Well-Defined pH-Responsive Self-Assembled Block Copolymers for the Effective Codelivery of Doxorubicin and Antisense Oligonucleotide to Breast Cancer Cells

Abstract

The worldwide steady increase in the number of cancer patients motivates the development of innovative drug delivery systems for combination therapy as an effective clinical modality for cancer treatment. Here, we explored a design concept based on poly­(ethylene glycol)-b-poly­(2-(dimethylamino)­ethyl methacrylate)-b-poly­(2-hydroxyethyl methacrylate-formylbenzoic acid) [PEG-b-PDMAEMA-b-P­(HEMA-FBA)] for the dual delivery of doxorubicin (DOX) and GTI2040 (an antisense oligonucleotide for ribonucleotide reductase inhibition) to MCF-7 breast cancer cells. PEG-b-PDMAEMA-b-PHEMA, the precursor copolymer, was prepared through chain extensions from a PEG-based macroinitiator via two consecutive atom transfer radical polymerization (ATRP) steps. Then, it was modified at the PHEMA block with 4-formylbenzoic acid (FBA) to install reactive aldehyde moieties. A pH-responsive polymer–drug conjugate (PDC) was obtained by conjugating DOX to the polymer structure via acid-labile imine linkages, and subsequently self-assembled in an aqueous solution to form DOX-loaded self-assembled nanoparticles (DOX-SAN) with a positively charged shell. DOX-SAN condensed readily with negatively charged GTI2040 to form GTI2040/DOX-SAN nanocomplexes. Gel-retardation assay confirmed the affinity between GTI2040 and DOX-SAN. The GTI2040/DOX-SAN nanocomplex at N/P ratio of 30 exhibited a volume-average hydrodynamic size of 136.4 nm and a zeta potential of 21.0 mV. The pH-sensitivity of DOX-SAN was confirmed by the DOX release study based on the significant cumulative DOX release at pH 5.5 relative to pH 7.4. Cellular uptake study demonstrated favorable accumulation of GTI2040/DOX-SAN inside MCF-7 cells compared with free GTI2040/DOX. In vitro cytotoxicity study indicated higher therapeutic efficacy of GTI2040/DOX-SAN relative to DOX-SAN alone because of the downregulation of the R2 protein of ribonucleotide reductase. These outcomes suggest that the self-assembled pH-responsive triblock copolymer is a promising platform for combination therapy, which may be more effective in combating cancer than individual therapies.

Well-Defined pH-Sensitive Self-Assembled Triblock Copolymer-Based Crosslinked Micelles for Efficient Cancer Chemotherapy

“…PBA block was used to confer the structure with hydrophobicity that enables self-assembly as well as promotes the interaction with the hydrophobic DOX, thereby increasing the drug loading capacity. It is worth mentioning that the molecular weight of the final polymer was maintained below the renal filtration threshold (~45 kDa) to allow clearance from the body after releasing the payload [ 51 ]. The triblock copolymer was modified at the middle PHEMA block by reacting the OH groups with 4-pentenoic anhydride to install photoreactive olefin groups to the polymer structure.…”

Codelivery of CPT and siPHB1 with GSH/ROS Dual-Responsive Hybrid Nanoparticles Based on a [12]aneN3-Derived Lipid for Synergistic Lung Cancer Therapy

“…Then, the mixture was washed with saturated brine and extracted with DCM, and the organic phase was removed in vacuo. The residues were purified by column chromatography (DCM/MeOH = 10:1) to afford TSP as a dark red wax (0.22 g, 46% 44 Ten microliters of a pyrene solution (200 mg/L, acetone) was added to a series of vials. Then, the solution of CBN1−CBN3 in different concentrations was added to the vial.…”

“…The CMC values of CBN1 – CBN3 were determined according to the reported method . Ten microliters of a pyrene solution (200 mg/L, acetone) was added to a series of vials.…”

[12]aneN3-modified camptothecin and PEGylated AIEgens co-assembly into core–shell nanoparticles with ROS/NTR dual-response for enhanced cancer therapy

“…The CMC values of CNN1-CNN3 were determined according to the reported method. 51 A pyrene stock solution (200 mg L À1 ) in acetone was prepared, and 10 mL pyrene solution was added to a series of vials, respectively. CNN1-CNN3 solutions in MeOH with various concentrations (0.2, 0.5, 1.0, 2.0, 2.5, 5.0, 10, 20, 40, and 100 mg L À1 ) were subsequently added to the vials.…”

“…[12]aneN 3 -based gene carriers with the propensity of forming self-assembled NPs in aqueous solution. [22][23][24][25] According to the reported methods, 51 the critical micelle concentration (CMC) of compounds CNN1-CNN3 was calculated to be 2.9, 2.7, and 2.3 mg L À1 , respectively (Fig. S4, ESI †).…”