pH‐ and Redox‐Responsive Poly(ethylene glycol) and Cholesterol‐Conjugated Poly(amido amine)s Based Micelles for Controlled Drug Delivery

Abstract

An optimized condition is identified to prepare linear poly(amido amine)s via Michael Addition polymerization of trifunctional amine, 4-(aminomethyl)piperidine (AMPD), with an equimolar diacrylamide, N,N-cystaminebis(acrylamide) (BAC). Poly(ethylene glycol) (PEG) and cholesterol (CE) are conjugated to linear poly(BAC-AMPD) through the reactions with the secondary amino groups in the backbone, respectively, to form poly(BAC-AMPD)-g-PEG-g-CE. The chemical structures of poly(BAC-AMPD) and poly(BAC-AMPD)-g-PEG-g-CE are characterized using NMR and gel permeation chromatography (GPC). Transmission electron microscopy (TEM), dynamic light scattering (DLS) and (1)H NMR results show that micelles with PEG shells and hydrophobic cores composed of poly(BAC-AMPD) and CE are formed via self-assembly of poly(BAC-AMPD)-g-PEG-g-CE in aqueous solution, and the micelles of poly(BAC-AMPD)-g-PEG-g-CE can be degraded by the presence of L-dithiothreitol and show a limited cytotoxicity in vitro. The anti-cancer drug, doxorubicin (DOX), can be loaded into the micelles. The DOX loaded micelles of poly(BAC-AMPD)-g-PEG-g-CE show pH- and redox-responsive drug release and redox-induced formation of aggregates, and it is shown that the DOX loaded micelles can deliver DOX into cells and show a higher efficacy in killing cancer cells than free drug.

Preparation of thermo/redox/pH‐stimulative poly(N‐isopropylacrylamide‐co‐N,N′‐dimethylaminoethyl methacrylate) nanogels and their DOX release behaviors

“…In spite of the PND/DOX nanogels exhibiting higher cytotoxicity than free DOX (IC 50 : ~2.25 μM), the applications of PND‐MBA/DOX has been limited in drug carriers due to its non‐biodegradability, which caused the side effects after being accumulated in the human body . However, compared to PND‐MBA/DOX nanogels, the biodegradable PND‐BAC/DOX nanogels presented a better anticancer cytotoxicity in consequence with the pH/thermo/redox‐sensitive release behaviors, which caused more effective DOX drugs to accumulate around the cancer cells . The higher therapeutic efficacy may be the result from the better encapsulation ratio and the pH/thermo/redox‐sensitive release behaviors of the PND‐BAC/DOX nanogels, which provides a potential drug carrier for anticancer drugs.…”

“…7,27 However, compared to PND-MBA/-DOX nanogels, the biodegradable PND-BAC/DOX nanogels presented a better anticancer cytotoxicity in consequence with the pH/thermo/redox-sensitive release behaviors, which caused more effective DOX drugs to accumulate around the cancer cells. 7,28,29 The higher therapeutic efficacy may be the result from the better encapsulation ratio and the pH/thermo/redox-sensitive release behaviors of the PND-BAC/DOX nanogels, which provides a potential drug carrier for anticancer drugs.…”

Cholesterol and vitamin E-conjugated PEGylated polymeric micelles for efficient delivery and enhanced anticancer activity of curcumin: evaluation in 2D monolayers and 3D spheroids

“…Cholesterol has cellular compatibility compared to other polymeric systems. Cholesterol based nano-drug delivery systems are being extensively utilized in recent years for the delivery of various anticancer drugs [15,16].…”

pH- and redox-responsive self-assembly of amphiphilic hyperbranched poly(amido amine)s for controlled doxorubicin delivery

“…3,4 Typically, pH-responsive polymers contain amino [5][6][7] or imidazole groups, [8][9][10] acetal linkage 11 or hydrazine linkage [12][13][14][15][16] which can be protonated or hydrolyzed under acidic conditions, respectively, and majority of the redox-responsive polymers contain disulfide bonds. 1,2 The concentration of the representative reducing compound, glutathione (GSH), is 100-1000 times higher in the intracellular matrices than in the extracellular matrices.…”

“…1,2 The concentration of the representative reducing compound, glutathione (GSH), is 100-1000 times higher in the intracellular matrices than in the extracellular matrices. 7,[23][24][25] So far, majority of polymer drug delivery systems are from linear polymers, and few are from hyperbranched polymers. 7,17,18 Drug delivery systems can be formulated either by conjugating drugs to polymers covalently [19][20][21][22] or by loading the drugs into assemblies of polymers which are widely obtained via selfassembly of amphiphilic linear or branched polymers.…”