Enhanced tumor uptake and activity of nanoplex-loaded doxorubicin.
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ABSTRACT:
SUBMITTER: Zhao N
PROVIDER: S-EPMC6531033 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
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Project description:Doxorubicin-loaded PEGylated liposomes (commercially available as DOXIL or Lipodox) were surface functionalized with a cell-penetrating peptide, octa-arginine (R8). For this purpose, R8-peptide was conjugated to the polyethylene glycol-dioleoyl phosphatidylethanolamine (PEG-DOPE) amphiphilic co-polymer. The resultant R8-PEG-PE conjugate was introduced into the lipid bilayer of liposomes at 2 mol% of total lipid amount via spontaneous micelle-transfer technique. The liposomal modification did not alter the particle size distribution, as measured by Particle Size Analyzer and transmission electron microscopy (TEM). However, surface-associated cationic peptide increased zeta potential of the modified liposomes. R8-functionalized liposomes (R8-Dox-L) markedly increased the intracellular and intratumoral delivery of doxorubicin as measured by flow cytometry and visualizing by confocal laser scanning microscopy (CLSM) compared to unmodified Doxorubicin-loaded PEGylated liposomes (Dox-L). R8-Dox-L delivered loaded Doxorubicin to the nucleus, being released from the endosomes at higher efficiency compared to unmodified liposomes, which had marked entrapment in the endosomes at tested time point of 1h. The significantly higher accumulation of loaded drug to its site of action for R8-Dox-L resulted in improved cytotoxic activity in vitro (cell viability of 58.5 ± 7% for R8-Dox-L compared to 90.6 ± 2% for Dox-L at Dox dose of 50 ?g/mL for 4h followed by 24h incubation) and enhanced suppression of tumor growth (348 ± 53 mm(3) for R8-Dox-L, compared to 504 ± 54 mm(3) for Dox-L treatment) in vivo compared to Dox-L. R8-modification has the potential for broadening the therapeutic window of pegylated liposomal doxorubicin treatment, which could lead to lower non-specific toxicity.
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Project description:BackgroundThe enhancement of tumor retention and cellular uptake of drugs are important factors in maximizing anticancer therapy and minimizing side effects of encapsulated drugs. Herein, a delivery nanoplatform, armed with a pH-triggered charge-reversal capability and self-amplifiable reactive oxygen species (ROS)-induced drug release, is constructed by encapsulating doxorubicin (DOX) in pH/ROS-responsive polymeric micelle.ResultsThe surface charge of this system was converted from negative to positive from pH 7.4 to pH 6.8, which facilitated the cellular uptake. In addition, methionine-based system was dissociated in a ROS-rich and acidic intracellular environment, resulting in the release of DOX and ?-tocopheryl succinate (TOS). Then, the exposed TOS segments further induced the generation of ROS, leading to self-amplifiable disassembly of the micelles and drug release.ConclusionsWe confirms efficient DOX delivery into cancer cells, upregulation of tumoral ROS level and induction of the apoptotic capability in vitro. The system exhibits outstanding tumor inhibition capability in vivo, indicating that dual stimuli nano-system has great potential to function as an anticancer drug delivery platform.
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Project description:More efficient drug delivery system and formulation with less adverse effects are needed for the clinical application of broad-spectrum antineoplastic agent doxorubicin (DOX). Here we obtained outer-membrane vesicles (OMVs), a nano-sized proteoliposomes naturally released by Gram-negative bacteria, from attenuated Klebsiella pneumonia and prepared doxorubicin-loaded O0MVs (DOX-OMV). Confocal microscopy and in vivo distribution study observed that DOX encapsulated in OMVs was efficiently transported into NSCLC A549 cells. DOX-OMV resulted in intensive cytotoxic effects and cell apoptosis in vitro as evident from MTT assay, Western blotting and flow cytometry due to the rapid cellular uptake of DOX. In A549 tumor-bearing BALB/c nude mice, DOX-OMV presented a substantial tumor growth inhibition with favorable tolerability and pharmacokinetic profile, and TUNEL assay and H&E staining displayed extensive apoptotic cells and necrosis in tumor tissues. More importantly, OMVs' appropriate immunogenicity enabled the recruitment of macrophages in tumor microenvironment which might synergize with their cargo DOX in vivo. Our results suggest that OMVs can not only function as biological nanocarriers for chemotherapeutic agents but also elicit suitable immune responses, thus having a great potential for the tumor chemoimmunotherapy.
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Project description:OBJECTIVE:Nano micelles (NMs) have been widely used for various biomedical applications due to its unique physiochemical properties. This study aimed to investigated the anti-tumor effect of doxorubicin (Dox)-loaded Pluronic P123 (P123) and PEG2000-DSPE mixed NMs in drug-resistant breast cancer cells. RESULTS:The expression of P-gp and MDR1 gene was highly expressed in MCF-7R but not MCF-7 cells. The cellular uptake of P123-PEG2000-DSPE (Dox) was higher than that of free Dox and PEG2000-DSPE (Dox) in MCF-7R cells. Furthermore, compared with free Dox, both PEG2000-DSPE (Dox) and P123-PEG2000-DSPE (Dox) significantly diminished cell viability, and promoted cell apoptosis in MCF-7R cells. In addition, the P123-modified NMs obviously inhibited the expression of P-gp and MDR1. CONCLUSIONS:P123-PEG2000-DSPE (Dox) had a superior anti-tumor activity than PEG2000-DSPE (Dox) in MCF-7R cells through P-gp-mediated drug excretion and drug resistance mechanisms. METHODS:The PEG2000-DSPE NMs (PEG2000-DSPE), P123 and PEG2000-DSPE mixed NMs (P123-PEG2000-DSPE), Dox-loaded PEG2000-DSPE NMs (PEG2000-DSPE (Dox)), and Dox-loaded Pluronic P123 and PEG2000-DSPE mixed NMs (P123-PEG2000-DSPE (Dox)) were prepared, and then the morphologies and the size distribution of PEG2000-DSPE (Dox) and P123-PEG2000-DSPE (Dox) were observed by transmission electron microscopy (TEM) and dynamic light scattering (DLS), respectively.
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Project description:Chemotherapeutics that can trigger immunogenic cell death (ICD) and release tumor-specific antigens are effective on treating a variety of cancers. The codelivery of chemotherapeutics with adjuvants is a promising strategy to achieve synergistic therapeutic effect. However, low drug loading and complicated preparation of current delivery systems lead to carrier-associated toxicity and immunogenicity. Herein, we developed a facile approach to construct liposomal spherical nucleic acids (SNA) by the self-assembly of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)-doxorubicin conjugate and DOPE-matrix metalloproteinases-9 (MMP-9) responsive peptide-CpG conjugate (DOPE-MMP-CpG). Liposomal SNAs efficiently co-delivered DOX and CpG into tumors and released the two drugs upon biological stimuli of MMP-9 enzyme in tumor microenvironment (TME) and high concentration of endogenous glutathione in tumor cells. We demonstrated that liposomal SNA enhanced activation of dendritic cells (DCs), promoted expansion of CD8+ and CD4+ T cells in both tumors and spleen, inhibited tumor growth, and extended animal survival. This work provided a simple strategy of delivering chemotherapeutics and adjuvants to tumors with synergistic therapeutic effect and reduced side effect.
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Project description:Doxorubicin (DOX) is an effective anthracycline antibiotic drug which is commonly used in a broad range cancer therapy. However, due to dose depending side effects and toxicity to non-cancerous tissues, its clinical applications are restricted. To overcome these limitations, human serum albumin (HSA) has been investigated as a biocompatible drug delivery vehicle. In this study, human serum albumin submicron particles (HSA-MPs) were fabricated by using the Co-precipitation-Crosslinking-Dissolution technique (CCD technique) and DOX was loaded into the protein particles by absorption. DOX-HSA-MPs showed uniform peanut-like shape, submicron size and negative zeta-potential (-13 mV). The DOX entrapment efficiency was 25% of the initial amount. The in vitro release in phosphate buffered saline pH 7.4 was less than 1% within 5 h. In contrast, up to 40% of the entrapped DOX was released in presence of a protein digesting enzyme mixture (Pronase®) within the same time. In addition, in vitro cytotoxicity and cellular uptake of DOX-HSA-MPs were evaluated using the lung carcinoma cell line A549. The results demonstrated that DOX-HSA-MPs reduced the cell metabolic activities after 72 h. Interestingly, DOX-HSA-MPs were taken up by A549 cells up to 98% and localized in the cell lysosomal compartment. This study suggests that DOX-HSA-MPs which was fabricated by CCD technique is seen as a promising biopolymer particle as well as a viable alternative for drug delivery application to use for cancer therapy.
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Project description:Irreversible electroporation (IRE) is a novel non-thermal ablative treatment for cancer patients with unresectable tumor. IRE kills tumor cells by applying a strong electric field across the cell membrane, thereby creating irreparable pores. Compared to conventional thermal ablation, IRE is effective in perivascular tissues and can preserve the surrounding sensitive structures. However, tumor cells may survive in the regions exposed to insufficient electric field strength, and cause tumor relapse afterwards. We prepared a doxorubicin-loaded polymeric micelles system (M-Dox) using oil-in-water emulsion. The resultant M-Dox was 37.9 ± 3.2 nm in size with a Dox loading of 4.3% by weight. M-Dox is toxic to multiple human cancer cell lines with IC50 values in nanomolar and micromolar range. When combined with IRE in a hepatic carcinoma mouse xenograft model, the tumor treated with the combination therapy (IRE + M-Dox) was the highest in both M-Dox uptake and percentage of necrosis. Immunohistochemical staining also confirmed that the fewest proliferating cells were present after the combination therapy. Our data suggested that M-Dox was an effective adjuvant treatment to enhance the anti-tumor efficacy of IRE.
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