Self-Assembled Cationic Biodegradable Nanoparticles from pH-Responsive Amino-Acid-Based Poly(Ester Urea Urethane)s and Their Application As a Drug Delivery Vehicle

Abstract

The objective of this study is to develop a new family of biodegradable and biologically active copolymers and their subsequent self-assembled cationic nanoparticles as better delivery vehicles for anticancer drugs to achieve the synergism between the cytotoxicity effects of the loaded drugs and the macrophage inflammatory response of the delivery vehicle. This family of cationic nanoparticles was formulated from a new family of amphiphilic cationic Arginine-Leucine (Arg-Leu)-based poly(ester urea urethane) (Arg-Leu PEUU) synthesized from four building blocks (amino acids, diols, glycerol α-monoallyl ether, and 1,6 hexamethylene diisocyanate). The chemical, physical, and biological properties of Arg-Leu PEUU biomaterials can be tuned by controlling the feed ratio of the four building blocks. The Arg-Leu PEUU copolymers have weight-average molecular weights from 13.4 to 16.8 kDa and glass-transition temperatures from -3.4 to -4.6 °C. The self-assembled cationic nanoparticles (Arg-Leu PEUU NPs) were prepared using a facile dialysis method. Arg-Leu PEUU NPs have average diameters ranging from 187 to 272 nm, show good biocompatibility with 3T3 fibroblasts, and they support bovine aortic endothelial cell (BAEC) proliferation and adhesion. Arg-Leu PEUU NPs also enhanced the macrophages' production of tumor necrosis factor-α (TNF-α) and nitric oxide (NO), but produced relatively low levels of interleukin-10 (IL-10), and therefore, the antitumor activity of macrophages might be enhanced. Arg-Leu PEUU NPs were taken up by HeLa cells after 4 h of incubation. The in vitro hemolysis assay showed the cationic Arg-Leu PEUU NPs increased their chance of endosomal escape at a more acidic pH. Doxorubicin (DOX) was successfully incorporated into the Arg-Leu PEUU NPs, and the DOX-loaded Arg-Leu PEUU NPs exhibited a pH-dependent drug release profile with accelerated release kinetics in a mild acidic condition. The DOX-loaded 6-Arg-4-Leu-4 A/L-2/1 NPs showed higher HeLa cell toxicity than the free DOX at the same concentration after 24 h of treatment. The results suggest the cationic Arg-Leu PEUU NPs could potentially be a useful carrier family for hydrophobic anticancer drugs and produce a synergistic effect between DOX cytotoxicity and the production of TNF-α and NO by macrophages.

Folate‐decorated arginine‐based poly(ester urea urethane) nanoparticles as carriers for gambogic acid and effect on cancer cells

“…and , no cytotoxicity to HeLa and A549 cells was observed for both blank FA‐Arg‐PEUU NPs at 20 and 60 µg/mL NP concentrations and 5 and 12 h incubation periods (two red columns on the left) with cell viability ranging from 94% to >100%. Similar good biocompatibility of Arg PEUU NPs without FA conjugated (up to 500 μg/mL in media) has been reported in prior studies . Free GA, GA‐loaded Arg‐PEUU, and FA‐Arg‐PEUU NPs showed time‐ and concentration‐dependent cytotoxicity toward both cells.…”

“…The presence of an aromatic peak (1604 cm −1 ) at the FT‐IR spectrum of FA‐Arg‐PEUU demonstrates the presence of FA when comparing with Arg‐PEUU. The FA spectrum showed a peak at 1690 cm −1 (carboxyl group), while the Arg‐PEUU showed characteristic bands of ester bond at 1720 cm −1 . The absorbance at 1110 cm −1 on Arg‐PEUUs and FA‐Arg‐PEUU indicates the presence of the C–O stretch of ether bond that comes from the PEG composition.…”

“…The synthesis method of diaminopolyethylene glycol 3400 (PEG3400‐NH 2 ) is described elsewhere . Linear Arg‐PEUU was synthesized using the prior reported method with modifications on building block feed ratio (Table ) …”

“…37,40 Linear Arg-PEUU was synthesized using the prior reported method with modifications on building block feed ratio (Table I). 21,23 To provide more polymer end groups for FA conjugating, branched Arg-PEUU was prepared by a core-first method. 1 mmol pentathritol (0.136 g) and 25 mmol HDI (4.2 g) were magnetically stirred in 10 mL DMSO with stannous 2-ethylhexanoate catalyst (1 wt % of total mass of reactants).…”

“…Biodegradable arginine (Arg)-based poly(ester amide) and poly(ester urea urethane) (PEUU) have been developed to promote wound healing quality and as gene and drug carriers. [16][17][18][19][20][21][22][23][24][25][26][27] Arg PEUU NPs are promising nanocarrier biomaterials prepared by a facile dialysis method with adjustable cationic charge that are able to undergo a quick binding process onto negatively charged cell membranes, followed by rapid drug uptake by cells. [28][29][30] Functionalized linear Arg-PEUUs are synthesized from 4 building blocks: Arg, diols, diisocyanate, and glycerol a-monoallyl ether.…”