Phenylboronic acid‐functionalized chondroitin sulfate A (CSA)–deoxycholic‐acid (DOCA)‐based nanoparticles (NPs) are prepared for tumor targeting and penetration. (3‐Aminomethylphenyl)boronic acid ...(AMPB) is conjugated to CSA–DOCA conjugate via amide bond formation, and its successful synthesis is confirmed using proton nuclear magnetic resonance spectroscopy (1H‐NMR). Doxorubicin (DOX)‐loaded CSA–DOCA–AMPB NPs with a mean diameter of ≈200 nm, a narrow size distribution, negative zeta potential, and spherical morphology are prepared. DOX release from NPs is enhanced at acidic pH compared to physiological pH. CSA–DOCA–AMPB NPs exhibit improved cellular uptake in A549 (human lung adenocarcinoma) cells and penetration into A549 multicellular spheroids compared to CSA–DOCA NPs as evidenced by confocal laser scanning microscopy and flow cytometry. In vivo tumor targeting and penetrating by CSA–DOCA–AMPB NPs, based on both CSA–CD44 receptor and boronic acid–sialic acid interactions, is revealed using near‐infrared fluorescence (NIRF) imaging. Penetration of NPs to the core of the tumor mass is observed in an A549 tumor xenografted mouse model and verified by three‐dimensional NIRF imaging. Multiple intravenous injections of DOX‐loaded CSA–DOCA–AMPB NPs efficiently inhibit the growth of A549 tumor in the xenografted mouse model and increase apoptosis. These boronic acid‐rich NPs are promising candidates for cancer therapy and imaging.
(3‐Aminomethylphenyl)boronic acid
(AMPB)‐functionalized chondroitin sulfate A (CSA)–deoxycholic acid (DOCA)‐based nanoparticles (NPs) are prepared for anticancer drug delivery and cancer diagnosis. Doxorubicin (DOX)‐loaded CSA–DOCA–AMPB NPs exhibit improved targeting, penetration, and therapeutic efficacies for CD44 receptor‐expressed tumors, compared to CSA–DOCA NPs, via CSA–CD44 receptor and boronic‐acid–sialic‐acid interactions.
Nanohybrid liposomes coated with amphiphilic hyaluronic acid–ceramide (HACE) was fabricated for targeted delivery of anticancer drug and in vivo cancer imaging. Nanohybrid liposomes including ...doxorubicin (DOX) and Magnevist, a contrast agent for magnetic resonance (MR) imaging, with 120–130nm mean diameter and a narrow size distribution were developed. DOX release from the developed formulation was improved at acidic pH (pH5.5 and 6.8) versus physiological pH (pH7.4). Cytotoxicity induced by the blank plain liposome was reduced by coating the outer surface of the nanohybrid liposome with HACE. Cellular uptake of DOX from the nanohybrid liposome was enhanced by HA and CD44 receptor interaction, versus the plain liposome. In vivo contrast-enhancing effects revealed that the nanohybrid liposome can be used as a tumor targeting MR imaging probe for cancer diagnosis. In a pharmacokinetic study in rats, in vivo clearance of DOX was decreased in the order DOX solution, plain liposome (F2), and nanohybrid liposome (F3), indicating prolonged circulation of the drug in the blood stream and improved therapeutic efficacy of the nanohybrid liposome (F3). Based on these findings, the nanohybrid liposomal system may be a useful candidate for real-time cancer diagnosis and therapy.
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Hydroxyapatite-binding albumin nanoclusters (NCs) were developed for improving the anticancer agent accumulation in bone tumors. Human serum albumin (HSA) was decorated with alendronate (AD), and ...doxorubicin (DOX)-loaded NCs (HSA-AD/DOX) were fabricated via the ball-milling technology, an innovative nano-fabrication method by which more than 90% of the secondary structures of albumin can be preserved. The targeting ability of NCs was confirmed using a novel in vitro bone cancer model, wherein hydroxyapatite and collagen, the major components of the bone matrix representing the highly mineralized bone tumor microenvironment, were co-cultured with HOS/MNNG, a human osteosarcoma cell line. The binding affinity of HSA-AD/DOX to hydroxyapatite was evaluated based on the DOX binding efficiency. HSA-AD/DOX showed a 5.04-fold higher affinity than HSA/DOX. The enhanced distribution of HSA-AD/DOX to bone tumors was verified using a newly developed mouse model bearing HOS/MNNG tumors with hydroxyapatite beads. HSA-AD/DOX led to a 52.0% increase in tumor accumulation compared to that of the unmodified HSA/DOX. This is mainly due to the hydroxyapatite-binding affinity of the AD moiety, which is supported by histological analyses performed on the dissected tumors. Furthermore, HSA-AD/DOX changed the protein expression patterns of the tumors, implying the enhanced apoptotic process. Overall, the targeting ability of HSA-AD/DOX are effectively translated into improved therapeutic efficacy in bone tumor-xenografted mice, suggesting that the developed NCs are a promising delivery system for bone tumor treatment.
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•Alendronate-decorated albumin nanoclusters successfully targeted hydroxyapatites in bone tumor microenvironment.•Doxorubicin adsoption was performed by innovative ball-milling technology, preserving more than 90% of the secondary structures of albumin.•Bone tumor homing ability and therapeutic efficacy of nanoclusters were verified in newly established in vitro and in vivo bone tumor models.•Our investigation presents potential clinical benefits of albumin nanoclusters in bone cancer therapy.
Diverse nanosystems for use in cancer imaging and therapy have been designed and their clinical applications have been assessed. Among a variety of materials available to fabricate nanosystems, ...poly(lactic-
-glycolic acid) (PLGA) has been widely used due to its biocompatibility and biodegradability. In order to provide tumor-targeting and diagnostic properties, PLGA or PLGA nanoparticles (NPs) can be modified with other functional materials. Hydrophobic or hydrophilic therapeutic cargos can be placed in the internal space or adsorbed onto the surface of PLGA NPs. Protocols for the fabrication of PLGA-based NPs for cancer imaging and therapy are already well established. Moreover, the biocompatibility and biodegradability of PLGA may elevate its feasibility for clinical application in injection formulations. Size-controlled NP's properties and ligand-receptor interactions may provide passive and active tumor-targeting abilities, respectively, after intravenous administration. Additionally, the introduction of several imaging modalities to PLGA-based NPs can enable drug delivery guided by in vivo imaging. Versatile platform technology of PLGA-based NPs can be applied to the delivery of small chemicals, peptides, proteins, and nucleic acids for use in cancer therapy. This review describes recent findings and insights into the development of tumor-targeted PLGA-based NPs for use of cancer imaging and therapy.
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► Flexible transethosomes were prepared. ► Physical characteristics of transethosomes were investigated. ► Transethosomes increased in vitro skin permeation and deposition of ...voriconazole. ► In vivo results showed that transethosomes increased skin deposition of voriconazole.
This study describes a novel carrier, transethosome, for enhanced skin delivery of voriconazole. Transethosomes (TELs) are composed of phospholipid, ethanol, water and edge activator (surfactants) or permeation enhancer (oleic acid). Characterization of the TELs was based on results from recovery, particle size, transmission electron microscopy (TEM), zeta potential and elasticity studies. In addition, skin permeation profile was obtained using static vertical diffusion Franz cells and hairless mouse skin treated with TELs containing 0.3% (w/w) voriconazole, and compared with those of ethosomes (ELs), deformable liposomes (DLs), conventional liposomes (CLs) and control (polyethylene glycol, PG) solutions. The recovery of the studied vesicles was above 90% in all vesicles, as all of them contained ethanol (7–30%). There was no significant difference in the particles size of all vesicles. The TEM study revealed that the TELs were in irregular spherical shape, implying higher fluidity due to perturbed lipid bilayer compared to that of other vesicles which were of spherical shape. The zeta potential of vesicles containing sodium taurocholate or oleic acid showed higher negative value compared to other vesicles. The elasticities of ELs and TELs were much higher than that of CLs and DLs. Moreover, TELs dramatically enhanced the skin permeation of voriconazole compared to the control and other vesicles (p<0.05). Moreover, the TELs enhanced both in vitro and in vivo skin deposition of voriconazole in the dermis/epidermis region compared to DLs, CLs and control. Therefore, based on the current study, the novel carrier TELs could serve as an effective dermal delivery for voriconazole.
A microemulsion system of docetaxel was prepared and evaluated for its solubilization capacity and oral bioavailability improvement. Based on a solubility study and pseudo ternary phase diagrams, ...microemulsions of about 30 nm in mean diameter were formulated with improved solubilization capacity towards the hydrophobic drug, docetaxel. The o/w microemulsion formulation (M-3) composed of Capryol 90 (oil), Cremophor EL (surfactant) and Transcutol (co-surfactant) enhanced the solubility of docetaxel up to 30 mg/mL, which maintained solubilization capacity for 24 h even after it was diluted 20 times with normal saline. The three formulations did not show significant difference in the
in vitro lipid digestion study. Both the ultrafiltration and dialysis studies revealed that the release of 80% of docetaxel was released from the microemulsions within 12 h
in vitro. Compared to the commercial product Taxotere
® (0.025 µg/cm
2), the apical to basolateral transport of docetaxel across the Caco-2 cell monolayer from the M-3 formulation (Capryol 90/Cremophor EL/Transcutol
=
29.4:24.9:12.4, w/w) was significantly improved (0.624 µg/cm
2,
p
<
0.01). Moreover, the oral bioavailability of the M-3 formulation in rats (34.42%) rose dramatically compared to that of the orally administered Taxotere
® (6.63%). This increase in bioavailability was probably due to the combined effect of the enhancement in solubility, the inhibition of P-gp efflux system and the increase in permeability. These results encourage further development of docetaxel microemulsions as an oral drug delivery system.
Increased oral bioavailability of docetaxel in the microemulsions was observed by the combined effects of enhanced solubility, P-gp inhibition and permeability enhancing effects.
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•CYP1A2/2C19/2E1/3 A4 and UGT1A1/1A6/2B7 may be involved in the metabolism of RA.•UGTs have higher capacity and lower affinity for RA metabolism than phase I enzymes.•RA inhibits ...CYP2C19 via a mixed mechanism.•RA inhibits CYP2E1 and UGT1A1/1A6/2B7 via a competitive mechanism.
In light of the widespread use of herbal medicines containing rosmarinic acid (RA) and limited literature available thereon, we investigated the metabolic interactions of RA with human cytochrome P450 monooxygenases (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs). The involvement of selected enzymes (CYP1A2, CYP2C19, CYP2E1, CYP3 A4, UGT1A1, UGT1A6, and UGT2B7) in the metabolism of RA and the inhibitory effect of RA on the enzyme activity were comprehensively evaluated using human recombinant isozyme system. Additionally, concentration-dependent RA metabolism mediated by phase I enzymes (including CYPs) or UGT was investigated in human liver microsome (HLM) system. A significant disappearance of RA was observed in the seven CYP and UGT isoforms studied, indicating their possible involvement in the metabolism of RA. Based on Michaelis-Menten kinetics, the metabolism study using HLM suggests that the UGT system may have a higher capacity and lower affinity for the metabolism of RA than phase I enzyme (including CYP) systems. Moreover, RA weakly inhibited CYP2C9 and 2E1 activities with IC50 values of 39.6 and 61.0 μM, respectively, while moderately inhibiting UGT1A1, 1A6, and 2B7 with IC50 values of 9.24, 19.1, and 23.4 μM, respectively. By constructing Line weaver–Burk plots, the type of inhibition exhibited by RA on CYP and UGT activities was determined as follows: CYP2C19, mixed inhibition; CYP2E1, UGT1A1, UGT1A6, and UGT2B7, competitive inhibition. Based on the comparison of the IC50 and Ki values obtained in the current study with the previously reported plasma concentrations of RA after oral dosing in humans, it is suggested that RA may significantly inhibit the activities of the tested UGTs, rather than CYPs, in clinical settings. Thus, the present study could provide a basis for further studies on clinically significant interactions between UGT substrate drugs and herbal medicines containing RA.
Polypseudorotaxane structure and polydopamine bond-based crosslinked hyaluronic acid (HA) hydrogels including donepezil-loaded microspheres were developed for subcutaneous injection. Both dopamine ...and polyethylene glycol (PEG) were covalently bonded to the HA polymer for catechol polymerization and inclusion complexation with alpha-cyclodextrin (α-CD), respectively. A PEG chain of HA-dopamine-PEG (HD-PEG) conjugate was threaded with α-CD to make a polypseudorotaxane structure and its pH was adjusted to 8.5 for dopamine polymerization. Poly(lactic-co-glycolic acid) (PLGA)/donepezil microsphere (PDM) was embedded into the HD-PEG network for its sustained release. The HD-PEG/α-CD/PDM 8.5 hydrogel system exhibited an immediate gelation pattern, injectability through single syringe, self-healing ability, and shear-thinning behavior. Donepezil was released from the HD-PEG/α-CD/PDM 8.5 hydrogel in a sustained pattern. Following subcutaneous injection, the weight of excised HD-PEG/α-CD/PDM 8.5 hydrogel was higher than the other groups on day 14. These findings support the clinical feasibility of the HD-PEG/α-CD/PDM 8.5 hydrogel for subcutaneous injection.
•Hyaluronic acid-dopamine-polyethylene glycol (HD-PEG) was synthesized and identified.•HD-PEG was threaded with alpha-cyclodextrin (α-CD) and pH was adjusted to 8.5.•Polypseudorotaxane structure and polydopamine bond-based hydrogel was fabricated.•Donepezil-loaded microspheres were embedded in hydrogel system for sustained release.•Rheological features of injectable hydrogel were tuned for slow biodegradation.
Although cyclodextrin-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their designs remain to be optimized for tumour retention. Here we ...report on the design of a tailored structure for renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery. Twenty cyclodextrin derivatives with different charged moieties and spacers are synthesized and screened for colloidal stability. The resulting five candidates are evaluated for biodistribution and an optimized structure is identified. The optimized cyclodextrin shows a high tumour accumulation and is used for delivery of doxorubicin and ulixertinib. Higher tumour accumulation and tumour penetration facilitates tumour elimination. The improved antitumour efficacy is demonstrated in heterotopic and orthotopic colorectal cancer models.
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•Amphiphilic chondroitin sulfate A-deoxycholic acid (CSA-DOCA) was synthesized.•Doxorubicin (DOX)-loaded CSA-DOCA nanoparticles were fabricated and characterized.•Developed ...nanoparticles exhibited sustained drug release and improved cytotoxicity.•In vivo tumor targetability via CSA-CD44 receptor interaction was demonstrated.
Chondroitin sulfate A-deoxycholic acid (CSA-DOCA)-based nanoparticles (NPs) were produced for tumor-targeted delivery of doxorubicin (DOX). The hydrophobic deoxycholic acid (DOCA) derivative was conjugated to the hydrophilic chondroitin sulfate A (CSA) backbone via amide bond formation, and the structure was confirmed by 1H-nuclear magnetic resonance (NMR) analysis. Loading the DOX to the CSA-DOCA NPs resulted in NPs with an approximately 230nm mean diameter, narrow size distribution, negative zeta potential, and relatively high drug encapsulation efficiency (up to 85%). The release of DOX from the NPs exhibited sustained and pH-dependent release profiles. The cellular uptake of DOX from the CSA-DOCA NPs in CD44 receptor-positive human breast adenocarcinoma MDA-MB-231 cells was reduced when co-treated with free CSA, indicating the interaction between CSA and the CD44 receptor. The lower IC50 value of DOX from the CSA-DOCA NPs compared to the DOX solution was also probably due to this interaction. Moreover, the ability of the developed NPs to target tumors could be inferred from the in vivo and ex vivo near-infrared fluorescence (NIRF) imaging results in the MDA-MB-231 tumor-xenografted mouse model. Both passive and active strategies appear to have contributed to the in vivo tumor targetability of the CSA-DOCA NPs. Therefore, these CSA-DOCA NPs could further be developed into a theranostic nanoplatform for CD44 receptor-positive cancers.
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