Permeation-Enhancing Nanoparticle Formulation to Enable Oral Absorption of Enoxaparin.

This study tests the hypothesis that association complexes formed between enoxaparin and cetyltrimethylammonium bromide (CTAB) augment permeation across the gastrointestinal mucosa due to improved encapsulation of this hydrophilic macromolecule within biocompatible poly (lactide-co-glycolide, PLGA RG 503) nanoparticles. When compared with free enoxaparin, association with CTAB increased drug encapsulation efficiency within PLGA nanoparticles from 40.3 ± 3.4 to 99.1 ± 1.0%. Drug release from enoxaparin/CTAB PLGA nanoparticles was assessed in HBSS, pH 7.4 and FASSIFV2, pH 6.5, suggesting effective protection of PLGA-encapsulated enoxaparin from unfavorable intestinal conditions. The stability of the enoxaparin/CTAB ion pair complex was pH-dependent, resulting in more rapid dissociation under simulated plasma conditions (i.e., pH 7.4) than in the presence of a mild acidic gastrointestinal environment (i.e., pH 6.5). The intestinal flux of enoxaparin complexes across in vitro Caco-2 cell monolayers was greater when encapsulated within PLGA nanoparticles. Limited changes in transepithelial transport of PLGA-encapsulated enoxaparin complexes in the presence of increasing CTAB concentrations suggest a significant contribution of size-dependent passive diffusion as the predominant transport mechanism facilitating intestinal absorption. Graphical abstract.

Lipid-coated superparamagnetic nanoparticles for thermoresponsive cancer treatment.

Poor aqueous solubility, chemical instability, and indiscriminate cytotoxicity have limited clinical development of camptothecin (CPT) as potent anticancer therapeutic. This research aimed at fabricating thermoresponsive nanocomposites that enhance solubility and stability of CPT in aqueous milieu and enable stimulus-induced drug release using magnetic hyperthermia. 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and l-α-dipalmitoylphosphatidyl glycerol (DPPG) (1:1, mol/mol) were immobilized on the surface of superparamagnetic Fe3O4 nanoparticles (SPIONs) via high affinity avidin-biotin interactions. Heating behavior was assessed using the MFG-1000 magnetic field generator. Encapsulation efficiency and drug release were quantified by fluorescence spectroscopy. Anticancer efficacy of medicated nanoparticles was measured in vitro using Jurkat cells. The results revealed that drug incorporation did not significantly alter particle size, zeta potential, magnetization, and heating properties of lipid-coated SPIONs. Drug loading efficiency was 93.2 ±â€¯5.1%. Drug release from medicated nanoparticles was significantly faster at temperatures above the lipid transition temperature, reaching 37.8 ±â€¯2.6% of incorporated payload after 12 min under therapeutically relevant hyperthermia (i.e., 42 °C). Medicated SPIONs induced greater cytotoxicity than CPT in solution suggesting synergistic activity of magnetically-induced hyperthermia and drug-induced apoptosis. These results underline the opportunity for thermoresponsive phospholipid-coated SPIONs to enable clinical development of highly lipophilic and chemically unstable drugs such as CPT for stimulus-induced cancer treatment.

Stability and magnetically induced heating behavior of lipid-coated Fe3O4 nanoparticles.

Magnetic nanoparticles that are currently explored for various biomedical applications exhibit a high propensity to minimize total surface energy through aggregation. This study introduces a unique, thermoresponsive nanocomposite design demonstrating substantial colloidal stability of superparamagnetic Fe3O4 nanoparticles (SPIONs) due to a surface-immobilized lipid layer. Lipid coating was accomplished in different buffer systems, pH 7.4, using an equimolar mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and l-α-dipalmitoylphosphatidyl glycerol (DPPG). Particle size and zeta potential were measured by dynamic laser light scattering. Heating behavior within an alternating magnetic field was compared between the commercial MFG-1000 magnetic field generator at 7 mT (1 MHz) and an experimental, laboratory-made magnetic hyperthermia system at 16.6 mT (13.7 MHz). The results revealed that product quality of lipid-coated SPIONs was significantly dependent on the colloidal stability of uncoated SPIONs during the coating process. Greatest stability was achieved at 0.02 mg/mL in citrate buffer (mean diameter = 80.0 ± 1.7 nm; zeta potential = -47.1 ± 2.6 mV). Surface immobilization of an equimolar DPPC/DPPG layer effectively reduced the impact of buffer components on particle aggregation. Most stable suspensions of lipid-coated nanoparticles were obtained at 0.02 mg/mL in citrate buffer (mean diameter = 179.3 ± 13.9 nm; zeta potential = -19.1 ± 2.3 mV). The configuration of the magnetic field generator significantly affected the heating properties of fabricated SPIONs. Heating rates of uncoated nanoparticles were substantially dependent on buffer composition but less influenced by particle concentration. In contrast, thermal behavior of lipid-coated nanoparticles within an alternating magnetic field was less influenced by suspension vehicle but dramatically more sensitive to particle concentration. These results underline the advantages of lipid-coated SPIONs on colloidal stability without compromising magnetically induced hyperthermia properties. Since phospholipids are biocompatible, these unique lipid-coated Fe3O4 nanoparticles offer exciting opportunities as thermoresponsive drug delivery carriers for targeted, stimulus-induced therapeutic interventions. PACS: 7550Mw; 7575Cd; 8185Qr.