Original articleIn situ and in silico evaluation of amine- and folate-terminated dendrimers as nanocarriers of anesthetics
Graphical abstract
Introduction
Dendrimers are hyperbranched three-dimensional macromolecules with globular or ellipsoidal shapes. Relevant properties include their nanoscale size, the presence of hydrophobic or hydrophilic cavities, a wide variety of possible functionalities at their peripheries, and extremely low polydispersity [1], [2]. The structure of the dendrimers exhibits significantly novel and distinct physical, chemical, and biological properties in comparison to traditional linear polymers [2], [3], [4]. Dendrimers have attracted considerable attention because of wide and almost limitless variations on their chemical structure. There exist numerous methodologies for their synthesis, and their unique structures show characteristic properties, which render them a reliable alternative to traditional polymers in a wide range of applications. One alternative is, the design of new nanocontainers and nanodevices for biomedical applications [1], [5], such as drug delivery systems [6], [7], antiviral agents, and magnetic resonance imaging contrast agents [8], [9]. Among the most frequently used dendrimers in biomedical applications are the poly(amidoamine) (PAMAM) dendrimers, which were first synthesized by Tomalia in 1985, being the most thoroughly investigated and characterized as well as the easiest to obtain commercially [1].
PAMAM dendrimers with different surface functionalities have the ability to encapsulate a wide variety of guest molecules for the purpose of drug delivery. It has been reported that PAMAM dendrimers could be efficient delivery systems with the benefits of enhanced drug solubility, prevention of drug degradation, increased circulation time, sustained/controlled drug release and potential drug targeting [10]. In addition, the advances in dendrimer surface engineering, i.e. the conjugation of functional groups to the chain ends of dendrimer surface, could provide stimuli-responsive properties to PAMAM dendritic delivery systems, which could add value to drug delivery efficiency and therapeutic efficacy [11].
The functional groups of amine-terminated PAMAM bind a ligand through hydrogen bonds, electrostatic interactions, and hydrophobic interactions [12], [13], [14]. In this study, we examined the interactions between amine- and folate-terminated PAMAM dendrimers of fifth generation and pain relief drug such as morphine and tramadol (Fig. 1). PAMAM dendrimers modified with folic acid (FA) via covalent conjugation neutralize the remaining amines of the dendrimers surfaces, decreases the toxicity of the dendrimers and encapsulate varius drug for targeted therapy [15]. For morphine and tramadol, the conventional pharmaceutical formulations must be administered every four and eight hours, respectively, a frequency which often compromises patient compliance. A modified release formulation would increase the dosage interval and thus reduce fluctuations in circulating concentrations of the drug.
In the present study, folate-terminated PAMAM dendrimers of generation five (PAMAM G5-FA) were prepared by simple chemical modification of PAMAM G5 and evaluated for controlled drug delivery of the common pain relief drugs morphine and tramadol. The driving force that controls the drug release behavior was analyzed by molecular simulation techniques in terms of the structure and energetics of each one of the complexes.
Section snippets
Polyamine-conjugation of the dendrimers PAMAM G5 with folic acid
The γ-carboxylic acid group of folic acid was covalently conjugated to the free surface amine groups of PAMAM G5 through a carbodiimide mediated amide linkage. A higher molar ratio of 1:140 was used to get all the 128-amine groups of the PAMAM G5 dendrimer conjugated. The conjugates were characterized using mass spectrometry and the spectra shows that only 23 folate molecules were attached to the PAMAM G5 dendrimer (Fig. 2) [16]. The amount of folate was also determined by 1H NMR experiments
Conclusions
PAMAM G5-FA was synthesized by surface modification of PAMAM G5. Mass spectrometry analysis confirmed that around 23 folic acid molecules were attached to PAMAM G5. The synthesized dendrimers were evaluated for controlled drug delivery of morphine and tramadol. It was found that PAMAM G5-FA improved characteristics for drug delivery property PAMAM G5. The amine and folate-terminated PAMAM-G5 dendrimers at different pH were studied by MD simulation techniques. The calculated Rg values were in
Materials
PAMAM G5 dendrimer was purchased in (Dendritech, Midland, MI), N-hydroxybenzotriazole (HOBt), 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimide HCl (EDC), folic acid, dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF) were purchased from Sigma Aldrich Co. (Saint-Louis, MO, USA), dialysis membrane (M.W cut off of 500 Da) was purchased from Spectrum laboratories, Inc., Rancho Dominguez, CA.
Synthesis of folate–dendrimer conjugates
Conjugation of PAMAM G5 dendrimer with folic acid (FA) was carried out by a condensation between the
Acknowledgments
We thank a partial contribution to the Programa Iniciativa Científica Milenio (ICM) del Ministerio de Economía, Fomento y Turismo, Fraunhofer Chile Research Foundation – Innova-Chile Corfo (FCR-CSB 09CEII-6991), and Proyecto Anillo Científico ACT1107. A.V.J. thanks the Doctoral Program of Applied Sciences of Talca University, as well as CONICYT-Chile for a doctoral fellowship. V.C.S. is in debt to CONICYT for doctoral fellowship No. 21121007 and University of Talca for Doctoral Program in
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