Hydrophobic modified poly(l‐glutamic acid) graft copolymer micelles with ultrahigh drug loading capacity for anticancer drug delivery

Abstract

Self‐assembled polymeric nanoparticle (NP) drug carriers are capable of encapsulated and controlled delivery, facilitating improvements in the therapeutic efficiency of drugs. Here we report a series of poly(l‐glutamic acid)‐g‐methoxy poly(ethylene glycol)/4‐phenylbutyl ester (PLG‐g‐mPEG/PB) copolymers, which were synthesized by esterification of 4‐phenylbutanol (PB) and PLG‐g‐mPEG in different feed ratios. The copolymers obtained form into nano‐sized micelles in aqueous solution by a self‐assembly process, with lower critical micelle concentration value for higher PB ratio in the copolymers. Variable temperature infrared spectroscopy and circular dichroism were used to prove the breaking of intermolecular hydrogen bonds after PB modification. Podophyllotoxin (PPT), an effective anticancer agent, was incorporated into the inner core of the micelle system by physical entrapment through hydrophobic interaction between the drug and the PB‐modified copolymers. Both the drug loading content and the loading efficiency increased with PB content in the PLG‐g‐mPEG/PB copolymers and reached an ultrahigh value of 28.2 wt% and 94%, respectively. The PPT‐encapsulated micelles (PPT‐NPs) were stable at pH 7.4 but dissociated and released 80% of loaded PPT in a weak acidic environment (pH 5.0). The in vitro proliferation of non‐small‐cell lung cancer cells (A549) was significantly inhibited by PPT‐NPs in a cytotoxicity assay. These results demonstrate that hydrophobic modification is an efficient route for tuning the self‐assembly behaviour and drug encapsulation of PLG‐g‐mPEG copolymers, and our PLG‐g‐mPEG/PB will serve as a promising carrier for hydrophobic anticancer drug delivery. © 2021 Society of Industrial Chemistry.

Amphiphilic Polypeptides Obtained by the Post-Polymerization Modification of Poly(Glutamic Acid) and Their Evaluation as Delivery Systems for Hydrophobic Drugs

“…An alternative way to obtain polypeptides bearing the functional moieties of interest is the post-polymerization modification of a poly(amino acid) main chain [ 12 ]. In the case of poly(amino acids), this approach is mainly used to modify them with thermo-responsive moieties [ 12 ], PEG [ 12 ], sugars [ 8 , 13 ] and hydrophobic molecules [ 14 , 15 ]. In particular, Xue et al reported the modification of poly(L-ornithine- co -L-citrulline) with N-succinimidyl N-methylcarbamate to obtain thermo-responsive copolymers.…”

“…Amidation and azide-alkyne cycloaddition are among the most popular modification techniques [ 8 , 21 ]. In the case of hydrophobization, the modifications of poly(glutamic acid) with 4-phenylbutanol [ 15 ], p -aminoazobenzene [ 22 ], Boc-protected α,ω-aminoalcohols containing different alkyl spacers [ 23 ], cinnamyl alcohol [ 24 ] and coumarin derivative [ 25 ] are reported. The modification of poly(L-lysine) with L-histidine is one of the most popular approaches to obtaining polypeptides sensitive to physiological pH values [ 26 , 27 , 28 ].…”

Synthetic copolymers with natural product side‐chain pendents

“…These nanoaggregates are capable of encapsulating the hydrophobic dye NR inside their hydrophobic core, thus demonstrating their hydrophobic drug loading capability. 51 The copolymers with alanine and dehydroabietate pendents are expected to be biocompatible, as these are amino acid and natural product, respectively. 52 Currently, we are widening our research with other amino acid based copolymers having dehydroabietate pendents to achieve substantial efficacy of drug loading and controlled release of encapsulated drug at different pH values.…”

Special issue: self‐assembly and bioapplications

“…Various weaker interactions were employed in polymer self‐assembly systems, resulting in diverse/hierarchical nanomaterials 7–11 . In particular, the nanoassembles formed by synthetic biomacromolecules and amphiphilic copolymers are promising candidates in bio‐related applications 12–15 . Moreover, combining experiments and simulations to study the self‐assembly mechanism can advance mechanistic research in this field, 2,11 which is one of the vital development directions.…”

“…prepared polymeric micelles from poly(L‐glutamic acid) graft copolymer system, the drug loading content and the loading efficiency can reach an ultrahigh value of 28.2 wt% and 94%, respectively. This self‐assembly system can provide a promising carrier for hydrophobic anticancer drug delivery 13 . Jiang et al .…”