Dual Stimuli-Responsive Poly(N-isopropylacrylamide)-b-poly(l-histidine) Chimeric Materials for the Controlled Delivery of Doxorubicin into Liver Carcinoma

Abstract

A series of dual stimuli responsive synthetic polymer bioconjugate chimeric materials, poly(N-isopropylacrylamide)55-block-poly(L-histidine)n [p(NIPAM)55-b-p(His)n] (n=50, 75, 100, 125), have been synthesized by employing reversible addition-fragmentation chain transfer polymerization of NIPAM, followed by ring-opening polymerization of α-amino acid N-carboxyanhydrides. The dual stimuli responsive properties of the resulting biocompatiable and membrenolytic p(NIPAM)55-b-p(His)n polymers are investigated for their use as a stimuli responsive drug carrier for tumor targeting. Highly uniform self-assembled micelles (∼55 nm) fabricated by p(NIPAM)55-b-p(His)n polymers display sharp thermal and pH responses in aqueous media. An anticancer drug, doxorubicin (Dox), is effectively encapsulated in the micelles and the controlled Dox release is investigated in different temperature and pH conditions. Antitumor effect of the released Dox is also assessed using the HepG2 human hepatocellular carcinoma cell lines. Dox molecules released from the [p(NIPAM)55-b-p(His)n] micelles remain biologically active and have stimuli responsive capability to kill cancer cells. The self-assembling ability of these hybrid materials into uniform micelles and their efficiency to encapsulate Dox makes them a promising drug carrier to cancer cells. The new chimeric materials thus display tunable properties that can make them useful for a molecular switching device and controlled drug delivery applications needing responses to temperature and pH for the improvement of cancer chemotherapy.

Dextran-b-poly(L-histidine) copolymer nanoparticles for pH-responsive drug delivery to tumor cells

“…Many reports on PHS describe faster drug release at an acidic pH, and accelerated release of anticancer agents at acidic pH preferentially kills cancer cells. 20,22,23,[34][35][36] Because the extracellular pH in tumor tissue is acidic compared with normal tissues and cells, drug release may be faster in the tumor microenvironment, leading to death of tumor cells.. In practical terms, DexPHS nanoparticles were completely solubilized in acidic solutions with a pH less than 4.0 (results not shown).…”

Micelles Formed by Polypeptide Containing Polymers Synthesized Via N-Carboxy Anhydrides and Their Application for Cancer Treatment

“…Johnson et al [33] presented the synthesis of a series of novel temperature-responsive polymers of the poly(N-isopropylacrylamide)-b-poly(L-histidine) [p(NIPAM)-b-p(His)] type with 55 monomeric units of p(NIPAM) and 50, 75, 100 and 125 monomeric units of p(His). The authors employed a combination of the polymerization strategies of reversible addition-fragmentation chain transfer polymerization (RAFT) and ROP and envisioned the perspective of the use of this material as a pH-and temperature-responsive antitumor drug carrier.…”

Transferrin receptor-targeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer

“…Moreover, when PHIS becomes a strong polycation at acidic pH, it can facilitate endolysosome escape via the so-called "proton sponge" effect that ruptures the endosomal membrane. 15 The first PHIS-based copolymer micelles (PHIS-coupled polyethylene glycol-2000 [PHIS-PEG 2000 ]) were synthesized by Lee et al 16 However, the PHIS-PEG 2000 micelle gradually dissembled below pH 7.4 and is thus not suitable to serve as a drug carrier. Therefore, optimizing the triggering pH to a more acid pH plays a key role to construct PHIS-based drug delivery system.…”