Histamine-functionalized copolymer micelles as a drug delivery system in 2D and 3D models of breast cancer

Abstract

Histamine functionalized block copolymers based on poly(allyl glycidyl ether)-b-poly(ethylene oxide) (PAGE-b-PEO) were prepared with different ratios of histamine and octyl or benzyl groups using UV-initiated thiol-ene click chemistry. At neutral pH, the histamine units are uncharged and hydrophobic, while in acidic environments, such as in the endosome, lysosomes, or extracellular sites of tumours, the histamine groups are positively charged and hydrophilic. pH responsible polymer drug delivery systems is a promising route to site specific delivery of drugs and offers the potential to avoid side effects of systemic treatment. Our detailed in vitro experiments of the efficacy of drug delivery and the intracellular localization characteristics of this library of NPs in 2D and 3D cultures of breast cancer revealed that the 50% histamine-modified polymer loaded with DOX exhibited rapid accumulation in the nucleus of free DOX within 2 h. Confocal studies showed enhanced mitochondrial localization and lysosomal escape when compared to controls. From these combined studies, it was shown that by accurately tuning the structure of the initial block copolymers, the resulting self-assembled NPs can be designed to exploit histamine as an endosomal escape trigger and the octyl/benzyl units give rise to a hydrophobic core resulting in highly efficacious drug delivery systems (DDS) with control over intracellular localization. Optimization and rational control of the intracellular localization of both DDS and the parent drug can give nanomedicines a substantial increase in efficacy and should be explored in future studies.

Low density lipoprotein modified silica nanoparticles loaded with docetaxel and thalidomide for effective chemotherapy of liver cancer

“…In cancer therapy, it is known that drug-loaded DDS cannot compete with free drugs because drug release within DDS cannot reach 100% and, as a result, the cell viability of DDS is higher than that of free drugs ( 35 , 36 ). However, when applied in vivo , DDS show more advantages than free drugs as they can be modified to more specifically target tumor tissue and increase local drug concentration as well as avoid side effects ( 37 , 38 ). However, the co-delivery of DTX and TDD exerted much more potent anti-cancer effects than either single drug-loaded formulation or free drugs at all the adopted drug concentrations.…”

Monodisperse Cylindrical Micelles and Block Comicelles of Controlled Length in Aqueous Media

“…61 In addition, PAGE is an analog of poly(ethylene oxide) with a high density of allyl groups along its backbone that can be readily functionalized. [62][63][64] This is particularly important because it opens up the possibility for the divergent preparation of a variety of BCPs for any targeted application with no need for protection-deprotection procedures. In fact, it has been shown that the allyl groups on PAGE backbone can be readily modified with biologically-relevant molecules of interest via thiol-ene radical coupling.…”

Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

“…It was found that the histamine functionality facilitated endosomal escape and enhanced doxorubicin targeting to the mitochondria as compared to free Dox. [128] Chen et al have prepared nanoparticles that were composed of a quaternary ammonium-functionalized chitosan derivative and a chitosan derivative modified with N-glycyrrhetinic acid moieties via Schiff base PEG spacer. These nanoparticles were used for the delivery of brucine.…”

“…Positive charges [103] Linear polymers [24,[104][105][106][107]113,[116][117][118][119][120][121][122][123][124] Branched polymers [24,106,113,115,116,[125][126][127] Dendrimers [108][109][110][111][112]116] Charge-reversal [103] Linear polymers [11,22,129,132,133,135] Micelles [128,130,131,134,236] Dendrimers [136] Volumetric expansion Nanoparticles [237] Membranedisrupting peptides Endosomes/ lysosomes [102] N-terminal HA2 peptide derivative Linear polymers [21] INF-7 peptide Linear polymers [137,138] GALA PEGylated liposomes …”

“…Poly(l-histidine) or in general, imidazole-rich polymers, micelles, and nanoparticles have found interest since the pK a of the imidazole group (6.15) allows a rapid transition from an uncharged state in the extracellular milieu to a positively charged state upon endocytic internalization. [22,103,[128][129][130][131][132] Another strategy that has been pursued is to mask positively charged groups with another functionality that is cleaved under acidic conditions and restore the positive charges. In one example, the primary amine groups of PLL were amidized with 1,2-dicarboxyliccyclohexene anhydride.…”