Potentiated Skin Permeation and Antitumor Efficacy of Fulvestrant-Loaded High-Permeation Vesicles for Localized Breast Cancer Treatment

Abstract

Fulvestrant (FLV) is a selective estrogen receptor degrader used for hormone receptor-positive breast cancer. Nevertheless, its delivery is limited by low aqueous solubility and repeated intramuscular administration. Considering these drawbacks, a high-permeation vesicle-in-gel system (HPV-gel) was explored as a localized transdermal approach for FLV and evaluated for its physicochemical, permeation, cellular, pharmacokinetic, antitumor, and safety performance. Accordingly, FLV/HPVs were prepared using soya phosphatidylcholine and a ternary permeation-enhancer combination of sodium oleate (SO), diethylene glycol monoethyl ether (DEGEE), and propylene glycol (PG). Enhancer proportions were optimized using a D-optimal mixture design based on vesicle size, PDI, and entrapment efficiency. The optimized composition contained 80% phospholipid and 20% of a permeation enhancer mixture, comprising SO, DEGEE, and PG in a ratio of 6:1.5:2.5. FLV/HPVs showed a particle size of 94.02 ± 1.10 nm, a PDI of 0.241 ± 0.029, a zeta potential of –38.6 ± 1.2 mV, an entrapment efficiency of 85.79 ± 3.72%, a practical drug loading of 8.58 ± 0.16%, and a deformability index of 1.62 ± 0.08. The optimized vesicles were incorporated into a 1.5% w/v Carbopol 934P gel and compared with FLV-gel and FLV/Lipo-gel with the same gel base and an equivalent FLV amount. FLV/HPVs-gel showed sustained drug release and increased FLV permeation by nearly 8-fold and 3-fold compared with FLV-gel and FLV/Lipo-gel, respectively, with higher intradermal retention and deeper dermal distribution. Following topical administration, FLV/HPVs-gel increased Cmax by ∼8.3- and ∼2-fold and AUC0-168 h by ∼8.1- and ∼2.6-fold compared with FLV-gel and FLV/Lipo-gel, respectively, while showing plasma concentration–time profile closer to FLV (i.m.). In 4T1 tumor-bearing mice, FLV/HPVs-gel showed the strongest tumor-suppressive effect, accompanied by greater intratumoral penetration, while biochemical parameters, major organ histology, TEWL, and skin histology indicated acceptable systemic and local safety. Overall, FLV/HPVs-gel improved skin permeation, drug exposure, and antitumor activity, suggesting its potential as a noninvasive transdermal approach for FLV in breast cancer therapy.