Abstract
The design of nanoparticle delivery materials possessing biological activities is an attractive strategy for the development of various therapies. In this study, 11 cationic amphiphilic 4-(N-alkylpyridinium)-1,4-dihydropyridine (1,4-DHP) derivatives differing in alkyl chain length and propargyl moiety/ties number and position were selected for the study of their self-assembling properties, evaluation of their cytotoxicity in vitro and toxicity on microorganisms, and the characterisation of their interaction with phospholipids. These lipid-like 1,4-DHPs have been earlier proposed as promising nanocarriers for DNA delivery. We have revealed that the mean diameter of freshly prepared nanoparticles varied from 58 to 513 nm, depending upon the 4-(N-alkylpyridinium)-1,4-DHP structure. Additionally, we have confirmed that only nanoparticles formed by 4-(N-dodecylpyridinium)-1,4-DHP derivatives 3 and 6, and by 4-(N-hexadecylpyridinium)-1,4-DHP derivatives 10 and 11 were stable after two weeks of storage. The nanoparticles of these compounds were found to be homogenous in size distribution, ranging from 124 to 221 nm. The polydispersity index (PDI) values of 1,4-DHPs samples 3, 6, 10, and 11 were in the range of 0.10 to 0.37. We also demonstrated that the nanoparticles formed by 4-(N-dodecylpyridinium)-1,4-DHP derivatives 3, 6, and 9, and 4-(N-hexadecylpyridinium)-1,4-DHP derivatives 10 and 11 had zeta-potentials from +26.07 mV (compound 6) to +62.80 mV (compound 11), indicating a strongly positive surface charge and confirming the relative electrostatic stability of these nanoparticle solutions. Transmission electron microscopy (TEM) images of nanoaggregates formed by 1,4-DHPs 3 and 11 confirmed liposome-like structures with diameters around 70 to 170 nm. The critical aggregation concentration (CAC) value interval for 4-(N-alkylpyridinium)-1,4-DHP was from 7.6 µM (compound 11) to 43.3 µM (compound 6). The tested 4-(N-alkylpyridinium)-1,4-DHP derivatives were able to quench the fluorescence of the binary 1,6-diphenyl-1,3,5-hexatriene (DPH)—1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) system, demonstrating hydrophobic interactions of 1,4-DHPs with phospholipids. Thus, 4-(N-dodecylpyridinium)-1,4-DHP derivative 3 quenched the fluorescence of the DPH–DPPC system more efficiently than the other 4-(N-alkylpyridinium)-1,4-DHP derivatives. Likewise the compound 3, also 4-(N-dodecylpyridinium)-1,4-DHP derivative 9 interacted with the phospholipids. Moreover, we have established that increasing the length of the alkyl chain at the quaternised nitrogen of the 4-(N-alkylpyridinium)-1,4-DHP molecule or the introduction of propargyl moieties in the 1,4-DHP molecule significantly influences the cytotoxicity on HT-1080 (human fibrosarcoma) and MH-22A (mouse hepatocarcinoma) cell lines, as well as the estimated basal cytotoxicity. Additionally, it was demonstrated that the toxicity of the 4-(N-alkylpyridinium)-1,4-DHP derivatives on the Gram-positive and Gram-negative bacteria species and eukaryotic microorganism depended on the presence of the alkyl chain length at the N-alkyl pyridinium moiety, as well as the number of propargyl groups. These lipid-like compounds may be proposed for the further development of drug formulations to be used in cancer treatment.
Highlights
Over the past few decades, scientists worldwide have made efforts to expand the discovery and development of a broad range of nanoparticle delivery systems
Mixtures containing 40 μL of DPPC stock solution (6 × 10−5 M) and 40 μL of DPH diluted stock solution (15 × 10−6 M) were incubated at 50 ◦C for 0.5 h in the dark; an aliquot of 4-(N-alkylpyridinium)-1,4-DHP derivatives was added with the following incubation at 50 ◦C for 0.5 h in the dark, after which samples were cooled to room temperature and the fluorescence intensity was measured by a Tecan multiplate reader Infinite1000 (Tecan Austria GmbH, Salzburg, Austria)
The synthesis of selected 4-(N-alkylpyridinium)-1,4-dihydropyridine derivatives 1–11 differing in alkyl chain length and propargyl moiety/ties number and position was carried out by previously described methods [22,26]
Summary
Over the past few decades, scientists worldwide have made efforts to expand the discovery and development of a broad range of nanoparticle delivery systems. These studies had been generally supported by the pharmaceutical and food industries as end-users. Synthetic nanoparticle-forming cationic lipid-like compounds have been developed as delivery agents for the transfer of genetic materials, including plasmid DNA (pDNA) molecules, into cells [2,3,4] and recently for therapy and diagnostic applications [5,6,7,8]. Our group elaborated and studied multiple liposomes forming cationic 1,4-dihydropyridine (1,4-DHP) amphiphiles, which were capable of transfecting pDNA into different cell lines in vitro. MMoorreeoovveerr,, tthhee ccyyttoottooxxiicciittyy of 4-(NN-alkylpyyrriiddiinniiuumm))--11,,44--DDHHPPss ddeerriivvaattiivveess oonn HT-1080 (human ffiibrosarcoma) and MH-22A (mouse hepatocarcinoma) cell lines has been evaluated, and an approximate LLDD5500 vvaalulueehahsabs ebeenepnrepdriecdteidct.eAdd. dAitdiodnitaiollny,atlolyx,ictiotyxiocnitysixopnroskixarpyrootikca(rbyaocttiecri(ab)ascptecriaes) sapnedcioenseaenudkaornyeoteiuc k(yaeryasott)icm(iyceroaostr)gamniicsrmoosrpgeacniiessmhasvpeecbieeesnheasvtiembaetend.eTshtiemhayteddro. pThhoebhicyidnrtoeprahcotiboinc ibnettewraecetnio4n-(Nbe-atwlkeyelpny4ri-d(Nin-iaulkmy)l-p1y,4r-iDdHinPiudme)r-i1v,a4t-iDveHs Pandde1r,i2v-adtipvaelsmaintodyl1-s,2n--dgilpycaelmroi-t3o-yplh-sons-pghloycherooli-n3ep(DhPosPpCh)omchoodleinl em(eDmPbPrCan) ems ohdaselbmeeenmstburdanieeds. hTahseboebetnainsteuddriesdu. lTtshwe iollbptaroinveideraesbualstsiswfoilrltphreofvuirdtheear buansdiserfsotratnhdeinfugrothf ethr eunstdruercsttuarned–aincgtivoiftythreelsattriuocntsuhriep–sacotfivthiteyserecloamtiopnosuhnipds.of these compounds
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