Micelles Based on Biodegradable Poly(l-glutamic acid)-b-Polylactide with Paramagnetic Gd Ions Chelated to the Shell Layer as a Potential Nanoscale MRI−Visible Delivery System

Abstract

There is much interest in the development of a nanoscale drug delivery system with MRI visibility to optimize the delivery efficiency and therapeutic efficacy under image guidance. Here we report on the successful fabrication of nanoscale micelles based on biodegradable poly( L-glutamic acid)- b-polylactide (PG- b-PLA) block copolymer with paramagnetic Gd3+ ions chelated to their shell. PG- b-PLA was synthesized by sequential polymerization reactions: anionic polymerization of L-lactide followed by ring-opening polymerization of benzyl glutamate N-carboxylic anhydride. The metal chelator p-aminobenzyldiethylenetriaminepenta(acetic acid) (DTPA) was readily conjugated to the side chain carboxylic acids of poly( L-glutamic acid). The resulting copolymer formed spherical micelles in aqueous solution with an average diameter of 230 nm at pH 7.4. The size of PG(DTPA)- b-PLA micelles decreased with increasing pH value. DTPA-Gd chelated to the shell layer of the micelles exhibited significantly higher spin-lattice relaxivity (r1) than a small-molecular-weight MRI contrast agent, indicating that water molecules could readily access the Gd ions in the micelles. Because of the presence of multiple carboxylic acid functional groups in the shell layer, polymeric micelles based on biodegradable PG(DTPA-Gd)- b-PLA may be a suitable platform for the development of MRI-visible, targeted nanoscale drug delivery systems.

Synthesis and characterization of the biomaterial poly(lactic acid‐co‐Nε‐carbobenzoyloxy‐L‐lysine) via direct melt copolymerization

“…Because these amphiphilic polymers contain both biodegradable esters and amide groups in the chain, their biodegradation behaviors are different from those of the corresponding homopolymers and some copolyesters, and they exhibit a better hydrophilicity and biocompatibility than unmodified PLA; this makes PLAA very useful for biodegradable biomedical materials, including drugdelivery vehicles. [9][10][11][12][13][14][15][16][17] Particularly, because of the physiological and biochemical effects of lysine (Lys) for the human body, 18,19 great importance has been directed toward the application of Lys in medical and material fields recently. [12][13][14][15][16][17] To avoid unfavorable side reactions before use, the terminal amino group of Lys with multifunctional groups must be protected, and this is usually done by the use of N e -carbobenzoyloxy-Llysine [Lys(Z)] as a starting material during the synthesis of polymers based on Lys.…”

Acid-triggered core cross-linked nanomicelles for targeted drug delivery and magnetic resonance imaging in liver cancer cells

“…35,36 The removal of the benzyl group in PBLG block was achieved using an acid deprotection method. 37,38 After N,N-carbonyl diimidazole (CDI; Sigma-Aldrich, St Louis, MO, USA), activated by N,N-diisopropylamino ethylamine (DIPAEA; Sigma-Aldrich), was linked to the side carboxyl group of the synthesized allyl-polyethylene glycol-b-poly(Lglutamate) (allyl-PEG-PGA), the terminal allyl group was converted into an amino group on the base of a radical addition reaction of 2-aminoethanethiol hydrochloride, allowing it to link with folic acid (BR; Sinopharm Chemical Reagent Co, Ltd), preactivated by N-hydroxysuccinimide (NHS; SigmaAldrich) and dicyclohexylcarbodiimide (Sigma-Aldrich). 28,29 Then the main products were characterized by proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy (Mercury-Plus 300; Varian Medical Systems Inc, Palo Alto, CA, USA) as shown in Figure 2.…”

Synthesis and in vivo magnetic resonance imaging evaluation of biocompatible branched copolymer nanocontrast agents

“…To date, most polymer nanocontrast agents focus on Gd(III) chelates conjugated onto dendrimers, [16][17][18][19][20][21][22] liposomes, [23][24][25][26][27][28][29][30] micelles, [31][32][33][34][35] core cross-linked star polymers, 36,37 and hyperbranched polymers. [36][37][38] Polymer-based nanoparticle MRI contrast agents have demonstrated optimal pharmacokinetics and circulation half-life, increased tolerance to enzymatic degradation, as well as greater physical and chemical stability which improve their therapeutic value.…”