Targeted Delivery Of Doxorubicin Research Articles

Insights into Transfer of Supramolecular Doxorubicin/Congo Red Aggregates through Phospholipid Membranes.

Doxorubicin (DOX) is a commonly used chemotherapeutic drug, from the anthracycline class, which is genotoxic to neoplastic cells via a DNA intercalation mechanism. It is effective and universal; however, it also causes numerous side effects. The most serious of them are cardiotoxicity and a decrease in the number of myeloid cells. For this reason, targeted DOX delivery systems are desirable, since they would allow lowering the drug dose and therefore limiting systemic side effects. Recently, synthetic dyes, in particular Congo red (CR), have been proposed as possible DOX carriers. CR is a planar molecule, built of a central biphenyl moiety and two substituted naphthalene rings, connected with diazo bonds. In water, it forms elongated ribbon-shaped supramolecular structures, which are able to selectively interact with immune complexes. In our previous studies, we have shown that CR aggregates can intercalate DOX molecules. In this way, they preclude DOX precipitation in water solutions and increase its uptake by MCF7 breast cancer cells. In the present work, we further explore the interactions between DOX, CR, and their aggregates (CR/DOX) with phospholipid membranes. In addition to neutral molecules, the protonated doxorubicin form, DXP, is also studied. Molecular dynamics simulations are employed to study the transfer of CR, DOX, DXP, and their aggregates through POPC bilayers. Interactions of CR, DOX, and CR/DOX with model monolayers are studied with Langmuir trough measurements. This study shows that CR may support the transfer of doxorubicin molecules into the bilayer. Both electrostatic and van der Waals interactions with lipids are important in this respect. The former promote the initial stages of the insertion process, the latter keep guest molecules inside the bilayer.

Smart chitosan nanogel for targeted doxorubicin delivery, ensuring precise release, and minimizing side effects in Ehrlich ascites carcinoma-bearing mice

In recent decades, bio-polymeric nanogels have become a forefront in medical research as innovative in-vivo drug carriers. This study introduces a pH-sensitive chitosan nanoparticles/P(N-Isopropylacrylamide-co-Acrylic acid) nanogel (CSNPs/P(NIPAm-co-AAc)), making significant advancements. The nanogel effectively encapsulated doxorubicin hydrochloride (Dx. HCl), a model drug, within its compartments through electrostatic binding. Comparing nano chitosan (CSNPs) before and after integrating copolymerized P(NIPAm-co-AAc), highlighting an improved and adaptable nanogel structure with responsive behaviors. The intraperitoneal delivery of Dx-loaded nanogel (Dx@N.gel) to Ehrlich ascites carcinoma (Eh)-bearing mice at doses equivalent to 1.5 and 3 mg/kg of Dx per day for 14 days exhibited superiority over the administration of free Dx. Dx@N.gel demonstrated heightened anticancer activity, significantly improving mean survival rates in Eh mice. The nanogel's multifaceted defense mechanism mitigated oxidative stress, inhibited lipid peroxidation, and curbed nitric oxide formation induced by free Dx. It effectively countered hepatic DNA deterioration, normalized elevated liver and cardiac enzyme levels, and ameliorated renal complications. This pH-responsive CSNPs/P(NIPAm-co-AAc) nanogel loaded with Dx represents a paradigm shift in antitumor drug delivery. Its efficacy and ability to minimize side effects, contrasting sharply with those of free Dx, offer a promising future where potent cancer therapies seamlessly align with patient well-being.

The Effect of Dual-Functional Hyaluronic Acid-Vitamin E Succinate Micelles on Targeting Delivery of Doxorubicin [Retraction

[This retracts the article DOI: 10.2147/IJN.S113882.].

Aptamer- and Lauric Acid-Modified Au Nanocrystals for Targeted Doxorubicin Delivery and Combined Phototherapy, Chemotherapy, and Immunotherapy

Aptamer- and Lauric Acid-Modified Au Nanocrystals for Targeted Doxorubicin Delivery and Combined Phototherapy, Chemotherapy, and Immunotherapy

Heparin Biofunctionalized Selenium Nanoparticles as Potential Antiangiogenic-Chemotherapeutic Agents for Targeted Doxorubicin Delivery.

Combining antiangiogenic and chemotherapeutic agents has shown promising clinical benefits in cancer cures when the therapeutic intervention takes into account the tissue and molecular targets. Moreover, the risk of induced drug resistance is minimized when multiple pathways are involved in the treatment regimen, yielding a better therapeutic outcome. Nanodrug delivery systems have proven to be a prudent approach to treating complex disease pathologies. As such, combining antiangiogenic and chemotherapeutic drugs within multimodal nanocarriers synergistically augments the clinical efficiency of the drugs. This study reports the combinatorial efficacy of heparin (Hep), selenium NPs (SeNPs), and doxorubicin (Dox) to inhibit tumor growth and progression. Both Se@Hep-NPs and Se@Hep-Dox-NPs with excellent water dispersity having a size and charge in the range of 250 ± 5 and 253 ± 5 nm and -53 ± 0.4 and -48.4 ± 6.4 mV, respectively, showed strong anticancer potential assessed through in vitro assays like cell viability, specificity, colony formation, and wound scratch in MCF7 cells. Strong synergistic interactions among SeNPs, Hep, and Dox in Se@Hep-Dox-NPs render it to be an antiangiogenic and proapoptotic cancer cell death inducers. In vivo imaging highlights the dual-mode attributes of Se@Hep-NPs with desirable passive tumor targeting and biomedical imaging ability when tagged with Cy7.5, while Se@Hep-Dox-NPs significantly reduce the tumor burden and prolong the longevity of subcutaneous EAC-bearing mice. Histopathology studies reveal no signs of toxicity in major organs. Collectively, these results qualify Se@Hep-Dox-NPs as a plausible clinical therapeutic candidate.

Construction of cyclodextrin microporous organic network based drug delivery platform for controllable release and targeting delivery of doxorubicin

Rational design and fabrication of effective drug delivery systems (DDS) are crucial for improving the therapeutic effectiveness and overcoming the shortcomings of chemotherapy. Herein, we report the construction of a novel cyclodextrin microporous organic network (CD-MON)-based DDS via a convenient thiol‑yne click reaction and dehydration condensation modification for the controllable release and targeted delivery of doxorubicin (DOX), a typical chemotherapy drug. The constructed DDS afforded multiple hydrophobic, hydrogen-bonding, and host-guest interaction sites, allowing for the efficient loading of DOX. The obtained DDS also exhibited good sustained and long-term release of DOX. Additionally, the proposed DDS offers good biocompatibility and exhibits an obvious aggregation-induced emission. Furthermore, the introduction of folic acid (FA) into the CD-MON-based DDS provided excellent targeting capacity for FA receptor-positive NCI-H226 cells. This study proved the universality of the design, synthesis, and application of CD-MON-based DDS, revealing the great potential of CD-MONs in drug delivery.

Lysinated Multiwalled Carbon Nanotubes with Carbohydrate Ligands as an Effective Nanocarrier for Targeted Doxorubicin Delivery to Breast Cancer Cells.

Multiwalled carbon nanotubes (MWCNTs) are elongated, hollow cylindrical nanotubes made of sp2 carbon. MWCNTs have attracted significant attention in the area of drug delivery due to their high drug-loading capacity and large surface area. Furthermore, they can be linked to bioactive ligands molecules via covalent and noncovalent bonds that allow for the targeted delivery of anticancer drugs such as doxorubicin. The majority of methodologies reported for the functionalization of MWCNTs for drug delivery are quite complex and use expensive linkers and ligands. In the present study, we report a simple, cost-effective approach for functionalizing MWCNTs with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker. The doxorubicin (Dox)-loaded functionalized MWCNTs were characterized using FT-IR, NMR, Raman, XRD and FE-SEM. The drug-loaded MWCNTs were evaluated for drug loading, drug release and cell toxicity in vitro, in breast cancer cells. The results indicated that the carbohydrate-modified lysinated MWCNTs had greater Dox loading capacity, compared to carboxylated MWCNTs (COOHMWCNTs) and lysinated MWCNTs (LyMWCNTs). In vitro drug release experiments indicated that the carbohydrate functionalized LyMWCNTs had higher Dox release at pH 5.0, compared to the physiological pH of 7.4, over 120 h, indicating that they are suitable candidates for targeting the tumor microenvironment as a result of their sustained release profile of Dox. Doxorubicin-loaded galactosylated MWCNTs (Dox-GAMWCNTs) and doxorubicin loaded mannosylated MWCNTs (Dox-MAMWCNTs) had greater anticancer efficacy and cellular uptake, compared to doxorubicin-loaded lactosylated MWCNTs (Dox-LAMWCNTs) and pure Dox, in MDA-MB231 and MCF7 breast cancer cells. However, neither the ligand conjugated multiwall blank carbon nanotubes (GAMWCNTs, MAMWCNTs and LAMWCNTs) nor the lysinated multiwalled blank carbon nanotubes produced significant toxicity in the normal cells. Our results suggest that sugar-tethered multiwalled carbon nanotubes, especially the galactosylated (Dox-GAMWCNTs) and mannosylated (Dox-MAMWCNTs) formulations, may be used to improve the targeted delivery of anticancer drugs to breast cancer cells.

SPIONs Conjugate Supported Anticancer Drug Doxorubicin's Delivery: Current Status, Challenges, and Prospects.

Considerable efforts have been directed towards development of nano-structured carriers to overcome the limitations of anticancer drug, doxorubicin’s, delivery to various cancer sites. The drug’s severe toxicity to cardio and hepatic systems, low therapeutic outcomes, inappropriate dose–demands, metastatic and general resistance, together with non-selectivity of the drug have led to the development of superparamagnetic iron oxide nanoparticles (SPIONs)-based drug delivery modules. Nano-scale polymeric co-encapsulation of the drug, doxorubicin, with SPIONs, the SPIONs surface end-groups’ cappings with small molecular entities, as well as structural modifications of the SPIONs’ surface-located functional end-groups, to attach the doxorubicin, have been achieved through chemical bonding by conjugation and cross-linking of natural and synthetic polymers, attachments of SPIONs made directly to the non-polymeric entities, and attachments made through mediation of molecular-spacer as well as non-spacer mediated attachments of several types of chemical entities, together with the physico-chemical bondings of the moieties, e.g., peptides, proteins, antibodies, antigens, aptamers, glycoproteins, and enzymes, etc. to the SPIONs which are capable of targeting multiple kinds of cancerous sites, have provided stable and functional SPIONs–based nano-carriers suitable for the systemic, and in vitro deliveries, together with being suitable for other biomedical/biotechnical applications. Together with the SPIONs inherent properties, and ability to respond to magnetic resonance, fluorescence-directed, dual-module, and molecular-level tumor imaging; as well as multi-modular cancer cell targeting; magnetic-field-inducible drug-elution capacity, and the SPIONs’ magnetometry-led feasibility to reach cancer action sites have made sensing, imaging, and drug and other payloads deliveries to cancerous sites for cancer treatment a viable option. Innovations in the preparation of SPIONs-based delivery modules, as biocompatible carriers; development of delivery route modalities; approaches to enhancing their drug delivery-cum-bioavailability have explicitly established the SPIONs’ versatility for oncological theranostics and imaging. The current review outlines the development of various SPIONs-based nano-carriers for targeted doxorubicin delivery to different cancer sites through multiple methods, modalities, and materials, wherein high-potential nano-structured platforms have been conceptualized, developed, and tested for, both, in vivo and in vitro conditions. The current state of the knowledge in this arena have provided definite dose-control, site-specificity, stability, transport feasibility, and effective onsite drug de-loading, however, with certain limitations, and these shortcomings have opened the field for further advancements by identifying the bottlenecks, suggestive and plausible remediation, as well as more clear directions for future development.

Redox-responsive waterborne polyurethane nanocarriers for targeted doxorubicin delivery

Nanocarriers of different origins that respond to stimuli have been synthesized and used in various biomedical applications, such as intracellular drug delivery. To develop highly efficient nanocarriers, novel clickable and cleavable soybean oil-based polyurethane nanomicelles (CPUM), and polyurethane-hyaluronic acid nanomicelles (CPUM-HA) were prepared. The prepared nanocarriers exhibited controlling self-assembly properties, stimuli-responsiveness, good cytocompatibility, and high loading capacity for doxorubicin (DOX). The addition of the reducing agent glutathione (GSH) to the drug release medium resulted in GSH-triggered species size change (aggregation of nanomicelles) and enhanced release of DOX, leading to higher cytotoxicity in tumors. MTT, confocal laser scanning microscopy (CLSM), and flow cytometry results showed that the CPUM-HA-DOX nanocarriers exhibited increased cytotoxicity and cellular uptake compared to the CPUM-DOX nanocarriers. The in vivo and ex vivo results suggested that the CPUM-HA nanomicelles could provide a potential platform for effective targeted delivery of cytotoxic drug molecules to the tumor tissue and breast cancer therapy in the clinic.

New ZnFe2O4@SiO2@graphene quantum dots as an effective nanocarrier for targeted DOX delivery and CT-DNA binder

The current study pronounces the synthesis and characterization of ZnFe2O4, ZnFe2O4@SiO2, graphene quantum dots (GQDs) and ZnFe2O4@SiO2@GQDs nanoparticles by different techniques such as VSM, XRD, IR, UV–Vis and SEM. For application in targeted drug delivery, then GQDs were immobilized on the surface ZnFe2O4@SiO2 via covalent linkage to surface amino groups.The competence of ZnFe2O4@SiO2@GQDs nanoparticles was assessed by loading and releasing of doxorubicin (DOX) as a standard anticancer drug at pH = 5 (pH of cancerous cell) and pH = 7.4 (pH of healthy cell). The attained results authenticate the pH sensitive release behavior of ZnFe2O4@SiO2@GQDs nanoparticles by releasing more DOX at cancerous pH (70%) than healthy pH (28%). To appraise the biological manner, ZnFe2O4@SiO2@GQDs nanoparticles were screened for their CT-DNA binding tendency by means of spectroscopic methods. The gained results of absorption spectroscopy and competitive fluorescence studies disclosed that nanoparticles bind to DNA through the intercalation mode and the loading of DOX on the nanocarrier has increased CT-DNA binding affinity up to 300 times. The cytotoxicity activity of ZnFe2O4@SiO2@GQDs and ZnFe2O4@SiO2@GQDs/DOX by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay revealed on cancerous HeLa cell and healthy HEK-293 cell revealed that both nanoparticles exhibit concentration-dependent behavior on both cell lines, so that with increasing nanoparticle concentration, the cell viability percentage decreases, although nanocarriers containing DOX expression a more severe effect. Treatment of HeLa cells with 10 µg/mL of the ZnFe2O4@SiO2@GQDs/DOX nanoparticles showed that the nanoparticles induce cell death by apoptosis and cause detention of cell cycle in G2 phase. The results of the study expression the potential of the nanocarrier for targeted and controlled drug delivery, which should be given more attention and modified as a nanocarrier.

PH-responsive Functionalized Extracellular Vesicles as Targeted Doxorubicin Delivery Vehicles for the Treatment of Hepatocarcinoma

Luo, Yuyu MM; Wang, Yijun Pro.; Gao, Yingtang Pro, PhD; Luo, Ying PhD; Zou, Liaonan MD, FACS Author Information

PH and ultrasound dual-responsive drug delivery system based on PEG–folate-functionalized Iron-based metal–organic framework for targeted doxorubicin delivery

In recent years, the use of metal–organic frameworks (MOFs) as drug nanocarriers has gained attention because of their extraordinary physical and chemical properties. In this work, dual-responsive iron-based MOFs were synthesized via the microwave-assisted method using FeCl 3 .6 (H 2 O) as the metal cluster and 2-aminoterephthalic acid (NH 2 -BDC) as the organic linker (namely NH 2 -Fe-BDC) and loaded with the anti-cancer drug doxorubicin (DOX). The DOX-loaded MOFs were further functionalized with polyethylene glycol-folate (PEG–FA), yielding PEG–FA-NH 2 -Fe-BDC. The folate moiety is used to specifically target several cancers overexpressing the folate receptor (FR). These nanoparticles were characterized using Fourier-Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Thermogravimetric Analysis (TGA), and Dynamic Light Scattering (DLS). The FTIR confirmed the PEG–FA conjugation to the MOFs, while the XRD patterns confirmed the crystallinity of the nanoparticles. TGA results demonstrated the thermal stability of the MOFs. Moreover, the DLS analysis showed that regular MOFs had a particle diameter of 577 nm, while the PEG–FA-functionalized MOF had a particle diameter of 461 nm, which demonstrates the improved colloidal stability of the functionalized MOF. The DOX encapsulation efficiency was determined to be approximately 97%, while the encapsulation capacity was around 14.5 wt%. Furthermore, the in-vitro release profiles were studied under different pH values (5.3 and 7.4) with and without low-frequency ultrasound (LFUS, at 40 kHz). The results confirmed the sonosensitivity of the nanovehicles, with US-triggered release efficiency reaching up to 90% after 280 min (at a pH of 5.3). The MTT study revealed that these nanocarriers are non-toxic at lower concentrations. Their toxicity increases at higher concentrations. Furthermore, the cellular uptake was investigated via flow cytometry, and the results showed that the conjugation of the PEG-FA moiety to the MOF’s surface significantly enhanced uptake by cancer cells. Accordingly, this study showed the pH/US dual-responsive capability of NH 2 -Fe-BDC and PEG–FA-NH 2 -Fe-BDC.

Targeted doxorubicin delivery and release within breast cancer environment using PEGylated chitosan nanoparticles labeled with monoclonal antibodies

Breast cancer has been one of the top chronic and life-threatening diseases worldwide. Nano-drug therapeutic systems have proved their efficacy as a selective treatment compared to the traditional ones that are associated with serious adverse effects. Here, biodegradable chitosan nanoparticles (CSNPs) were synthesized to provide selective and sustained release of doxorubicin (DOX) within the breast tumor microenvironment. CSNPs surface was modified using Polyethylene glycol (PEG) to enhance their blood circulation timing. To provide high drug selectivity, CSNPs functionalized with two different types of breast cancer-specific monoclonal antibodies (mAb); anti-human mammaglobin (Anti-hMAM) and anti-human epidermal growth factor (Anti-HER2). Anti-hMAM PEGylated DOX loaded CSNPs and Anti-HER2 PEGylated DOX loaded CSNPs nano-formulations were the most cytotoxic against MCF-7 cancer cells than L-929 normal cells compared to free DOX. Finally, we believe that dose-dependent system toxicity of freely ingested DOX can be managed with such targeted nano-formulated drug delivery platforms.

Doxorubicin delivery to breast cancer cells with transferrin-targeted carbon quantum dots: An in vitro and in silico study

The proficient and targeted delivery (TD) of therapeutic drugs is a significant challenge in the clinical healing of cancer. In this study, highly luminescent carbon quantum dots (CQDs) were synthesized via citric acid carbonization and modified by transferrin (TF) to improve the water-solubility and increase the interaction ability with target cell receptors. The CQDs based nanocarrier was developed for the imaging and the TD of doxorubicin (Dox) as a model of anti-breast cancer drug. The physicochemical properties of Dox-loaded TF-CQDs were characterized using TEM, UV–Vis and FT-IR spectrophotometry, and fluorescence spectroscopy. The cytotoxicity potentiality of the nanocarrier was investigated by the MTT test across MCF-7 cell lines which exhibited more decrease in cell viability than TF-CQDs or Dox alone. The efficiency of the in vitro release was investigated in the optimum conditions of pH and the release time. The cellular uptake study revealed that TF-CQDs was more efficiently endocytosed by the MCF-7 cells than Dox. The Dox-TF conjugate was more toxic than Dox due to its overcome on multidrug resistance of cancer cells. Furthermore, the binding energy between Dox and TF-CQDs were investigated employing the molecular docking (Mdoc) approach. It was shown that Dox-TF-CQDs nano-carrier can be an excellent TD system for the therapy of breast cancer.

A photoluminescent folic acid-derived carbon dot functionalized magnetic dendrimer as a pH-responsive carrier for targeted doxorubicin delivery

A fluorescent folic acid carbon dot-grafted magnetic dendrimer was synthesized as a potential carrier for targeted delivery of DOX drug in an acidic medium (pH 5). The carrier showed biodegradability, high colloidal stability, and good biocompatibility towards A549 cells.

Three core-shell polymersomes for targeted doxorubicin delivery: Sustained and acidic release

The novel core-shell polymersomes with sustained and pH-responsive drug delivery properties is developed in this work. Doxorubicin hydrochloride (DOX) loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles were prepared as a core, and then modified with polymer shells through electrostatic assembly. Three polymers, amino-terminated poly (ethylene glycol)-folate (NH2-PEG-FA), poly (allylamine hydrochloride) (PAH) and quaternary chitosan (QCS) were selected for constructing the shell layer. The successful modifications of polymer shell on the spherical DOX@PLGA core were characterized by SEM, TEM, particle size and zeta-potential. It was verified that DOX was well dispersed in core of polymersomes. In vitro drug release studies showed that DOX@PLGA core performed well in acidic pH triggered drug release. The core-shell polymersomes, especially for DOX@PLGA@PEG-FA, can be used to form pH-sensitive systems for smart and sustained drug release. FA, as the targeting agent, was exposed onto the polymersomes surface, possible for interacting with folate receptors on many cancer cells membranes. Fitted experimental data with various kinetic models, the drug release mainly follows the Fickian diffusion mechanism in the polymer system, and the erosion mechanism only existed at acidic pH. All the presented results make the proposed polymersomes a promising system for controlled and selected drug delivery.

Poly (isopropyl-oxazoline) micelle nanocarrier as dual-responsive prodrug for targeted doxorubicin delivery

Preparation of a novel type of dual-responsive nanocarrier with thermal and pH-responsive bonds was achieved by polymerization of the poly (2-isopropyl-2-oxazoline) using methoxy-poly (ethylene glycol) as macro-initiator. The obtained copolymer was functionalized with hydrazine through reductive amination, and then doxorubicin was conjugated to functionalized copolymer chains. This reaction was leading to both doxorubicin loading enhancement and pH-responsive hydrazone linkages. The self-assembly of block copolymer-doxorubicin conjugate was occurred by dialysis bag into micelle nanocarrier. The doxorubicin which is the merely hydrophobic segment inside the micelle core was linked to the terminal branches of the copolymer chain. The synthesized copolymer micelle was demonstrated desirable critical micelle concentration (CMC) value (0.02 mg/ml). The entrapment efficacy and drug loading content in the prodrug micelle nanocarrier were obtained 73% and 9.6% respectively. In vitro doxorubicin release results demonstrated fact release profile in low pH and high temperature conditions. The cell viability of the prodrug nanocarriers was studied against HDF cells which shown suitable cytotoxicity. Whereas, the empty micelles show proper biocompatibility and their toxicity is negligible. According to the desirable result of the research, the novel nanocarrier can be a promising candidate for the smart target delivery applied in cancer therapy.

Transferrin-binding peptide functionalized polymersomes mediate targeted doxorubicin delivery to colorectal cancer in vivo

Transferrin receptor (TfR) is a promising target validated in the clinical trials for managing various malignancies. Transferrin (Tf) and single chain antibody fragment can target TfR and are typically conjugated to nanomedicines via post-modification, which poses significant production challenges. Here, we report that the polymersomes functionalized with a Tf-binding peptide CGGGHKYLRW (TBP-Ps) can selectively and stably bind Tf and subsequently mediate targeted doxorubicin (Dox) delivery to TfR over-expressing HCT-116 colorectal cancer cells in vitro and in vivo. The Tf surface density of the polymersomes could be controlled by the surface content of TBP. Interestingly, modifying Dox-loaded TBP-Ps with Tf led to greatly increased cellular uptake and inhibitory effect of HCT-116 cells. Tf-bound TBP-Ps demonstrated rapid accumulation in the tumor xenografts in nude mice following i.v. injection. More importantly, Dox-loaded Ps with Tf binding significantly enhanced the antitumor efficacy in mice bearing HCT-116 tumors compared to polymersomes without Tf binding. Surface functionalization of the nanoparticles with Tf-binding peptide provides an appealing strategy in formulating Tf-targeted nanomedicines.

Dual-Ligand Modification of PEGylated Liposomes Used for Targeted Doxorubicin Delivery to Enhance Anticancer Efficacy.

Mannose receptor (CD206) and E-selectin are selectively expressed in M2-like tumor-associated macrophages (M2-TAMs) and activated endothelial cells of vessels surrounding tumor tissues. With the knowledge that D-mannose is the natural ligand of mannose receptors and L-fucose is the key calcium chelator for tumor-associated carbohydrate antigens (TACAs) binding to E-selectin, herein, we firstly reported D-mannose polyethylene glycol (PEG) conjugates (Man-PEG) and L-fucose PEG conjugates (Fuc-PEG) co-modified liposomal doxorubicin (DOX-MFPL) to improve tumor-targeting ability. The dual-ligand modified PEGylated liposomes (DOX-MFPL) were assessed by both in vitro and in vivo trials. Compared with the single-ligand D-mannose- or L-fucose-modified liposomes (DOX-MPL or DOX-FPL), DOX-MFPL achieved an increased distribution of DOX in tumor tissues. The antitumor study based on S180 tumor-bearing mice was conducted and the superior tumor inhibitory rate was shown with DOX-MFPL, probably owing to the superior tumor-targeting effect of DOX-MFPL and the modulation of the tumor microenvironment with the exhaustion of TAMs. In general, the dual-ligand drug delivery systems are expected to be promising in the development of specific and efficient methods for tumor treatment.

The use of iron oxide magnetic nanospheres and nanocubes for targeted doxorubicin delivery into 4t1 mouse breast carcinoma cells

Magnetic nanoparticles (MNP) are attracting increasing attention as promising materials for the treatment and diagnosis of cancer. The aim of this work was to explore the effect of the magnetic core shape of iron oxide nanoparticles (NP) on the efficiency of doxorubicin delivery into 4T1 cells. Nanospheres (NS) and nanocubes (NC) were synthesized by thermal decomposition of iron (III) oleate. This method of synthesis enables control over the NP shape and size. The NP were hydrophilized using Pluronic F-127. The obtained particles were doped with doxorubicin in a sodium phosphate buffer. The weight fractions of doxorubicin in the NS and NC were 15.22% and 15.44%, respectively. The IC50 of free doxorubicin was 1 μM. The IC50 of doxorubicin-loaded NS and NC were 6.4 μM and 5.5 μM, respectively. Unloaded NP did not exhibit any toxicity towards the cells at a studied range of concentrations between 1.77 mg/l and 227.2 mg/l. Free doxorubicin demonstrated more vigorous accumulation dynamics in 4T1 cells with a tendency to localize in the cell nucleus, whereas doxorubicin loaded onto iron oxide NP was mainly accumulated in the vesicles surrounding the nucleus and was able to enter it only after being incubated with the cells for 2 h. We conclude that doxorubicin loaded onto cubic-shaped NP is delivered into the cell nucleus a little bit more efficiently at early incubation stages in comparison with nanospheres, but the difference is insignificant.