Uptake Of Dox Research Articles

Simulation of in vitro embolization effect of drug-loaded microspheres

Drug-loaded microspheres are widely used in transcatheter arterial chemoembolization (TACE). Controlled drug release from drug-loaded microspheres reduces systemic toxicity, thus necessitating the development of microspheres with controlled release properties. In this study, three different sizes of sodium hyaluronate microspheres (SH) were prepared by a one-step solution drying method using 1,4-butanediol diglycidyl ether (BDDE) as a crosslinking agent. The average sizes of the three SH microspheres (small, medium and large) were 410 μm, 550 μm and 750 μm, respectively. The morphology of the small-sized SH microspheres (SS-SH) was solid spherical; the medium-sized SH microspheres (MS-SH) were semi-hollow spherical; and the large-sized SH microspheres (LS-SH) had a bowl with an opening on one side and a cavity inside. A drug-loaded microsphere (DOX@SH) was prepared by immersing SH microspheres in a doxorubicin hydrochloride (DOX) solution. The average size of the three DOX@SH microspheres increased to 607 μm, 876 μm and 1187 μm, respectively. The encapsulation efficiencies of small, medium and large-sized SH microspheres reached 97.09 %, 96.73 % and 74.87 % at 2 h in a 2 mg/mL DOX solution. The maximum drug loadings of the small, medium and large-sized SH microspheres were 0.38, 0.38 and 0.33 mg DOX/mg SH, respectively. All sizes of DOX@SH microspheres could be controlled and sustained to release and reach equilibrium after 48 h. The cumulative release rates of small, medium and large-sized DOX@SH microspheres (SS-DOX@SH, MS-DOX@SH and LS-DOX@SH) at 72 h were 24.3 %, 28.1 % and 33.8 % in a release medium of pH 6.5, respectively. Blood compatibility and cytotoxicity tests demonstrated that SH microspheres exhibit good biocompatibility. The cytotoxicity of DOX@SH microspheres to HepG2 cells and the uptake of DOX in HepG2 cells showed effective anti-tumor activity. Simulated embolization in vitro experiments indicated that the small-sized DOX@SH microspheres had a good embolization effect for 500–800 μm and 300–500 μm blood vessels. These findings indicate that the newly developed DOX@SH microspheres can be used as a promising drug-loaded embolization agent to enhance the treatment of hepatocellular carcinoma.

Thermal-responsive β-cyclodextrin-based magnetic hydrogel as a de novo nanomedicine for chemo/hyperthermia treatment of cancerous cells

A novel thermal-responsive β-cyclodextrin-based magnetic hydrogel [β-cyclodextrin-graft-poly(N-isopropylacrylamide)/Fe3O4 (β-CD-g-PNIPAAm/Fe3O4)] was fabricated as a novel nanomedicine for chemo/hyperthermia treatment of cancer cells. Firstly, β-CD was modified by maleic anhydride (MA) followed by copolymerization with NIPAAm monomer and thiol-end capped Fe3O4 nanoparticles (NPs) in the presence of a crosslinker through acrylamide–thiol polymerization system to afford a magnetic hydrogel. The saturation magnetization (δs) value for developed hydrogel was determined to be 8.2 emu g−1. The hydrogel was physically loaded with an anticancer agent, doxorubicin hydrochloride (Dox). The encapsulation efficiency (EE) of drug into the hydrogel was obtained as 73 %. The system represented acceptable thermal-triggered drug release behavior that best fitted with Higuchi model, demonstrating the release of drug is mostly controlled by diffusion mechanism. The anticancer performance of the β-CD-g-PNIPAAm/Fe3O4-Dox was evaluated using MCF7 cells by MTT-assay. In addition, flow cytometry analyses showed considerable cellular uptake of Dox in the cells treated with β-CD-g-PNIPAAm/Fe3O4-Dox (∼70 %) compared to free Dox (∼28 %). As results, in time period of 48 h by combination of chemo- and hyperthermia-therapies, the developed system displayed greater anticancer efficiency than the free Dox.

Codelivery of Doxorubicin and p53 Gene by β-Cyclodextrin-Based Supramolecular Nanoparticles Formed via Host-Guest Complexation and Electrostatic Interaction.

We developed a supramolecular system for codelivery of doxorubicin (Dox) and p53 gene based on a β-CD-containing star-shaped cationic polymer. First, a star-shaped cationic polymer consisting of a β-CD core and 3 arms of oligoethylenimine (OEI), named CD-OEI, was used to form a supramolecular inclusion complex with hydrophobic Dox. The CD-OEI/Dox complex was subsequently used to condense plasmid DNA via electrostatic interactions to form CD-OEI/Dox/DNA polyplex nanoparticles with positive surface charges that enhanced the cellular uptake of both Dox and DNA. This supramolecular drug and gene codelivery system showed high gene transfection efficiency and effective protein expression in cancer cells. The codelivery of Dox and DNA encoding the p53 gene resulted in reduced cell viability and enhanced antitumor effects at low Dox concentrations. With its enhanced cellular uptake and anticancer efficacy, the system holds promise as a delivery carrier for potential combination cancer therapies.

How Shilajit-Based Nanocarriers Alter Classical Doxorubicin Delivery to Breast Cancer Cells (MCF-7 and ZR-75-1).

Chemotherapy has been ineffective in cancer treatment, and efficient delivery of chemotherapeutic agents remains a challenge. In this study, we developed a doxorubicin-loaded shilajit-based nanocarrier (SHN-Dox) using a nanoprecipitation method to enhance Dox uptake into breast cancer cells (MCF-7 and ZR-75-1). After confirmation of the physicochemical properties of the nanocarriers, the cytotoxic and pro-apoptotic effects of SHN-Dox and the production of reactive oxygen species (ROS) were evaluated on breast cancer cells. SHN-Dox showed a spherical shape with a size of 244 nm and a sustainable release profile of Dox. It exhibited high cytotoxicity against MCF-7 and ZR-75-1 cells, effectively inducing DNA fragmentation in these cells. After 24 h of treatment, SHN-Dox increased the apoptosis rate in MCF-7 cells and raised ROS levels. Therefore, SHN-Dox is a promising carrier that might reduce the side effects of Dox on healthy cells and provide a new strategy for clinical cancer treatment.

Anisamide-conjugated hairpin antisense oligonucleotides prodrug co-delivering doxorubicin exhibited enhanced anticancer efficacy

Antisense oligonucleotides (ASONs)-based therapeutics offers tremendous promise for the treatment of diverse diseases. However, there is still a need to develop ASONs with enhanced stability against enzymes, improved drug delivery, and enhanced biological potency. In this study, we propose a novel anisamide (AA)-conjugated hairpin oligonucleotide prodrug loading with chemotherapeutic agent (doxorubicin, DOX) (AA-loop-ASON/DOX) for oncotherapy. Results indicated that the introduction of a hairpin conformation and AA ligand in prodrug significantly improved the stability against enzymatic hydrolysis, as well as the cellar uptake of ASONs and DOX. The incorporation of disulfide bonds could trigger mechanical opening, resulting in the release of ASON and DOX in response to the intracellular glutathione (GSH) in tumors. Moreover, the composite of DOX-loading ASONs prodrug exhibited a robust and selective inhibition of tumor cell proliferation. This paper introduces a novel design concept for nucleic acid-based therapeutics, aiming to enhance the delivery of drug and improve biological effectiveness.

P53/E2F7 axis promotes temozolomide chemoresistance in glioblastoma multiforme

BackgroundGlioblastoma multiforme (GBM) is the most aggressive form of brain cancer, and chemoresistance poses a significant challenge to the survival and prognosis of GBM. Although numerous regulatory mechanisms that contribute to chemoresistance have been identified, many questions remain unanswered. This study aims to identify the mechanism of temozolomide (TMZ) resistance in GBM.MethodsBioinformatics and antibody-based protein detection were used to examine the expression of E2F7 in gliomas and its correlation with prognosis. Additionally, IC50, cell viability, colony formation, apoptosis, doxorubicin (Dox) uptake, and intracranial transplantation were used to confirm the role of E2F7 in TMZ resistance, using our established TMZ-resistance (TMZ-R) model. Western blot and ChIP experiments provided confirmation of p53-driven regulation of E2F7.ResultsElevated levels of E2F7 were detected in GBM tissue and were correlated with a poor prognosis for patients. E2F7 was found to be upregulated in TMZ-R tumors, and its high levels were linked to increased chemotherapy resistance by limiting drug uptake and decreasing DNA damage. The expression of E2F7 was also found to be regulated by the activation of p53.ConclusionsThe high expression of E2F7, regulated by activated p53, confers chemoresistance to GBM cells by inhibiting drug uptake and DNA damage. These findings highlight the significant connection between sustained p53 activation and GBM chemoresistance, offering the potential for new strategies to overcome this resistance.

Glycyrrhetinic Acid Receptor-Mediated Zeolitic Imidazolate Framework-8 Loaded Doxorubicin as a Nanotherapeutic System for Liver Cancer Treatment.

In this study, we designed and developed a DOX nanodrug delivery system (PEG-GA@ZIF-8@DOX) using ZIF-8 as the carrier and glycyrrhetinic acid (GA) as the targeting ligand. We confirmed that DOX was loaded and PEG-GA was successfully modified on the surface of the nanoparticles. The in vitro release profile of the system was investigated at pH 5.0 and 7.4. The cellular uptake, in vitro cytotoxicity, and lysosomal escape characteristics were examined using HepG2 cells. We established an H22 tumor-bearing mouse model and evaluated the in vivo antitumor activity. The results showed that the system had a uniform nanomorphology. The drug loading capacity was 11.22 ± 0.87%. In acidic conditions (pH 5.0), the final release rate of DOX was 57.73%, while at pH 7.4, it was 25.12%. GA-mediated targeting facilitated the uptake of DOX by the HepG2 cells. PEG-GA@ZIF-8@DOX could escape from the lysosomes and release the drug in the cytoplasm, thus exerting its antitumor effect. When the in vivo efficacy was analyzed, we found that the tumor inhibition rate of PEG-GA@ZIF-8@DOX was 67.64%; it also alleviated the loss of the body weight of the treated mice. This drug delivery system significantly enhanced the antitumor effect of doxorubicin in vitro and in vivo, while mitigating its toxic side effects.

Fabrication of targeted PDA-Hemin-Dox-FA nanoplatform for enhanced chemodynamic therapy synergized with chemo/photothermal therapy

Chemotherapy (CT) is widely used in clinical practice due to its simple and convenient steps, but its characteristics of systemic administration also results in a lack of targeting and a tendency to develop drug resistance, which greatly limits its therapeutic effect. In order to overcome these problems, a PDA-Hemin-Dox-FA (PHDF) nanoplatform was constructed in this work for the combined treatment of tumors. Firstly, hemin was introduced into the self-polymerization of dopamine to synthesize PDA-Hmein (PH) nanoparticles. Then, the chemotherapy drug doxorubicin (Dox) and targeted folic acid (FA) were loaded onto PH surfaces through Schiff base and amide bonds respectively to construct PHDF. When PHDF enters the tumor cells through the targeting guidance of FA, the acidic microenvironment of the tumor will induce the cleavage of the Schiff base bond in PHDF to release Dox. The presence of hemin makes PHDF have high Fenton-like activity, which generate large amount of·OH to perform chemodynamic therapy (CDT). Driven by near infrared laser light, PHDF exhibited wonderful photo-thermal conversion performance which not only brings excellent photo-thermal therapy (PTT) effect, but also promotes the uptake of Dox and the production of·OH, leading to enhanced CT and CDT efficacy. Taken together, the PHDF nanoplatform constructed in this study shows good CT/PTT/CDT combined therapy against tumor cells and it also provides a promising alternative for the combination therapy of tumors.

Lysosomal-targeted doxorubicin delivery using RBC-derived vesicles to overcome drug-resistant cancer through mitochondrial-dependent cell death

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However, current DDSs require sophisticated design and construction based on xenogeneic nanomaterials, evoking feasibility and biocompatibility concerns. Herein, a simple but versatile biological DDS (bDDS) composed of human red blood cell (RBC)-derived vesicles (RDVs) with excellent biocompatibility was surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs that remarkably suppressed MDR in uterine sarcoma through a lysosomal-mitochondrial axis-dependent cell death mechanism. Dox-gluRDVs can efficiently deliver and accumulate Dox in lysosomes, bypassing drug efflux transporters and facilitating cellular uptake and retention of Dox in drug-resistant MES-SA/Dx5 cells. The transfer of lysosomal calcium to the mitochondria during mitochondria-lysosome contact due to lysosomal Dox accumulation may result in mitochondrial ROS overproduction, mitochondrial membrane potential loss, and activation of apoptotic signaling for the superior anti-MDR activity of Dox-gluRDVs in vitro and in vivo. This work highlights the great promise of RDVs to serve as a bDDS of Dox to overcome MDR cancers but also opens up a reliable strategy for lysosomal-mitochondrial axis-dependent cell death for fighting against other inoperable cancers.

Redox-sensitive self-assembled micelles based on low molecular weight chitosan-lipoic acid conjugates for the delivery of doxorubicin: Effect of substitution degree of lipoic acid

Amphiphilic low molecular weight chitosan-lipoic acid (LC-LA) conjugates with different degrees of substitution (DS) of LA were synthesized by N, N′‑carbonyldiimidazole (CDI) catalysis to self-assemble into redox-sensitive micelles. Critical micelle concentration (CMC), size, zeta potential, biocompatibility and redox-sensitive behavior of blank micelles were investigated. The results indicated that blank micelles with low CMC, nanoscale size and positive zeta potential showed excellent biocompatibility and redox-sensitive behavior. Doxorubicin (Dox) loaded micelles were prepared by encapsulating Dox into blank micelles. The loading ability, trigger-release behavior, antitumor activity and cellular uptake of Dox loaded micelles were studied. The results demonstrated that Dox loaded micelles with superior loading ability exhibited redox-trigger behavior, strong antitumor activity and increased cellular uptake efficiency against A549 cell. Besides, the effect of DS of LA on above properties was estimated. An increase in DS of LA reduced the CMC and cumulative release amount of Dox, but improved the loading efficiency, antitumor activity, and cellular uptake of Dox loaded micelles, which resulted from stronger interaction of hydrophobic groups in micelles with the DS of LA increased. Overall, self-assembled LC-LA micelles with good biosecurity and redox-sensitive behavior hold promising application prospects in Dox delivery and improving cancer therapeutic effect of Dox.

Organic disulfide crosslinked nucleic acid-based nanocarriers for anticancer drug applications

To improve the delivery efficiency of chemotherapeutic agents, selective drug carriers have been developed to encapsulate chemotherapeutic drugs. Green biomaterials, highly biocompatible with and non-toxic to organisms, have been attracting attention in the biomedical field. Kiwifruit-derived nucleic acids were treated with HCl to expose the aldehyde groups in their deoxyriboses. The product, DNA-HCl, was then crosslinked with two disulfides, cystamine (CTM) or cystine (CYS) under an emulsification process. As the aldehyde groups react with the primary amine in the disulfides, stable imine bonds form. When DNA-HCl-CTM and DNA-HCl-CYS enter cancerous microenvironments, the disulfide bonds will be catalyzed by overexpressed GSH and release the chemotherapeutic agent, DOX. We also found that when both solutions contain GSH, the above NGs release more DOX in the one with weak acidity than the one with a neutral pH. Therefore, when compared to cancer cells treated with free DOX and DOX/DNA-HCl NGs, those dosed with DOX/DNA-HCl-CTM and DOX/DNA-HCl-CYS NGs showed a higher uptake. The enhanced uptake of DOX induced apoptosis in cancer cells and cancer organoids, evidenced by DAPI-stained condensed DNA as well as caspase-3 and PARP expression. The results of this study verify a new approach to encapsulating chemotherapeutic drugs with modified nucleic acid while selectively triggering the cytotoxic effects in cancer cells.

Electrical stimulation-induced muscle contraction does not reduce intramuscular accumulation of Doxorubicin 24 hours following administration

Background: Doxorubicin (Dox) is a commonly used chemotherapeutic drug. Although an effective anti-cancer agent, it can be profoundly toxic to skeletal muscle (SM). Dox has been demonstrated to accumulate rapidly in SM, leading to tissue damage and cellular dysfunction. Exercise prior to Dox treatment may reduce drug accumulation. However, little is known about the effects of exercise on intramuscular accumulation following Dox administration. Electrical stimulation (stim) could be a low-effort way to exercise SM following Dox administration; however, it has yet to be investigated in this context. Aim: This study aimed to determine if various stim protocols could reduce Dox accumulation in rodent hindlimb muscles 24 hours following drug administration. Hypothesis: Stim-induced muscle contraction will reduce intramuscular accumulation of Dox in a time- and intensity-dependent manner when compared to unstimulated muscles. Methods: Male Sprague-Dawley rats (n=42) were randomly assigned to one of six stim protocols (1 Hz or 3 Hz, for 5, 15, or 30 minutes) or a true control group. Stim groups received a single intraperitoneal dose of Dox (4.5 mg/kg). Twenty-four hours following Dox administration, the assigned stim protocol was carried out on the left sciatic nerve while the right leg served as an intra-individual control. Tissues and plasma were immediately harvested following the stim protocol to determine the acute effects of SM contraction. Drug and metabolite concentrations were assessed in both tissue and plasma using high-performance liquid chromatography. Results: None of the stim protocols investigated led to a reduction in intramuscular accumulation of Dox in the white gastrocnemius [summed data: 3.09±0.76 (stimulated leg) vs. 2.49±0.16 nmol/kg (unstimulated leg), p>0.05] or the soleus [summed data: 1.8±0.27 (stimulated leg) vs.1.5±0.23 nmol/kg (unstimulated leg), p>0.05]. These data are supported by plasma Dox concentrations which were similar in all groups (p>0.05), suggesting minimal uptake or release of Dox by SM. The concentration of Doxorubicinol, a highly toxic metabolite of Dox, also remained unchanged in both muscles and plasma (p>0.05). Conclusion: Electrical stimulation-induced muscle contraction did not reduce intramuscular accumulation of Dox 24 hours following drug administration. While unable to reduce accumulation, stim may still be a valuable tool for maintaining muscle mass and function during Dox treatment. Further investigation is required to characterize and optimize the role of stim during chemotherapy. Funding: This study was funded by a Rene Guilbeault Research Award. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Morin Sensitizes MDA-MB-231 Triple-Negative Breast Cancer Cells to Doxorubicin Cytotoxicity by Suppressing FOXM1 and Attenuating EGFR/STAT3 Signaling Pathways.

Considerable emphasis is being placed on combinatorial chemotherapeutic/natural treatments for breast cancer. This study reveals the synergistic anti-tumor activity of morin and Doxorubicin (Dox) co-treatment on MDA-MB-231 triple-negative breast cancer (TNBC) cell proliferation. Morin/Dox treatment promoted Dox uptake and induced DNA damage and formation of nuclear foci of p-H2A.X. Furthermore, DNA repair proteins, RAD51 and survivin, and cell cycle proteins, cyclin B1 and forkhead Box M1 (FOXM1), were induced by Dox alone but attenuated by morin/Dox co-treatment. In addition, Annexin V/7-AAD analysis revealed that necrotic cell death after co-treatment and apoptotic cell death by Dox alone were associated with the induction of cleaved PARP and caspase-7 without Bcl-2 family involvement. FOXM1 inhibition by thiostrepton showed that co-treatment caused FOXM1-mediated cell death. Furthermore, co-treatment downregulated the phosphorylation of EGFR and STAT3. Flow cytometry showed that the accumulation of cells in the G2/M and S phases might be linked to cellular Dox uptake, p21 upregulation, and cyclin D1 downregulation. Taken together, our study shows that the anti-tumor effect of morin/Dox co-treatment is due to the suppression of FOXM1 and attenuation of EGFR/STAT3 signaling pathways in MDA-MB-231 TNBC cells, which suggests that morin offers a means of improving therapeutic efficacy in TNBC patients.

Dual size/charge-switchable and multi-responsive gelatin-based nanocluster for targeted anti-tumor therapy

Biopolymers with excellent biocompatibility and biodegradability show great potential for designing drug nanocarriers, while it's difficult to fabricate smart vehicles with multiple switching (size, surface, shape) based on biopolymers alone. Here, we report a dual size/charge-switchable and multi-responsive doxorubicin-loaded gelatin-based nanocluster (DOX-icluster) for improved tumor penetration and targeted anti-tumor therapy. The DOX-icluster was electrostatically assembled from folic acid and dimethylmaleic anhydride modified gelatin (FA-GelDMA) and small-sized DOX-loaded NH2 modified hollow mesoporous organosilicon nanoparticles (DOX-HMON-NH2). DOX-icluster had an initial size of about 199 nm at neutral pH. After accumulation in tumor tissue, the DMA bond of FA-GelDMA was cleaved and gelatin was degraded by matrix metalloproteinase (MMP-2), thus 48 nm and positively charged DOX-HMON-NH2 was released to facilitate penetration and cell internalization. DOX-HMON-NH2 was further degraded by intracellular glutathione (GSH) with releasing 48.1 % of DOX. The cellular uptake results indicated that the fabricated icluster promoted the uptake of DOX by 4T1 cells. With enhanced penetration efficacy, the tumor spheroids volume treated with DOX-icluster was reduced to 15.1 % on day 7. This cytocompatible multi-responsive gelatin-based icluster with size-shrinking and charge-reversible characteristics may be used as a significant drug carrier for tumor therapy.

Dual-targeting exosomes for improved drug delivery in breast cancer.

Aims: Theauthors investigated whether displaying more than one homing peptide enhanced the tumor-targeting efficiency of exosomes. Materials & methods: Exosomes from human embryonic kidney cells (HEK293F) were engineered to display either mono- or dual-tumor-penetrating peptides, iRGD and tLyp1. Exosomes were purified via tangential flow filtration followed by ultracentrifugation. Results: When loaded with doxorubicin (Dox), the dual iRGD-tLyp1 exosomes strongly enhanced Dox uptake in both MCF-7 and MDA-MB-231 breast cancer cell lines, superior to single iRGD or tLyp1 exosomes. The dual iRGD-tLyp1 exosomal Dox was also the most potent, with IC50/GI50 values being 3.7-17.0-times lower than those of free Dox and other exosomal Dox. Conclusion: Selecting appropriate combinatorial homing peptides could be an approach for future precision nanomedicine.

Monodisperse CaCO3-loaded gelatin microspheres for reversing lactic acid-induced chemotherapy resistance during TACE treatment

Transarterial chemoembolization (TACE) is an important approach for the treatment of unresectable hepatocellular carcinoma (HCC). However, the lactic acid-induced acidic tumor microenvironment (TME) may reduce the therapeutic outcome of TACE. Herein, monodispersed gelatin microspheres loaded with calcium carbonate nanoparticles (CaNPs@Gel-MS) as novel embolic agents were prepared by a simplified microfluidic device. It was found that the particle size and homogeneity of as-prepared CaNPs@Gel-MS were strongly dependent on the flow rates of continuous and dispersed phases, and the inner diameter of syringe needle. The introduction of CaNPs provided the gelatin microspheres with an enhanced ability to encapsulate the chemotherapeutic drug of DOX, as well as a pH-responsive sustained drug release behavior. In vitro results revealed that CaNPs@Gel-MS could largely increase the cellular uptake and chemotoxicity of DOX by neutralizing the lactic acid in the culture medium. In addition, CaNPs@Gel-MS exhibited an excellent and persistent embolic efficiency in a rabbit renal model. Finally, we found that TACE treatment with DOX-loaded CaNPs@Gel-MS (DOX/CaNPs@Gel-MS) had a much stronger ability to inhibit tumor growth than the DOX-loaded gelatin microspheres without CaNPs (DOX@Gel-MS). Overall, CaNPs@Gel-MS could be a promising embolic microsphere that can significantly improve anti-HCC ability by reversing lactic acid-induced chemotherapy resistance during TACE treatment.

Nano-gold micelles loaded Dox and Elacridar for reversing drug resistance of breast cancer.

The aim of this study was to provide a new effective carrier for rescuing the sensitivity of drug-resistant in breast cancer cells. Nano-gold micelles loaded with Dox and Elacridar (FP-ssD@A-E) were chemically synthesised. With the increase in the amount of Dox and Elacridar, the encapsulation rate of FP-ssD@A-E gradually increased, and the drug loading rate gradually decreased. FP-ss@A-E had a sustained-release effect. Dox, Elacridar, FP-ss@AuNPs, and FP-ssD@A-E significantly improved cell apoptosis, in which, FP-ssD@A-E was the most significant. FP-ssD@A-E significantly decreased the cell viability and improved the Dox uptake. The levels of VEGFR-1, P-gp, IL-6, and i-NOS were significantly decreased after Dox, Dox+Elacridar, FP-ss@AuNPs, and FP-ssD@A-E treatment. It was worth noting that FP-ssD@A-E had the most significant effects. The prepared FP-ssD@A-E micelles, which were spherical in shape, uniform in particle size distribution, and had good drug loading performance and encapsulation efficiency.

Nanomicelles co-loading CXCR4 antagonist and doxorubicin combat the refractory acute myeloid leukemia

Acute myeloid leukemia (AML) is featured with poor prognosis and high mortality, because chemo-resistance, nonspecific distribution and dose-limiting toxicity lead to a high rate of relapse and a very low 5-year survival percentage of less than 25%. CXCR4 is a highly expressed chemokine receptor in multiple types of AML cells and closely associated with the drug resistance and relapse. In this work, we integrate a chemically synthesized CXCR4 antagonistic peptide and doxorubicin using DSPE-mPEG2000 micelles (referred to as M-E5-Dox) that is applied to a very challenging refractory AML mouse model as well as human AML cell lines. Results showed that M-E5-Dox can effectively bind to the CXCR4-expressing AML cells, downregulating the signaling proteins mediated by CXCR4/CXCL12 axis and increasing the cellular uptake of Dox. Importantly, M-E5-Dox remarkably decreases the leukemic cells in the peripheral blood and bone marrow, as well as their infiltration in the spleen and liver of the AML mice, which in turn prolongs the survival significantly. Meanwhile, M-E5-Dox did not increase the cardiotoxicity of Dox. In conclusion, M-E5-Dox harnesses the functions of CXCR4 specific binding and CXCR4 antagonism of the peptide and the tumor cell killing capacity of Dox, which displays significant therapeutic effects and promising translational potentials for the treatment of refractory AML.

An Acid-Sensitive Nanofiber Conjugate Based on a Short Aromatic Peptide for Targeted Delivery of Doxorubicin in Liver Cancer

PurposeThis study aimed to construct a DOX conjugate with liver tumor targeting and acid sensitivity based on a short aromatic peptide FFYEE, which could amplify the tumor inhibition efficacy of DOX and alleviate tissue toxicity.MethodsA novel DOX-peptide conjugate, D-gal-FFYEE-hyd-DOX, was constructed by linking DOX to the side chain of FFYEE with acid-sensitive hydrazone bond and by modifying the C-terminal of peptide with α-D-galactosamine (D-gal) as targeting ligand. The structure of D-gal-FFYEE-hyd-DOX was characterized by mass spectrometry, infrared spectroscopy (IR), and UV-Vis spectroscopy (UV-Vis). The assembly characteristics of pentapeptide FFYEE and D-gal-FFYEE-hyd-DOX were observed by transmission electron microscope (TEM). In vitro drug release, cytotoxicity, endocytosis, in vivo antitumor experiment and histopathology analysis were investigated.ResultsPeptide FFYEE endowed the D-gal-FFYEE-hyd-DOX with self-assembly performance and improved biocompatibility. D-gal-FFYEE-hyd-DOX can self-assemble into nanofibers with a diameter of ~ 40 nm in neutral aqueous solution and significantly reduced the cytotoxicity of free DOX to L02 cells. In vitro drug release results showed that D-gal-FFYEE-hyd-DOX had acid sensitivity and controlled release characteristics. The cytotoxicity and endocytosis investigations confirmed that D-gal-FFYEE-hyd-DOX enhanced the cellular uptake of DOX and inhibition effect on HepG2 cells. In vivo antitumor experiment indicated that D-gal-FFYEE-hyd-DOX could significantly inhibit the growth of liver tumor in mice and reduce the side effects of DOX.ConclusionThe conjugate D-gal-FFYEE-hyd-DOX with liver tumor targeting and acid sensitivity has the characteristics of strong tumor inhibition and low toxicity, hinting the great clinical application potential for targeted delivery of DOX in cancer treatment.

Doxorubicin Loaded Dextran-coated Superparamagnetic Iron Oxide Na-noparticles with Sustained Release Property: Intracellular Uptake, Phar-macokinetics and Biodistribution Study.

Due to the short biological half-life and serious side effects (especially for heart and kidney), the application of Doxorubicin (Dox) in clinical therapy is strictly limited. To overcome these shortcomings, a novel sustained release formulation of doxorubicin-loaded dextran-coated superparamagnetic iron oxide nanoparticles (Dox-DSPIONs) was prepared. The purpose of this study was to evaluate the intracellular uptake behavior of Dox-DSPIONs and to investigate their pharmacokinetics and biodistribution properties. Confocal laser scanning microscopy was employed to study the intracellular uptake and release properties of Dox from Dox-DSPIONs in SMMC-7721 cells. Simple high-performance liquid chromatography with fluorescence detection (HPLC-FLD) method was established to study the pharmacokinetics and biodistribution properties of Dox-DSPIONs in vivo after intravenous administration and compared with free Dox. Intracellular uptake experiment indicated that Dox could be released sustainedly from Dox-DSPIONs over time. The pharmacokinetics parameters displayed that the T1/2and AUC0-24h of Dox-DSPIONs were higher than those of free Dox, while the Cmax of Dox-DSPIONs was significantly lower than that of free drug. The biodistribution behaviors of the drug were altered by Dox-DSPIONs in mice, which showed obvious liver targeting, and significantly reduced the distribution of the drug in the heart and kidney. Dox-DSPIONs have the sustained-release property in vitro and in vivo, which could significantly prolong blood circulation time, improve bioavailability, and reduce the side effects of Dox. Therefore, the novel formulation of the Dox-DSPIONs has the potential as a promising drug delivery system in cancer therapy.