Phosphonic acid‐functionalized poly(amido amine) macromers for biomedical applications

Abstract

Novel phosphonic acid-functionalized poly(amido amine) (PAA) macromers are synthesized through aza-Michael addition of 2-aminoethyl phosphonic acid or its mixture with 5-amino-1pentanol at different ratios onto N,N′ -methylene bis(acrylamide) to control the amount of phosphonic acid functionality. The macromers were homo-and copolymerized with 2hydroxyethyl methacrylate at different ratios to obtain hydrogels with various hydrophilicities.The hydrogels' swelling, biodegradation and mineralization properties were evaluated. The swelling and degradation rates of the gels can be tuned by the chemical structure of PAA macromer precursors as well as pH and CaCl2 pre-treatment. The hydrogels show compositiondependent mineralization in SBF and 5xSBF, as evidenced from Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX) analyses. The degradation products of the hydrogels have no effect on U-2 OS, Saos-2 and NIH 3T3 cells, suggesting their cytocompatibility. Overall, these materials have potential to be used as nontoxic degradable biomaterials.

(Bis)phosphonic Acid-Functionalized Poly(ethyleneimine)–Poly(amido amine)s for Selective In Vitro Transfection of Osteosarcoma Cells

“…This unexpected finding can be explained by the strong hydrogen-bonding interactions between hydroxyl groups of AP and PEI and/or electrostatic interactions of (bis)­phosphonic acid groups and excess PEI. , Based on these compositions, the number-average molecular weights ( M n ) of PAEIs were calculated using the molecular weights of PEI or TETA and PAA macromers (Table ). The molecular weights of ALE- or APA-functionalized PAA macromers were calculated from the total number of the ALE or APA and AP repeating units using their 1 H NMR spectra and the formula weights of ALE or APA and AP repeat units and the formula weight of the end group (MBA). , The number of ALE or APA and AP repeating units was calculated by integrating the double-bond protons with respect to methylene protons of ALE or APA (z for ALE or y for APA) and AP (r) (Figure a). The FTIR spectra of the PAEIs show strong peaks at 1651 and 1560 cm –1 due to CO stretching and NH bending.…”

“…PAA macromers with a controlled amount of (bis)­phosphonic acid groups were synthesized using aza-Michael addition reactions of primary amines (AP, ALE, or APA) and MBA at different AP/ALE or AP/APA ratios in 39–60% yield, following the procedures reported by our group (Scheme and Table S1). The synthesis and characterization of some of these macromers are also reported in our previous publications. , The PAA macromer lacking (bis)­phosphonic acid groups (PAA-c) is used as a control. Table summarizes the AP/ALE or AP/APA mole ratios used in the synthesis of PAA macromers and the composition of PAEIs as well as their molecular weights.…”

“…Acrylamide-terminated PAAs were first synthesized by the aza-Michael addition of amines (AP and (bis)phosphonic acidfunctionalized amines) and MBA at molar ratios of 1:1.1 (amine to MBA) as described in the literature. 27,47 Briefly, ALE or the potassium salt of APA, AP, and MBA (0.4 or 1.0 M in total) were dissolved in a water/methanol (v/v = 1 or 1/3) mixture and stirred in glass scintillation vials at 50 °C for 4 days (Table S1). After removal of methanol, the solution was diluted with water and dialyzed using a membrane with a molecular weight cutoff of 1000 Da in distilled water.…”

“…For this purpose, 5-amino-1-pentanol (AP)-bearing poly­(amido amine) (PAA)-based poly­(ethyleneimine) (PEI)-conjugated polymers, called herein PAEI, functionalized with phosphonic acid (APA) or bisphosphonic acid (ALE) are suggested. Few macromers from the aza-Michael addition of APA and ALE to N , N ′-methylene bisacrylamide (MBA) were produced by our group recently and used to develop hydrogels for facilitating hydroxyapatite formation. , Inspired by this, we suggest PAA macromers produced from MBA and AP with 10, 30, and 50 mol % ALE or APA incorporation for bone-targeting gene-transfection agents with low toxicity. AP is selected as the major component of the PAA macromer because among the 3000 poly­(β-amino ester)­s whose gene transfer efficiencies have been studied, the best transfection was seen with AP-containing polymers. ,, Branched 1.8 kDa PEI was preferred for the designed PAEIs, which is known as an ineffective molecular weight PEI for the gene transfection in its free form but with much lower toxicity compared to 25 kDa PEI. − …”

“…Few macromers from the aza-Michael addition of APA and ALE to N,N′-methylene bisacrylamide (MBA) were produced by our group recently and used to develop hydrogels for facilitating hydroxyapatite formation. 27,47 Inspired by this, we suggest PAA macromers produced from MBA and AP with 10, 30, and 50 mol % ALE or APA incorporation for bone-targeting genetransfection agents with low toxicity. AP is selected as the major component of the PAA macromer because among the 3000 poly(β-amino ester)s whose gene transfer efficiencies have been studied, the best transfection was seen with APcontaining polymers.…”