Rapamycin Nanoparticles Extend Lifespan by 70% in C. elegans
PEG-coated albumin nanoparticles dramatically boost rapamycin's lifespan-extending effects while preserving its anticancer activity in preclinical models.
Summary
Rapamycin is a promising drug for cancer and aging, but it barely dissolves in water, breaks down easily, and gets trapped in red blood cells. Researchers packed it into tiny particles made of human albumin, the main protein in blood, and coated them with PEG. The particles were about 180 to 200 nanometers wide, uniform, and held 72 to 81 percent of the drug. They released it slowly, about 40 percent over 24 hours, while free rapamycin crossed a membrane almost completely within 2 hours. In breast cancer cells, the particles were as potent as free rapamycin, with somewhat lower IC50 values. In roundworms, they extended lifespan by about 70 percent, more than the free drug, without changing fat content. The work is early and preclinical, but it supports albumin carriers for rapamycin.
Detailed Summary
Rapamycin is the best-studied drug for inhibiting mTOR, a central regulator of growth, metabolism, and aging. It is used to prevent transplant rejection and is being explored in cancer and age-related disease. Its clinical use is hampered by very poor water solubility (2.6 μg/mL), sensitivity to light, heat, and pH, and heavy sequestration in red blood cells after injection. A better delivery vehicle could make dosing more predictable, which matters for both oncology and longevity applications.
The team built nanoparticles from human serum albumin using ethanol desolvation at pH 4.9, then coated them with PEG 35,000 and freeze-dried them with sucrose. Two drug-to-albumin ratios were tested (NPA-RAP10 and NPA-RAP15), plus empty particles as a control. Albumin was chosen because it is biodegradable, has a long circulation time, interacts with tumor-associated receptors such as gp60 and SPARC, and underlies approved products such as Abraxane and Fyarro.
Physically, the particles performed well. Empty particles measured 143 ± 8 nm; loaded ones measured 181 ± 3 nm (RAP10) and 200 ± 4 nm (RAP15). Polydispersity stayed below 0.2 (0.063 and 0.115 for loaded particles), and zeta potential was about −30 mV. Encapsulation efficiency was 71.7% and 80.9%, corresponding to 26.3 and 46.3 μg of rapamycin per mg of particles. Electron microscopy showed spherical, homogeneous particles, and size and polydispersity were tracked in PBS for 24 hours.
Release was biphasic. About 20% of the drug came out in the first 2 hours, rising to roughly 40% by 24 hours, whereas about 90% of free rapamycin crossed the dialysis membrane within 2 hours. Of four kinetic models, the Weibull model fit best (adjusted R² 0.999 and 0.998), while Higuchi and first-order fits were poor (R² 0.62 to 0.83).
In cells, empty particles were not cytotoxic. Over 24 hours at 10 to 300 nM, NPA-RAP15 matched free rapamycin's profile with lower IC50 values: 150 versus 200 nM in MCF-7 breast cancer cells, and 100 versus 150 nM in non-tumorigenic MCF-10A cells. In C. elegans on a high-glucose diet, particles dosed at 75 μM drug did not change fat content but extended lifespan by about 70%, outperforming free rapamycin.
The main caveats are that this is a preliminary study. The lower IC50 in normal MCF-10A cells shows no cancer selectivity, and only 24-hour cell exposure was tested. Lifespan data come from a worm model under high-glucose, FUdR-treated conditions, and no mammalian pharmacokinetics, biodistribution, or safety data were provided. The work shows feasibility of an albumin carrier, not clinical benefit.
Key Findings
- Loaded albumin nanoparticles measured 181 ± 3 nm (NPA-RAP10) and 200 ± 4 nm (NPA-RAP15), with polydispersity index below 0.2 and zeta potential of about −30 mV
- Encapsulation efficiency was 71.7% (RAP10) and 80.9% (RAP15), with drug loading of 26.27 and 46.30 μg rapamycin per mg of nanoparticles
- Release was biphasic: about 20% in the first 2 h and about 40% by 24 h, versus roughly 90% of free rapamycin crossing the membrane within 2 h
- The Weibull model best described release kinetics (adjusted R² 0.999 for RAP10, 0.998 for RAP15), outperforming Higuchi (R² about 0.82) and first-order (R² about 0.62 to 0.65) fits
- In MCF-7 breast cancer cells, IC50 was 150 nM for NPA-RAP15 versus 200 nM for free rapamycin; empty nanoparticles showed no cytotoxicity
- In non-tumorigenic MCF-10A cells, IC50 also dropped from 150 nM (free drug) to 100 nM (NPA-RAP15), so the formulation showed no selectivity for cancer cells
- In C. elegans, rapamycin nanoparticles at 75 μM extended lifespan by about 70%, outperforming free rapamycin, without changing fat content
Methodology
Albumin nanoparticles were made by ethanol desolvation, PEG 35,000 coating, ultrafiltration, and lyophilization at two drug-to-albumin ratios (0.1 and 0.15). They were characterized by light scattering, zeta potential, TEM, HPLC-UV encapsulation analysis, and dialysis-based release modeled with four kinetic equations (n = 3). Cytotoxicity was tested for 24 h by resazurin assay in MCF-7 and MCF-10A cells in triplicate. The in vivo work used wild-type N2 C. elegans (about 50 worms per replicate, three days, triplicate) on high-glucose plates with FUdR, with Nile Red fat staining and daily lifespan scoring. Group comparisons used one-way ANOVA with Tukey's post hoc test, with significance set at p < 0.01.
Study Limitations
The authors describe this as a preliminary evaluation. Cell testing was limited to 24 h in two breast cell lines, and the lower IC50 in normal MCF-10A cells indicates no tumor selectivity. Lifespan was tested only in C. elegans under high-glucose conditions with FUdR, and no mammalian biodistribution, pharmacokinetic, or toxicity data were presented. Only about 40% of the drug was released over 24 h. No conflict-of-interest statement was present in the available text.
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