMIP shell protected the CNT core from fouling.
In continuous measurements of 100 μM levodopa over 50 DPV scans, the nanoMIP fibre retained around 99 % of its initial current, whereas bare SSCNTF fell to about 26 %.
Short-term implantation in rats also showed that the nanoMIP-coated electrode largely preserved its sensitivity. Cell-culture assays and short-term skin histology indicated good cytocompatibility and minimal acute tissue inflammation.
Testing NanoMIP In Vivo
To test the sensor in vivo, the researchers implanted the nanoMIP fibre subcutaneously in rats and calibrated its response using levodopa-spiked simulated body fluid. They then monitored interstitial fluid levodopa levels in real time following systemic dosing.
In healthy rats given intraperitoneal levodopa, the sensor tracked classic PK profiles: a rapid rise in concentration followed by a gradual decline.
In parallel, HPLC showed matching time courses in blood, with higher doses producing higher peak concentrations. Interstitial fluid levels lagged behind blood by about 12 to 15 minutes and were somewhat attenuated, reflecting drug distribution from the central (blood) to peripheral (tissue) compartment.
Across dosing conditions, levodopa levels measured by the sensor in interstitial fluid correlated strongly with blood HPLC values, with correlation coefficients of 0.95 to 0.96.
What The Pharmacokinetics Reveal
The team created a Parkinson’s disease rat model by injecting the neurotoxin 6-hydroxydopamine into the medial forebrain bundle. Histological analysis confirmed selective loss of dopaminergic neurons in the substantia nigra and striatum.
Using the same sensing system, they then recorded full 4-hour levodopa PK profiles in both healthy and PD rats after intravenous dosing.
In both normal and PD rats, the sensor captured rapid levodopa absorption and a short apparent half-life: roughly 31 minutes in healthy animals and 35 minutes in PD models. AUC and Cmax showed substantial variability between individual animals, often more pronounced than the differences between disease and control groups.
Overall drug exposure and peak levels were similar across groups; however, PD rats had a shorter terminal elimination half-life (T½β), indicating faster late-phase clearance.
These results suggest that, at least in this model, individual physiology may be as important as disease status in shaping levodopa PK. They also reinforce clinical observations that levodopa’s short half-life makes it hard to maintain stable therapeutic levels, especially with conventional intermittent dosing.
To see how real-time sensing could guide dosing, the team tested both intermittent and continuous regimens in rats.
In one experiment, a healthy rat received either two injections of 0.06 mg g-1 levodopa or four injections of 0.03 mg g-1 (30 minutes apart, same total dose), with both reaching similar average steady-state levels, but the four-dose schedule gave smoother, less variable concentration changes.
In another, continuous intraperitoneal infusion at rates from ultra-fast bolus-like delivery down to slow drip showed that lower rates increased overall exposure, reduced peak levels, and dampened fluctuations, and that ramping the rate up or down produced corresponding spikes or stabilization in the levodopa signal. These results clearly demonstrated how continuous PK readouts could be used to tune dosing in real time.
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Implications And Next Steps
The authors argue that their nanoMIP fibre sensor addresses several key barriers to interstitial fluid-based levodopa monitoring: selectivity at low concentrations, resistance to chemical and biological fouling, and rigorous in vivo validation against the gold-standard HPLC method.
By embedding the sensor in a wearable, wireless platform, they also sketch a technical path towards more patient-friendly therapeutic drug monitoring.
However, the work remains preclinical. All experiments were performed in rats, over relatively short timescales, and without direct correlation to behavioural symptom control. Translation to human use will require long-term stability studies, definition of clinically relevant levodopa thresholds in interstitial fluid, and trials that link sensor readings to motor outcomes under different dosing regimens.
Even so, the study illustrates how continuous PK monitoring could support adaptive, feedback-based levodopa delivery to smooth out fluctuations and reduce the risk of dyskinesias and off-time episodes.
The same sensing strategy could potentially be adapted to other neuroactive drugs where narrow therapeutic ranges and high variability pose similar challenges.
Journal Reference
Zhou, Y. et al. (2025). A nanoMIP sensor for real-time in vivo monitoring of levodopa pharmacokinetics in precision Parkinson’s therapy. Nature Communications, 16(1), 10796. DOI: 10.1038/s41467-025-65853-2
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