Breast cancer cell targeting of L-leucine-PLGA conjugated hybrid solid lipid nanoparticles of betulin via L-amino acid transport system-1

The aim of fabricating hybrid solid lipid nanoparticles (HSLN) was to enhance the delivery of betulin to triple negative breast cancer cells through the intravenous route <i>via</i> L-amino transporter system-1, using L-leucine-PLGA conjugate (Conj-HSLN) by hot high pressure homogenisation method. Betulin (BN), having potent anticancer and antioxidant activity, faces challenges due to poor water solubility and permeability, affecting its bioavailability. The results revealed Conj-HSLN with particle size 318.3 ± 0.25 nm. The percent cumulative BN release from Conj-HSLN was 57.763%, 24h. The cytotoxicity study in MB-MDA-231 cell depicts, LD₅₀ 67.73 µg/ml in Conj-HSLN. Pharmacokinetics study reveals enhanced C_max and half-life in Conj-HSLN (32.12 ± 0.25 µg/ml, 4.72 ± 0.53 h) than raw BN (1.31 ± 0.21 µg/ml, 7.54 ± 0.34 h). Enhanced distribution at tumour site (11.5967% ID, 2h) in Conj-HSLN signifies the role of L-leucine in the transport system. Pharmacodynamic study shows mean tumour volume of 765.3 ± 85.884, and 1450.01 ± 219.361 mm³ in Conj-HSLN, and BN, respectively, at 3^rd week of treatment. Standardised uptake value attributed reduced glucose uptake, due to inhibited tumour growth and proliferation, confirmed by tumour biomarkers assay, VEGF and Caspase-9. In conclusion, the targeted controlled release L-leucine conjugated-BN loaded HSLN is stable, safe, and effective against triple negative breast cancers.