Codelivery of multiple drugs with one kind of drug carriers provided a promising strategy to suppress the drug resistance and achieve the synergistic therapeutic effect in cancer treatment. In this paper, we successfully developed both methotrexate (MTX) and mitomycin C (MMC) loaded PEGylated chitosan nanoparticles (CS-NPs) as drug delivery systems, in which MTX, as a folic acid analogue, was also employed as a tumor-targeting ligand. The new drug delivery systems can coordinate the early phase targeting effect with the late-phase anticancer effect. The (MTX+MMC)-PEG-CS-NPs possessed nanoscaled particle size, narrow particle size distribution, and appropriate multiple drug loading content and simultaneously sustained drug release. In vitro cell viability tests indicated that the (MTX+MMC)-PEG-CS-NPs exhibited concentration- and time-dependent cytotoxicity. Moreover, in vitro cellular uptake suggested that the (MTX+MMC)-PEG-CS-NPs could be efficiently taken up by cancer cells by FA receptor-mediated endocytosis. On the other hand, the (MTX+MMC)-PEG-CS-NPs can codelivery MTX and MMC to not only achieve the high accumulation at the tumor site but also more efficiently suppress the tumor cells growth than the delivery of either drug alone, indicating a synergistic effect. In fact, the codelivery of two anticancer drugs with distinct functions and different anticancer mechanisms was key to opening the door to their targeted drug delivery and synergistic anticancer effect. Therefore, the (MTX+MMC)-PEG-CS-NPs as targeted drug codelivery systems might have important potential in clinical implications for combination cancer chemotherapy.
Most present drug-phospholipid delivery systems were based on a water-insoluble drug-phospholipid complex but rarely water-soluble drug-phospholipid complex. Mitomycin C (MMC) is a water-soluble anticancer drug extensively used in first-line chemotherapy but is limited by its poor aqueous stability in vitro, rapid elimination from the body, and lack of target specificity. In this article, we report the MMC-soybean phosphatidylcholine complex-loaded PEG-lipid-PLA hybrid nanoparticles (NPs) with Folate (FA) functionalization (FA-PEG-PE-PLA NPs@MMC-SPC) for targeted drug delivery and dual-controlled drug release. FA-PEG-PE-PLA NPs@MMC-SPC comprise a hydrophobic core (PLA) loaded with MMC-SPC, an amphiphilic lipid interface layer (PE), a hydrophilic shell (PEG), and a targeting ligand (FA) on the surface, with a spherical shape, a nanoscaled particle size, and high drug encapsulation efficiency of almost 95%. The advantage of the new drug delivery systems is the early phase controlled drug release by the drug-phospholipid complex and the late-phase controlled drug release by the pH-sensitive polymer-lipid hybrid NPs. In vitro cytotoxicity and hemolysis assays demonstrated that the drug carriers were cytocompatible and hemocompatible. The pharmacokinetics study in rats showed that FA-PEG-PE-PLA NPs@MMC-SPC significantly prolonged the blood circulation time compared to that of the free MMC. More importantly, FA-PEG-PE-PLA NPs@MMC-SPC presented the enhanced cell uptake/cytotoxicity in vitro and superior tumor accumulation/therapeutic efficacy in vivo while reducing the systemic toxicity. A significant accumulation of MMC in the nuclei as the site of MMC action achieved in FA-PEG-PE-PLA NPs@MMC-SPC made them ideal for MMC drug delivery. This study may provide an effective strategy for the design and development of the water-soluble drug-phospholipid complex-based targeted drug delivery and sustained/controlled drug release.
The design of nanoscale drug delivery systems for the targeted codelivery of multiple therapeutic drugs still remains a formidable challenge (ACS Nano, 2013, 7, 9558-9570; ACS Nano, 2013, 7, 9518-9525). In this article, both mitomycin C (MMC) and methotrexate (MTX) loaded DSPE-PEG micelles (MTX-M-MMC) were prepared by self-assembly using the dialysis technique, in which MMC-soybean phosphatidylcholine complex (drug-phospholipid complex) was encapsulated within MTX-functionalized DSPE-PEG micelles. MTX-M-MMC could coordinate an early phase active targeting effect with a late-phase synergistic anticancer effect and enable a multiple-responsive controlled release of both drugs (MMC was released in a pH-dependent pattern, while MTX was released in a protease-dependent pattern). Furthermore, MTX-M-MMC could codeliver both drugs to significantly enhance the cellular uptake, intracellular delivery, cytotoxicity, and apoptosis in vitro and improve the tumor accumulation and penetration and anticancer effect in vivo compared with either both free drugs treatment or individual free drug treatment. To our knowledge, this work provided the first example of the systemically administrated, orthogonally functionalized, and self-assisted nanoscale micelles for targeted combination cancer chemotherapy. The highly convergent therapeutic strategy opened the door to more simplified, efficient, and flexible nanoscale drug delivery systems.
Multifunctional nanocomposites hold great potential to integrate therapeutic and diagnostic functions into a single nanoscale structure. In this paper, we prepared the MTX-PEG-CS-IONPs-Cy5.5 nanocomposites by functionalizing the surface of chitosan-decorated iron oxide nanoparticles (CS-IONPs) with polyethylene glycolated methotraxate (MTX-PEG) and near-infrared fluorescent cyanin dye (Cy5.5). A clinically useful PEGylated anticancer prodrug, MTX-PEG, was also developed as a tumor cell-specific targeting ligand for self-targeted cancer treatment. In such nanocomposites, the advantage was that the orthogonally functionalized, self-targeted MTX-PEG-CS-IONPs-Cy5.5 can synergistically combine an early phase selective tumor-targeting efficacy with a late-phase cancer-killing effect, which was also confirmed by dual model (magnetic resonance and fluorescence) imaging. Furthermore, with the aids of the folate (FA) receptor-mediated endocytosis (able to turn cellular uptake "off" in normal cells and "on" in cancer cells) and pH/intracellular protease-mediated hydrolyzing peptide bonds (able to turn drug release "off" in systemic circulation and "on" inside endo/lysosomes), the MTX-PEG-CS-IONPs-Cy5.5 could deliver MTX to FA receptors-overexpressed cancer cells, showing the improved anticancer activity with the reduced side effects. Together, the MTX-PEG-CS-IONPs-Cy5.5 could act as a highly convergent, flexible, and simplified system for dual model imaging and synergistically self-targeted cancer therapy, holding great promise for versatile biomedical applications in future.
Poly-adenosine diphosphate-ribose polymerase (PARP) implements posttranslational mono- or poly-ADP-ribosylation modification of target proteins. Among the known 18 members in the enormous family of PARP enzymes, several investigations about PARP1, PARP2, and PARP5a/5b have been launched in the past few decades; more specifically, PARP14 is gradually emerging as a promising drug target. An intact PARP14 (also named ARTD8 or BAL2) is constructed by macro1, macro2, macro3, WWE, and the catalytic domain. PARP14 takes advantage of nicotinamide adenine dinucleotide (NAD+) as a metabolic substrate to conduct mono-ADP-ribosylation modification on target proteins, taking part in cellular responses and signaling pathways in the immune system. Therefore, PARP14 has been considered a fascinating target for treatment of tumors and allergic inflammation. More importantly, PARP14 could be a potential target for a chemosensitizer based on the theory of synthetic lethality and its unique role in homologous recombination DNA repair. This review first gives a brief introduction on several representative PARP members. Subsequently, current literatures are presented to reveal the molecular mechanisms of PARP14 as a novel drug target for cancers (e.g., diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, and hepatocellular carcinoma) and allergic inflammatory. Finally, potential PARP inhibitor-associated adverse effects are discussed. The review could be a meaningful reference for innovative drug or chemosensitizer discovery targeting to PARP14.
Lipid–MMC in cooperation with pegylated lipid–MTX based on PEG–PE–PLA hybrid NPs can coordinate an early-phase targeting effect with a late-phase anticancer effect.
We constructed 10-hydroxycamptothecin (CPT) "nanodrugs" with functionalization of lipid-PEG-methotrexate (MTX) to prepare high-drug-loaded, and sustained/controlled-release MTX-PEG-CPT nanorods (NRs), in which MTX drug itself can serve as a specific "targeting ligand". The self-targeted nanodrug can codeliver both CPT and MTX drugs with distinct anticancer mechanisms. Furthermore, MTX-PEG-CPT NRs significantly reduced burst release, improved blood circulation and tumor accumulation, enhanced cellular uptake, and synergistically increased anticancer effect against tumor cells compared with MTX-PEG-CPT nanospheres (NSs) and either both free drugs or individual free drug. Therefore, the synergistic targeting/therapeuticy nano-multi-drug codelivery assisted by shape design may advantageously offer a promising new strategy for nanomedicine.
A mitomycin C (MMC)-soybean phosphatidyhlcholine complex loaded in phytosomes was previously reported for the purpose of developing a MMC drug delivery system (Mol. Pharmaceutics 2013, 10, 90-101), but this approach was limited by rapid elimination from the body and lack of target specificity. In this article, to overcome these limitations, MMC-soybean phosphatidyhlcholine complex-loaded phytosomes (MMC-loaded phytosomes) as drug carriers were surface-functionalized with folate-PEG (FA-PEG) to achieve reduced toxicity and a superior MMC-mediated therapeutic effect. For this purpose, FA was conjugated to DSPE-PEG-NH2, and the resultant DSPE-PEG-FA was introduced into the lipid moiety of the phytosomes via a postinsertion technique. The prepared FA-PEG-functionalized MMC-loaded phytosomes (FA-PEG-MMC-loaded phytosomes) have a particle size of 201.9 ± 2.4 nm, a PDI of 0.143 ± 0.010, a zeta potential of -27.50 ± 1.67 mV, a spherical shape, and sustained drug release. The remarkable features of FA-PEG-MMC-loaded phytosomes included increased cellular uptake in HeLa cells and higher accumulation in H22 tumor-bearing mice over that of the PEG-MMC-loaded phytosomes. Furthermore, FA-PEG-MMC-loaded phytosomes were associated with enhanced cytotoxic activity in vitro and an improved antitumor effect in vivo compared to that resulting from free MMC injection. These results suggest that FA-PEG-MMC-loaded phytosomes may be useful drug delivery systems for widening the therapeutic window of MMC in clinical trials.
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