Controlled drug delivery strategies: Advances on the synthesis and molecular dynamics of dendrimers, and optimization of liposomes preparation by Dual Asymmetric Centrifugation
Authors
Sampogna-Mireles, DianaIssue Date
2017-12-01Keywords
DendrimersDrug delivery systems
Folic acid
Pristimerin
Selectivity
Molecular Dynamics
Liposomes
Dual Asymmetric Centrifugation
biotechnology
Advisors
Valencia Gallegos, Jesús ÁngelCommittee Member / Sinodal
Guitiérrez Uribe, Janet AlejandraElizondo Martínez, Perla
Hernández Hernández, José Ascención
Aguilar Jimenéz, Oscar Alejandro
Discipline
Ingeniería y Ciencias Aplicadas / Engineering & Applied SciencesMetadata
Show full item recordAbstract
In early phase of drug development, New Chemical Entities (NCEs) are used as highly active drugs, with limited availability, and high cost. This study presents two alternatives of drug delivery systems, site-specific dendrimers and liposomes, with potential use as carriers of highly active drugs like pristimerin. Advances in the synthesis of site-specific dendrimers with bis-MPA as branching precursor and three key building blocks are reported, including compounds with folic acid (FA) to provide selectivity to folate receptors of cancer cells, pristimerin as cancer drug model, and fluorescein isothiocyanate (FITC) as fluorescent dye for future evaluation as cancer treatment. Five different dendrimer syntheses were reported, differing on their nucleus (bis-MPA or ethylene glycol) and the linker of folic acid (PEG 3350 and triethylene glycol TEG). Different purification techniques, such as normal-phase and reverse-phase column chromatography, size exclusion chromaography, dialysis and ultrafiltration, were probed according to their chemical characteristics and solubility. Characterization was carried out by FT-IR, MALDITOF-MS and/or NMR. Theoretical evidence generated in this work supports that FA-PEG750 and FA-PEG3350 dendrimers can be applied to selectively carry drugs and interact with cancer cell receptors (FR-α). Another drug delivery carrier and a viable alternative to the use of dendrimers is liposomes. Liposomes are the most mature drug carriers for passive and active targeting commercially available in oncology and other disease treatments. Dual Asymmetric Centrifugation (DAC) is a novel, fast, simple, and reproducible method for liposomal formulation screening, it facilitates liposomes preparation, and favors small diameters (<120 nm) in a small scale, with high drug encapsulation (EE). An optimization of DAC parameters (type and volume of buffer, beads size, centrifugation speed and time) was done to obtain liposomes of 70-80 nm with high encapsulation efficiency (71%). Also, dialysis was the best method for liposomes purification in comparison to Zeba-Spin and Micro-Spin size-exclusion columns, and can be applied to other drug delivery systems, like dendrimers. Over all, site-specific dendrimers demand a meticulous control on their structure during synthesis. Their preparation is time consuming and analytically complex. Meanwhile, theoretical evidence supports their potential to selectively carry drugs and interact with cancer cell receptors. Meanwhile, liposomes are a faster, easier and versatile alternative as drug delivery carriers of highly toxic drugs.