Synthesis and Characterization of Folic Acid-Functionalized DPLA-co-PEG Nanomicelles for the Targeted Delivery of Letrozole

Abstract

An effective treatment for hormone-dependent breast cancer is chemotherapy using cytotoxic agents such as letrozole (LTZ). However, most anticancer drugs, including LTZ, are classified as class IV biopharmaceuticals, which are associated with low water solubility, poor bioavailability, and significant toxicity. As a result, developing a targeted delivery system for LTZ is critical for overcoming these challenges and limitations. Here, biodegradable LTZ-loaded nanocarriers were synthesized by solvent emulsification evaporation using nanomicelles prepared with dodecanol-polylactic acid-co-polyethylene glycol (DPLA-co-PEG). Furthermore, cancer cell-targeting folic acid (FA) was conjugated into the nanomicelles to achieve a more effective and safer cancer treatment. During our investigation, DPLA-co-PEG and DPLA-co-PEG-FA displayed a uniform and spherical morphology. The average diameters of DPLA-co-PEG and DPLA-co-PEG-FA nanomicelles were 86.5 and 241.3 nm, respectively. Our preliminary data suggest that both nanoformulations were cytocompatible, with ≥90% cell viability across all concentrations tested. In addition, the amphiphilic nature of the nanomicelles led to high drug loading and dispersion in water, resulting in the extended release of LTZ for up to 50 h. According to the Higuchi model, nanomicelles functionalized with FA have a greater potential for the controlled delivery of LTZ into target cells. This model was confirmed experimentally, as LTZ-containing DPLA-co-PEG-FA was significantly and specifically more cytotoxic (up to 90% cell death) toward MCF-7 cells, a hormone-dependent human breast cancer cell line, when compared to free LTZ and LTZ-containing DPLA-co-PEG. Furthermore, a half-maximal inhibitory concentration (IC50) of 87 ± 1 nM was achieved when MCF-7 cells were exposed to LTZ-containing DPLA-co-PEG-FA, whereas higher doses of 125 ± 2 and 100 ± 2 nM were required for free LTZ and LTZ-containing DPLA-co-PEG, respectively. Collectively, DPLA-co-PEG-FA represents a promising nanosized drug delivery system to target controllably the delivery of drugs such as chemotherapeutics.

Design, Synthesis, and Comparison of PLA-PEG-PLA and PEG-PLA-PEG Copolymers for Curcumin Delivery to Cancer Cells

“…The study of nanocarrier behavior is essential to ensure steady and controlled drug release at the target site. Hence, the determination of structural properties, surface characterization, and permeation tendency into the biomembrane is critical for designing carriers such as copolymers for the delivery of drugs [ 42 , 43 , 44 ]. The extent of hydrophilicity and hydrophobicity is an important characteristic of the copolymers, which can be approximately accessed via contact angle [ 45 , 46 ].…”

“…In all cellular assays, the cells were treated with different concentrations (0–60 µM) of free curcumin, PLA-PEG-PLA, PEG-PLA-PEG, curcumin-PLA-PEG-PLA, and PEG-PLA-PEG-curcumin, for 48 h. PBS-treated cells were taken as control (cnt). Percent cell death was calculated by following Equation (7), and the IC50 values for curcumin, curcumin-PLA-PEG-PLA, and curcumin-PEG-PLA-PEG were determined [ 42 ]. …”