Phenylboronic Acid-Functionalized Copolypeptides: Facile Synthesis and Responsive Dual Anticancer Drug Release

Abstract

The incorporation of a phenylboronic acid group has appeared as an attractive strategy to build smart drug delivery systems. Here, we report novel synthesis of phenylboronic acid-functionalized copolypeptides based on an L-boronophenylalanine Ncarboxyanhydride (BPA-NCA) monomer and their application for robust co-encapsulation and responsive release of dual anticancer drugs. By employing different poly(ethylene glycol) (PEG) initiators and copolymerizing with varying NCA monomers, linear and star PEG-poly(L-boronophenylalanine) copolymers (PEG-PBPA, star-PEG-PBPA), PEG-poly(L-tyrosine-co-L-boronophenylalanine) [PEG-P(Tyr-co-BPA)], PEG-poly(L-lysine-co-L-boronophenylalanine) [PEG-P(Lys-co-BPA)], and PEG-poly(β-benzyl-L-aspartateco-L-boronophenylalanine) [PEG-P(BLA-co-BPA)] were obtained with controlled compositions. Interestingly, PEG-PBPA selfassembled into uniform micellar nanoparticles that mediated robust co-encapsulation and hydrogen peroxide (H 2 O 2 ) and acidresponsive release of dual antitumor drugs, curcumin (Cur) and sorafenib tosylate (Sor). These dual drug-loaded nanoparticles (PBN-Cur/Sor) exhibited a greatly enhanced anticancer effect toward U87 MG-luciferase glioblastoma cells. The facile synthesis of phenylboronic acid-functionalized copolypeptides from BPA coupled with their robust drug loading and responsive drug release behaviors make them interesting for construction of smart cancer nanomedicines.

Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia

“…NP was constructed through the self-assembly of PEG-b-P(BPAco-Tyr) copolymer that was synthesized by simultaneous copolymerization of BPA-NCA and Tyr-NCA monomers in the presence of PEG-NH 2 (M n = 5.0 kg mol −1 ) as previous report (Scheme S1, Supporting Information). [19] 1 H NMR spectrum of 1), corroborating that the NCA copolymerization proceeded in a controlled manner and copolypeptides with tailored chain length and functionalities could be readily obtained. MALDI-TOF and gel permeation chromatography (GPC) measurements revealed that PEGb-P(BPA-co-Tyr) had similar molecular weights to those measured by 1 H NMR and narrow polydispersities with an M w /M n of around 1.10 (Figure 1E, Table 1).…”

“…Boronic ester bonds not only promote strong interactions of drugs with nanovehicles under physiological conditions, but also provide acid/H 2 O 2 ‐triggered responsivity. [ 19,21 ] Indeed, NPAT revealed obvious dissociation and swelling after incubating in phosphate buffered salt (PBS) (pH 5.5) or PBS with 100 × 10 −6 m H 2 O 2 for 6 h (Figure 1J). Besides, enzymes like proteinase K (PK) could induce the nanoparticle swelling and aggregation as characterized by the presence of new bands at around 800 and 8000 nm owing to the enzymatic degradation of polypeptide segments.…”

“…NP was constructed through the self‐assembly of PEG‐ b ‐P(BPA‐ co ‐Tyr) copolymer that was synthesized by simultaneous copolymerization of BPA‐NCA and Tyr‐NCA monomers in the presence of PEG‐NH 2 ( M n = 5.0 kg mol −1 ) as previous report (Scheme S1, Supporting Information). [ 19 ] 1 H NMR spectrum of PEG‐ b ‐P(BPA‐ co ‐Tyr) discerned characteristic signals of PEG ( δ 3.50), BPA ( δ 7.22, 7.68), and Tyr ( δ 6.61, 6.95) (Figure S2A, Supporting Information). The number of BPA and Tyr units could be acquired by comparing the integrals of signal at δ 3.50 (methylene of PEG) with those at δ 7.68 (benzene ring of BPA) and δ 6.61 (benzene ring of Tyr), respectively.…”

Bottlebrush polymer with dual functionality for osteoarthritis treatment: curcumin delivery and lubrication properties

“…31 In contrast to the other type of linkage like ester, it was revealed that curcumin-loaded drug carriers via boronate ester show a burst release within the first two days and later with a sustained release. 32–34 The drug release pattern showed 40% burst release during 1st day, followed by a 75% overall release at pH 6, and 25% burst release during 1st day, followed by a 57% overall release at pH 7.4. As seen in the release profile, the release rate was faster in acidic pH than in neutral, because the borate ester could be cleaved under acidic conditions, thereby facilitating faster curcumin elution.…”

Antibody-Mediated Nanodrug of Proteasome Inhibitor Carfilzomib Boosts the Treatment of Multiple Myeloma

“…Taking advantage of the “like dissolves like” mechanism, PMs-CFZ presented a decent drug loading level with a drug loading content (DLC) up to 11.2 wt % (Figure A). The introduction of extra physical interactions including π–π stacking, hydrogen bonding, and coordination has been proven to benefit drug loading and stability. − In contrast, less than 4.5 wt % of DLC was accomplished for CFZ in liposome and polycarbonate-based nanosystems. ,, DLS measurement demonstrated that PMs-CFZ had an average diameter of lower than 85 nm and a narrow distribution (PDI < 0.16).…”