Amphiphilic Chitosan Derivatives Research Articles

PH sensitive adriamycin-incorporated nanoparticles self-assembled from amphiphilic chitosan derivatives with enhanced antioxidant and antitumor activities

Development of secure and efficient drug delivery systems to overcome physicochemical challenges in cancer clinical treatment is one of the most active fields, and novel drug carriers are actively sought. In this work, the successful synthesis of amphiphilic chitosan derivatives containing pyridine cations and folic acid (TMACMCF) was confirmed by FTIR and 1H NMR spectroscopy. The critical micelle concentration (CMC) of TMACMCF was studied, and the results indicated that it possessed a relatively low CMC (0.186 mg/mL). Self-assembled nanoparticles (TMACMCF-ADM NPs) for the entrapment and delivery of adriamycin (ADM) were synthesized based on TMACMCF, and the morphology, particle size, zeta potential, sustained release performance, antioxidant and antitumor activities, and cytotoxicity were investigated. The particle size of TMACMCF-ADM NPs was 163.79 ± 7.31 nm, and the morphology observed by SEM and TEM showed spherical or oval particles. TMACMCF-ADM NPs showed excellent entrapment of ADM with entrapment efficiency and drug loading efficiency of 65.04 ± 1.20 % and 22.73 ± 0.40 %, respectively. The release performance results showed that in vitro release profiles of ADM from NPs exhibited pH-sensitive controlled and sustained release properties. The assay of antioxidant activity exhibited that TMACMCF-ADM NPs possessed significantly improved scavenging ability against three kinds of radicals (Superoxide-radical, DPPH radical, and ABTS radical). Moreover, the assay of antitumor activity by CCK-8 test exhibited that nanoparticles led to statistically significant enhancement in inhibition index for four kinds of cancer cells (BGC-823, MCF-7, HEPG-2, and A549). This work provides a promising carrier for secure and effective entrapment and delivery of ADM.

Enhancing Oral Delivery and Anticancer Efficacy of 7-Ethyl-10-Hydroxycamptothecin through Self-assembled Micelles of Deoxycholic Acid Grafted N'-nonyl-trimethyl Chitosan

Irinotecan (CPT-11) is used as a first or second-line chemotherapy drug for the treatment and management of colorectal cancers. In vitro studies have shown that 7-ethyl-10-hydroxycamptothecin (SN38), the active metabolite of CPT-11, displays promising anticancer efficacy. However, its poor aqueous solubility and hydrolytic degradation result in its lower oral bioavailability and impracticable clinical application. To overcome these limitations, a novel amphiphilic chitosan derivative, deoxycholic acid decorated N’-nonyl-trimethyl chitosan, was synthesized. Nano-micelles loaded with SN38 were subsequently prepared to enhance the bioavailability and anti-tumor efficacy of the drug through oral administration. The nano-micelles demonstrated improved dilution stability, enhanced greater mucosal adherence, significant P-gp efflux inhibition, and increased drug transport in the intestine by paracellular and transcellular pathways. Consequently, both the in vivo pharmacokinetic profile and therapeutic efficacy of SN38 against cancer were substantially improved via the micellar system. Thus, the developed polymeric micelles can potentially enhance the SN38 oral absorption for cancer therapy, offering prospective avenues for further exploration.

Drug Polymeric Carrier of Aceclofenac Based on Amphiphilic Chitosan Micelles.

Amphiphilic micelles based on chitosan (CS) were applied as drug carriers of aceclofenac (ACF) as a potential method to induce its bioavailability and therapeutic efficiency. N-octyl-N,O-succinyl CS (OSCS), an amphiphilic CS derivative, was successfully synthesized and loaded physically by ACF at different pH values and using different dosages of ACF, forming ACF-loaded polymeric micelles (PMs). The obtained PMs and ACF-loaded PMs were characterized by different analytical techniques, including AFM, TEM, DLS, UV-vis spectrophotometry, 1H NMR spectroscopy, and FT-IR spectroscopy. The pH 5 sample with a 30% ACF/polymer ratio showed the highest ACF loading capacity (LC) and entrapment efficiency (EE). In vitro release behaviors of pure ACF and ACF-loaded PMs at each release point indicated that the release profile of pH-responsive PMs loaded with ACF demonstrated quicker release rates (94% after 480 min) compared to the release behavior noticed for free ACF (59.56% after 480 min). Furthermore, the release rates exhibit a notable rise when the pH is increased from 1.2 to 4.7. In the carrageenan-induced inflammation model of paw edema in rats, it has been demonstrated that the injection of ACF-loaded PMs (at a dose of 10 mg/kg) resulted in a strengthened inflammatory activity compared to the injection of free ACF at equivalent dosages as well as at time intervals. However, the use of ACF-loaded PMs for a duration of 6 h displayed a notable reduction of paw edema, with an inhibition percentage of 85.09%, in contrast to the 74.9% inhibition percentage observed for the free ACF medication.

N-lauric-O-carboxymethyl chitosan: Synthesis, characterization and application as a pH-responsive carrier for curcumin particles

A pH-responsive amphiphilic chitosan derivative, N-lauric-O-carboxymethyl chitosan (LA-CMCh), is synthesized. Its molecular structures are characterized by FTIR, 1H NMR, and XRD methods. The influencing factors are investigated, including the amount of lauric acid (LA), carboxymethyl chitosan (CMCh), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), and N-hydroxysuccinimide (NHS), and their molar ratio, reaction time, and reaction temperature on the substitution. The degrees of substitution (DS) of the lauric groups on the –NH2 groups are calculated based on the integrated data of 1H NMR spectra. The optimum reaction condition is obtained as a reaction time of 6 h, a reaction temperature of 80 °C, and a molar ratio of lauric acid to O-carboxymethyl chitosan to N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride to N-hydroxysuccinimide of 1:3:4.5:4.5, respectively. The crystallinity and initial decomposition temperature of LA-CMCh decrease, but the maximum decomposition temperature increases. The crystallinity is reduced due to the introduction of LA and the degree of hydrogen bonding among LA-CMCh molecules. LA-CMCh could self-aggregate into particles, which size and critical aggregation concentration depend on the degree of substitution and medium pH. LA-CMCh aggregates could load curcumin up to 21.70 %, and continuously release curcumin for >200 min. LA-CMCh shows nontoxicity to fibroblast HFF-1 cells and good antibacterial activity against S. aureus and E. coli, indicating that it could be used as an oil-soluble-drug carrier.

Applications of Amphiphilic Chitosan Derivatives in Drug Delivery Systems: A Review Article

Chitosan has unique physicochemical characteristics to make it safe and effective as a carrier of some drugs. However, some drawbacks restricted its applications in drug delivery systems. Chemical modifications occurred on the backbone of chitosan to overcome the disadvantages properties of chitosan. Chitosan derivatives were synthesized by inserting the hydrophobic moieties into the chitosan molecule. The resulting amphiphilic derivatives with low toxicity may form self-assembled nanoparticles that can deliver a drug to different body sites. The preparation and applications of the hydrophobic chitosan derivatives will be reviewed in this article.

Genipin-crosslinked amphiphilic chitosan films for the preservation of strawberry

As a material for films used to keep fruits fresh, chitosan has attracted extensive interest because of its advantages of degradability, environmental friendliness, and biocompatibility. In this study, two amphiphilic chitosan derivative films were prepared by crosslinking N-2-hydroxypropyl-3-butyl ether-O-carboxymethyl chitosan (HBCC) and N-2-hydroxypropyl-3-(2-ethylhexyl glycidyl ether)-O-carboxymethyl chitosan (H2ECC)) with genipin, an excellent natural cross-linking agent. The microstructures, mechanical properties, water vapor permeability, swelling ratios, light transmittance, wettability, thermal stability, antibacterial properties, and biocompatibility of the crosslinked films were characterized. The results showed that the crosslinked films had compact structures, low moisture permeability, strong water resistance, strong ultraviolet resistance, unaffected visible light transmittance, and good hydrophilicity. Compared with the uncrosslinked films, the tensile strength of the genipin-crosslinked ones was increased by 328.33 % (HBCC) and 397.83 % (H2ECC). More importantly, the crosslinked films had strong antibacterial activity against Staphylococcus aureus and Escherichia coli and were non-toxic to endothelial cells. The crosslinked films could effectively prolong the preservation time of strawberries, inhibit the decay of strawberries, and inhibit the reduction of vitamin C in strawberries. In conclusion, genipin-crosslinked HBCC and H2ECC films are potential fruit preservation materials.

Amphiphilic quaternized chitosan: Synthesis, characterization, and anti-cariogenic biofilm property

Hydrophobized chitosan derivatives, hexyl chitosan (HCS), dodecyl chitosan (DCS), and phthaloyl chitosan (PhCS) of approximately 30 and 50% degree of substitution (%DS) reacted with glycidyltrimethylammonium chloride (GTMAC) to incorporate hydrophilic positively charged groups of N-[(2-hydroxyl-3-trimethylammonium)propyl] and yielded amphiphilic quaternized chitosan derivatives. They can assemble into spherical nanoparticles with a hydrodynamic diameter of ~100–300 nm and positive ζ-potential values (+15 to +56). Their anti-biofilm efficacy was evaluated against the dental caries pathogen, Streptococcus mutans. Among all derivatives, the one having 30%DS of hexyl group and prepared by reacting with 1 mol equivalent of GTMAC (H30CS-GTMAC) showed the best performance in terms of its aqueous solubility, the lowest minimum inhibitory concentration (138 μg/mL) and the minimum bactericidal concentration (275 μg/mL) which are superior to the unmodified chitosan. Its equivalent anti-biofilm efficacy to that of chlorhexidine suggests that it can be a greener antibacterial agent for oral care formulations.

Effect of Vitamin B12-conjugated Nanocomposite on Drug-resistant Gastric Cancer Cells

Sericin nanomicelles (Sericin-PBLG) have the properties of efficiently and stably encapsulating hydrophobic chemotherapeutics in aqueous solution. The vitamin B12 (VB12) modified amphiphilic chitosan derivative can improve the delivery effect of oral drugs and has a targeting function. In this study, a new type of sericin nanomedicine (VB12-sericin-PBLG-PTX) loaded with paclitaxel was successfully synthesized. The particle size of VB12-sericin-PBLG-PTX nanomicelles is 121.5 ±1.6 nm. The nanomicelles can reduce the activity of gastric carcinoma cells and gastric carcinoma drug-resistant cells, and increase the apoptosis rate of gastric carcinoma cells and gastric carcinoma drug-resistant cells, and achieve a good anti-tumor effect.

Solution properties of N-(2-allyl-butyl ether)-O-carboxymethyl chitosan and N-(2-allyl-isooctyl ether)-O-carboxymethyl chitosan

pH-sensitive and amphiphilic chitosan derivatives can be used as hydrophobic drug carriers, and their rheological properties play a key role in their performance. In this paper, two pH-responsive and amphiphilic chitosan derivatives, N-(2-allyl-butyl glycidyl ether)-O-carboxymethyl chitosan (HBCC) and N-(2-ethylhexyl glycidyl ether)-O-carboxymethyl chitosan (H2ECC) were synthesized, and their rheological properties were studied. The influence of parameters including concentrations of HBCC and H2ECC, the degree of substitution, solution pH, and [Ca2+] on the rheological properties were investigated. The results showed that the overlap and entanglement concentration of HBCC and H2ECC was ca. 1.7 wt% and 5 wt%, respectively. The dilute and semidilute solutions showed Newtonian behavior. Above 5 wt%, strong networks formed, and shear-thinning behavior appeared at high shear rates (>10 s−1) for entangled solutions. A high degree of substitution and pH near the isoelectric points of HBCC and H2ECC corresponded to a low viscosity and viscoelasticity. In addition, Ca2+ played a shielding effect on the –COO− groups at low concentrations (<10 mmol/L), whereas it acted as a cross-linker when [Ca2+] ≥ 20 mmol/L. The intermolecular hydrogen bonds were examined by molecular dynamics simulations. The results provide new information related to the application of HBCC and H2ECC for hydrophobic drug packaging and transportation.

Modular synthesis of amphiphilic chitosan derivatives based on copper-free click reaction for drug delivery

Amphiphilic chitosan derivatives have attracted wide attention as drug carriers due to their physicochemical properties. However, obtaining a desired amphiphilic chitosan derivative by tuning the various functional groups was complex and time-consuming. Therefore, a facile and common synthesis strategy would be promising. In this study, a modular strategy based on strain-promoted azide-alkyne cycloaddition (SPAAC) click reaction was designed and applied in synthesizing deoxycholic acid- or octanoic acid-modified N-azido propionyl-N,O-sulfate chitosan through tuning the hydrophobic groups. Additionally, chitosan derivatives with the same substitute groups were prepared via amide coupling as controls. We demonstrated that these derivates via the two strategies showed no obvious difference in physicochemical properties, drug loading ability and biosafety, indicating the feasibility of modular strategy. Notably, the modular strategy exhibited advantages including high reactivity, flexibility and reproducibility. We believe that this modular strategy could provide varied chitosan derivatives in an easy and high-efficiency way for improving multifunctional drug carriers.

Hypoxia‐sensitive micelles based on amphiphilic chitosan derivatives for drug‐controlled release

AbstractNatural chitosan (CS) is composed of a larger hydrophilic skeleton with great biocompatibility. A hypoxia sensitive amphiphilic conjugate (CS‐NBCF) was synthesized by conjugating CS with nitrobenzyl chloroformate (NBCF). Subsequently, nano micelles with high stability (CMC = 0.0030 mg/ml) were formed by self‐assembly of the polymers in deionized water. The hypoxia‐responsive function was demonstrated by examining the size variations of polymeric micelles under the hypoxia conditions. Doxorubicin (DOX) was encapsulated into the micellar core, the drug loading and encapsulation efficiency of DOX were 15.0% and 52.6%, respectively. The in vitro release experiments showed that DOX could be released rapidly in hypoxic environment, and the release amount was up to 68% in 24 h. It was found from the cytotoxicity experiment that that the toxicity of the blank micelles was low, while DOX‐loaded micelles exhibited a good anti‐cancer effect under hypoxic conditions, and the cell inhibition rate of MCF‐7 was high up to 63%. As a result, the demonstrated properties endowed as‐developed polymeric micelles with promising application as drug delivery system in tumor treatment.

N-(2-hydroxy)-propyl-3-trimethylammonium, O-palmitoyl chitosan: Synthesis, physicochemical and biological properties

Two samples of N-(2-hydroxy)-propyl-3-trimethylammonium, O-palmitoyl chitosan (DPCat) with different average degrees of quaternization named as DPCat35 (DQ¯ = 35%) and DPCat80 (DQ¯ = 80%), were successfully synthesized by reacting glycidyltrimethylammonium chloride (GTMAC) with O-palmitoyl chitosan (DPCh) derivative (DS¯ = 12%). Such amphiphilic derivatives of chitosan were fully water-soluble at 1.0 < pH < 12.0 and showed significant electrostatic stability enhancement of a self-assembly micellar nanostructure (100–320 nm) due to its positively-charged out-layer. In vitro mucoadhesive and cytotoxicity essays toward healthy fibroblast cells (Balb/C 3T3 clone A31 cell), human prostate cancer (DU145) and liver cancer (HepG2/C3A) cell lines revealed that the biological properties of DPCat derivatives were strongly dependent on DQ¯. Additionally, DPCat35 had better interactions with the biological tissue and with mucin glycoproteins at pH 7.4 as well as exhibited potential to be used on the development of drug delivery systems for prostate and liver cancer treatment.

Cationic nanoparticles self-assembled from amphiphilic chitosan derivatives containing poly(amidoamine) dendrons and deoxycholic acid as a vector for co-delivery of doxorubicin and gene

Combination treatment through the co-delivery of drugs and genes by nanoformulations may achieve a synergistic effect. In our previous study, poly(amidoamine) dendronized chitosan derivative (PAMAM-Cs) showed good gene transfection efficiency and low cytotoxicity. Here, we incorporated hydrophobic deoxycholic acid (DCA) onto the chitosan backbone of PAMAM-Cs to obtain an amphiphilic derivative—PAMAM-Cs-DCA, which could self-assemble into cationic nanoparticles (NPs). The resulting NPs with diameters of 140–220 nm can encapsulate the hydrophobic anticancer drug doxorubicin (DOX) in the core while bind pDNA via the positively charged PAMAM shell. PAMAM-Cs-DCA NPs could completely complex with pDNA at a ratio of nitrogen to phosphorous (N/P) low as 1 and the complexes achieved a transfection efficiency up to 74 % at N/P 20. Moreover, low-dose co-delivered DOX could enhance the transgene expression, showing a synergistic effect. These results suggest that PAMAM-Cs-DCA NPs hold great promise to co-deliver chemotherapeutics and nucleic acid drugs.

Grafting of 18β-Glycyrrhetinic Acid and Sialic Acid onto Chitosan to Produce a New Amphipathic Chitosan Derivative: Synthesis, Characterization, and Cytotoxicity.

Chitosan is the only cationic polysaccharide found in nature. It has broad application prospects in biomaterials, but its application is limited due to its poor solubility in water. A novel chitosan derivative was synthesized by amidation of chitosan with 18β-glycyrrhetinic acid and sialic acid. The chitosan derivatives were characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, and measurement of the zeta potential. We also investigated the solubility, cytotoxicity, and blood compatibility of chitosan derivatives. 18β-glycyrrhetinic acid and sialic acid could be grafted onto chitosan molecular chains. The thermal stability of the synthesized chitosan derivatives was decreased and the surface was positively charged in water and phosphate-buffered saline. After chitosan had been modified by 18 β-glycyrrhetinic acid and sialic acid, the solubility of chitosan was improved greatly in water and phosphate-buffered saline, and percent hemolysis was <5%. Novel amphiphilic chitosan derivatives could be suitable polymers for biomedical purposes.

Investigation of partially myristoylated carboxymethyl chitosan, an amphoteric-amphiphilic chitosan derivative, as a new material for cosmetic and dermal application.

BackgroundCationic amphiphilic chitosan derivatives can form polymeric micelles, which are useful cosmetic materials, but they form polyion complexes with anionic polymers, which can cause formulation difficulties.AimsThis study aimed to evaluate the usefulness of partially myristoylated carboxymethyl chitosan, an amphoteric‐amphiphilic chitosan derivative, as a new material for cosmetics in the absence of a surfactant comprising an anionic polymer.MethodsAn anionic polymer and 1,2‐decanediol (an antimicrobial agent)‐containing partially myristoylated carboxymethyl chitosan nanoemulsified lotion and glabridin (an antimelanogenic agent)‐containing partially myristoylated carboxymethyl chitosan polymeric micelle were prepared using a pressure homogenization method. The release of interleukin‐1α, cell viability, and melanogenesis inhibition was evaluated on a human skin model. Antimicrobial activity was evaluated using agar dilution method.ResultsA mixture of partially myristoylated carboxymethyl chitosan and carboxyvinyl polymer did not form a polyion complex, but it formed a hydrophilic gel. The anionic polymer‐containing partially myristoylated carboxymethyl chitosan nanoemulsified formulation was stable, with no decrease in cell viability and horny layer exfoliation, which are typically observed with Tween 60. Compared with the formulation with methyl paraben (0.2%), the formulation to which 1,2‐decanediol (0.05%) was added improved the antibacterial activity against methicillin‐resistant Staphylococcus aureus and Propionibacterium acnes; however, no interleukin‐1α upregulation was observed. The glabridin‐containing partially myristoylated carboxymethyl chitosan polymeric micelles enhanced melanogenesis inhibition and percutaneous glabridin delivery to the epidermis compared with conventional emulsified micelles.ConclusionsThese results suggest that partially myristoylated carboxymethyl chitosan‐forming polymeric micelles, in combination with 1,2‐decanediol and glabridin, may be useful for surfactant‐free cosmetic emulsions.

Structurally accurate lipophilic Pt1Ag28 nanoclusters based cancer theranostic micelles for dual-targeting/aggregation enhanced fluorescence imaging and photothermal/photodynamic therapies

Theranostics including imaging and therapy has become an advanced trend for cancer treatment. It is of great significance to develop new theranostics agent for precision medicine research. In this regard, structurally precise metal nanoclusters (NCs) with ultra-small diameter and potential theranostic functions are no doubt to be a priority. In this study, we firstly investigated the photothermal and photodynamic properties of structurally precise oil-soluble bimetallic NCs (Pt1Ag28) and tactfully solubilize them into the hydrophobic inner cavity of biodegradable amphiphilic chitosan derivative (ACD) micelles via hydrophobic interaction. Positively charged Pt1Ag28@ACD with suitable particle size (∼60 nm) could not only realize effectively passive targeted delivery, but also be easily uptaken by negatively charged cancer cells for increasing targeting effect. Further, the aggregation induced emission fluorescence imaging (AIE FI)-guided enhanced photothermal/photodynamic therapy (PTT/PDT) on tumor is finally nicely achieved by the micelle solubilization of ACD micelles to Pt1Ag28 NCs, which were demonstrated by in vitro and in vivo experimental results. This theranostic platform overcomes the difficulty of lipophilic NCs entering water-phase organisms, provides enlightenment for the universal study of the interaction mechanism between organisms and oil-soluble NCs at the atomic level in future precision medicine research.

Uptake and in vitro anticancer activity of oleic acid delivered in nanocapsules stabilized by amphiphilic derivatives of hyaluronic acid and chitosan

The nanoemulsion-based delivery systems have gained particular attention due to effective encapsulation and protection of hydrophobic active compounds. However, several features like limited stability, cellular uptake or release of payloads still need to be addressed. We investigated the uptake of the nanocapsules based on the amphiphilic derivative of hyaluronate with oleic acid cores (oil-in-water nanoemulsion) and their anticancer activity in vitro. The core-shell nanocapsules exhibiting long term stability in dispersion showed an enhanced uptake by cancer cells and effectively killed them only if composed of hyaluronate-based shells and oleic acid cores - the anionic chitosan-based shells and/or corn oil cores were used for control experiments. We concluded that the nanocapsules stabilized by the amphiphilic derivative of hyaluronic acid may serve as very stable and efficient delivery systems for oil-soluble compounds without necessity of application of low molecular weight (co)surfactants. The in vitro studies indicated anticancer activity of such delivered oleic acid and crucial role of hyaluronate shell of the nanocapsules in its efficient delivery and enzyme-triggered disintegration inside cells. Corn oil was shown as a nutrient that can serve as an inert vehicle in the studied nanoemulsion that exhibit application potential in food, dietary supplement industry and medicine.

&lt;i&gt;In Vitro&lt;/i&gt; and &lt;i&gt;In Vivo&lt;/i&gt; Evaluation of Amphiphilic Chitosan Derivatives for Inhibition of Organic Cation Transport Function

This study explored the interaction of amphiphilic chitosan derivatives, N-benzyl-N,O-succinyl chitosan (BSCS), N-naphthyl-N,O-succinyl chitosan (NSCS) and N-octyl-N,O-succinyl chitosan (OSCS), with renal organic cation transporter 2 (OCT2). The influence of amphiphilic chitosan derivatives on renal OCT2 transport function was determined by monitoring the transport of a positively charged substrate into human renal proximal tubular epithelial cells (RPTEC/TERT1 cells), and murine kidney. Amphiphilic chitosan derivatives inhibited 3H-MPP (a substrate of OCT2) transport in the renal cells in a concentration-reliance characteristic. OSCS reduced the accumulation of the cationic drug, cisplatin, in RPTEC/TERT1 cells. This effect was more pronounced than that of other chitosan derivatives. In addition, co-administration of cisplatin and OSCS significantly reduced cisplatin accumulation compared with receiving cisplatin alone. This result was accompanied by the decrease in nephrotoxicity induced by cisplatin. In conclusion, OSCS inhibited OCT2 function and reduced cationic drug disposition in human renal proximal tubular cells and murine kidney.

Simultaneous delivery of anti-miRNA and docetaxel with supramolecular self-assembled "chitosome" for improving chemosensitivity of triple negative breast cancer cells.

At present, treating of triple negative breast cancer (TNBC) mainly depends on chemotherapy with more toxic side effects, but the effect is limited and it is highly prone to drug resistance. Gene therapy using anti-microRNAs maybe one of alternative therapeutic strategies. Due to the poor cell permeability and significant in vivo decomposition rate of anti-microRNAs, which limits their clinical application, we developed a core-shell supramolecular nanovector of "chitosome" that were self-assembled from the synthetic amphiphilic chitosan derivatives. The constructed chitosomes could co-load hydrophilic anti-miR-21 and hydrophobic docetaxel (DTX) into one combo nanocarrier with entrapment efficiency of more than 80%, as well as spherical morphology and average particle size of 90nm. In comparison with the naked ones, anti-miR-21 encapsulated with chitosomes showed significantly increased cellular transfection and stability against degradation by nuclease in serum. Compared with DTX or anti-miR-21 formulations used alone, the co-delivery of the two drugs with the combo chitosome obtained improved chemosensitivity of TNBC cells to DTX treatment through their synergistic mechanisms. Taken together, the developed chitosome could be a promising candidate for simultaneous delivery of insoluble chemotherapeutic drugs and gene agents for TNBC therapy. Graphical abstract.

Novel amphiphilic chitosan micelles as carriers for hydrophobic anticancer drugs.

Chitosan was grafted with O-methyl-O'-succinylpolyethylene glycol and oleic acid after a two-step carbodiimide coupling. The structural and physicochemical characterization of the compounds confirmed the successful conjugation of the hydrophilic and hydrophobic moieties to the chitosan backbone. The amphiphilic chitosan derivative obtained allowed the formation of polymeric micelles with an average size of 140nm, a polydispersity index <0.234, and a positive superficial charge. Camptothecin, used as a model hydrophobic drug, was successfully carried into the polymeric micelles with an encapsulation efficiency of 78%. The in vitro drug release was evaluated in simulated gastrointestinal fluids, exhibiting a low release of camptothecin in gastric media and a controlled release in intestinal fluids. Furthermore, it was demonstrated that chitosan micelles were able to stabilize camptothecin, protecting up to 75% of the drug from hydrolysis, preserving its active lactone form. This new chitosan amphiphilic system exhibits great potential to load hydrophobic drugs, acting as a promising delivery system.