Aromatic Nitrogen Mustard-Based Autofluorescent Amphiphilic Brush Copolymer as pH-Responsive Drug Delivery Vehicle

Abstract

Delivery of clinically approved nonfluorescent drugs is facing challenges because it is difficult to monitor the intracellular drug delivery without incorporating any integrated fluorescence moiety into the drug carrier. The present investigation reports the synthesis of a pH-responsive autofluorescent polymeric nanoscaffold for the administration of nonfluorescent aromatic nitrogen mustard chlorambucil (CBL) drug into the cancer cells. Copolymerization of poly­(ethylene glycol) (PEG) appended styrene and CBL conjugated N-substituted maleimide monomers enables the formation of well-defined luminescent alternating copolymer. These amphiphilic brush copolymers self-organized in aqueous medium into 25–68 nm nanoparticles, where the CBL drug is enclosed into the core of the self-assembled nanoparticles. In vitro studies revealed ∼70% drug was retained under physiological conditions at pH 7.4 and 37 °C. At endolysosomal pH 5.0, 90% of the CBL was released by the pH-induced cleavage of the aliphatic ester linkages connecting CBL to the maleimide unit. Although the nascent nanoparticle (without drug conjugation) is nontoxic, the drug conjugated nanoparticle showed higher toxicity and superior cell killing capability in cervical cancer (HeLa) cells rather than in normal cells. Interestingly, the copolymer without any conventional chromophore exhibited photoluminescence under UV light irradiation due to the presence of “through-space” π–π interaction between the CO group of maleimide unit and the adjacent benzene ring of the styrenic monomer. This property helped us intracellular tracking of CBL conjugated autofluorescent nanocarriers through fluorescence microscope imaging. Finally, the 4-(4-nitrobenzyl)­pyridine (NBP) colorimetric assay was executed to examine the ability of CBL-based polymeric nanomaterials toward alkylation of DNA.

Biobased thermosensitive polyrotaxanes constructed by polymerization of cyclodextrin-triterpenoid inclusion complexes

“…MTT cytotoxicity assays were performed to evaluate the cytotoxicity of CD-based PRs. 39 As shown in Fig. 5A, HepG2 cells retained about 90% viability after incubation for 24 h in the presence of CD-based PRs below a concentration of 100 µg mL −1 , indicating that the three CD-based PRs had no significant cytotoxicity.…”

Stimuli-Responsive Polymeric Nanocarriers for Drug Delivery, Imaging, and Theragnosis

“…pH stimuli helped in the effective apoptosis of cancer cells via this platform [ 7 ]. Saha et al reported on the development of a pH-triggered auto-fluorescent polymeric nanoplatform for the delivery of nonfluorescent aromatic nitrogen mustard chlorambucil (CBL) to cancer tumors [ 8 ]. pH variance is, therefore, a fundamental variable for the evolution of sophisticated DDSs.…”

Styrene‐Maleimide/Maleic Anhydride Alternating Copolymers: Recent Advances and Future Perspectives

“…Also, these polymers are biocompatible, less toxic, and easy to prepare than most other aggregation‐induced emission luminogens (AIEgens). Being empowered with these advantages, S‐MA alternating copolymer is used as novel stimuli‐responsive polymeric materials, [ 126,127 ] for sensing application, [ 128 ] for drug delivery, [ 129 ] etc.…”

“…Amino acid‐derived PSMI‐based alternating polyampholyte was reported by Saha et al where both the comonomers were functionalized with leucine. [ 129 ] It was observed that the synthesized deprotected polymer becomes charge‐neutral at pH 7.0. Further, this polymeric material can selectively sense carbon disulfide (CS 2 ) in the aqueous and vapor phase (naked‐eye colorimetric detection) with great sensitivity.…”