Boron‐Containing Lipids and Liposomes: New Conjugates of Cholesterol with Polyhedral Boron Hydrides

Abstract

As eries of boron-containing lipids werep repared by reactions of cyclic oxonium derivatives of polyhedron boranesa nd metallacarboranes (closo-dodecaborate anion, cobalt and iron bis(dicarbollides)) with amine and carboxylic acids which are derived from cholesterol. Stable liposomal formulations,o nt he basis of synthesized boron-containing lipids, hydrogenated soybean l-a-phosphatidylcholinea nd (HSPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) as excipients,w ere prepared and then characterizedb yd ynamic light scattering(DLS) that revealed the formation of particles to be smaller than 200 nm in diameter.T he resulting liposomal formulationss howed moderate to excellent loading and entrapmente fficiency, thus justifying the design of the compounds to fit in the lipid bilayer and ensuringease of in vivo use for futurea pplication. The liposomalf ormulations based on cobalt and iron bis(dicarbollide)-based lipids were found to be nontoxic against both human breast normale pithelial cells MCF-10A and human breast cancer cells MCF-7.

Preparing (Metalla)carboranes for Nanomedicine

“…Recently, Bregadze et al (2020) reported cholesterol derivatives of closo-dodecaborane, cobalt and iron bis(dicarbollide), which form liposomes together with hydrogenated (Soy) L-α-phosphatidylcholine (HSPC) and 1,2-distearoylsn-glycero-3-phosphoethanol-amine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG). [119] DLS and TEM experiments were performed to identify the size distribution of the new liposomes and the lipid bilayer structure. One sample with different sizes was presented, however, without showing the size distribution from TEM experiments; unfortunately, no detailed information was given on the DLS measurements.…”

“…The boron medicinal chemistry literature is rich of examples of elaborated and well-established synthetic approaches to boron-loaded NP platforms and biological macrovectors, [108][109][110]112,113,138,150,175,176] which are accompanied by experiments to determine the loading efficiency and investigate drug release kinetics, at least as preliminary evaluation under simulated biological conditions, especially in the latest works. [107,119,149,177,178] Loading efficiency is generally investigated using a combination of LS techniques (SLS, DLS), calorimetry (mostly, ITC) and 1 H NMR spectroscopy, particularly in the case of (co)polymeric matrices as carrier systems (Figure 9). [110][111][112][113]116] These techniques can give direct access to nano-object formation mechanisms, preferential binding sites and motifs, which indirectly give (semi-)quantitative information on, for example, maximum loading capacity and/or loading-carrier ratios, often expressed as segment/probe ratios (see, e. g., ref.…”

“…Finally, in the case of liposomes and metallic nanocarriers (Au-and AgNPs, magnetic Fe 3 O 4 -NPs), boron loading is typically measured by 1 H nuclear magnetic resonance dispersion (NMRD), provided that a suitable imaging probe such as gadolinium(III) [123,175] is present, inductively coupled plasma atomic or optical emission spectroscopy (ICP-AES/OES) and/or mass spectrometry (ICP-MS), microwave-induced plasma mass spectrometry (MIP-MS), elemental analysis, energy-dispersive Xray spectroscopy (EDX), and UV/vis spectroscopy. [107,119,138,150,174,[182][183][184] One highlight among the synthetic approaches to boronrich drug-carrier systems is the work by Sumitani et al (2012), which uses a "synthetic chemist" approach (covalent vs. noncovalent bonding) to tackle an effective problem of applicability for AB-type amphiphilic block copolymers, that is, drug leakage during blood circulation. [185] Leakage of covalently bonded 1-(4vinylbenzyl)-closo-ortho-carborane from core-polymerised ace-talated and methacryloylated poly(ethylene glycol)-block-poly-(lactide) (acetal-PEG-b-PLA-MA) micelles in 10 wt% FBS solution was significantly suppressed, compared to analogous noncrosslinked micelles, as determined by ICP-AES.…”

“…[198,202a,b] Liposomal and polymeric formulations deserve specific attention, when translated to the application of (metalla)carboranes in medicine, since the use of liposomes and polymers (or copolymers) as nanosized drug delivery platforms is widely spread in the (metalla)carboranes literature, especially for applications in boron neutron capture therapy (BNCT), often justified by improved target selectivity, solubility properties and/or accumulation profiles. [43,108,119,138,146,149,150,178,185,186] It is particularly striking that the term "toxicity" is practically exclusively used to indicate the ability of the (metalla)carborane-based drug, with or without carrier, to promote cell death in the tumour cell line or tissue examined (acute toxicity), and is solely evaluated in terms of half-maximal inhibitory concentration (IC 50 ). A handful of examples exist, where IC 50 values were calculated for (metalla)carborane and borate compounds against model cell cultures for immune response, based on simple in vitro colorimetric assays, which will be briefly discussed below.…”

“…[220] Protein corona effects on liposomal formulations should thus be properly investigated in the medicinal boron chemistry community, since they have been exploited for 25 years already as selective drug carriers for BNCT agents. [119,134,138,150,172,175,183,184]…”