Co-Delivery of Metformin Enhances the Antimultidrug Resistant Tumor Effect of Doxorubicin by Improving Hypoxic Tumor Microenvironment.

Doxorubicin (DOX) is a first-line chemo drug for cancer therapy, yet it fails to treat multi-drug-resistant tumors. Hypoxia is a major causative factor leading to chemotherapy failure. Particularly, hypoxia up-regulates its responsive transcription factor-hypoxia-inducible factors (HIF)-to induce the overexpression of drug resistant genes. Metformin (MET) is recently found to cooperate with DOX against multiple tumors. As a mitochondrial inhibitor, MET could suppress tumor oxygen consumption, and thereby modulate the hypoxic tumor microenvironment. In this study, we used cationic liposomes to codeliver both DOX and MET for treating multi-drug-resistant breast cancer cells-MCF7/ADR. Faster release of MET enhanced the cytotoxicity of DOX through attenuating hypoxic stress both in vivo and in vitro. MET diminished the cellular oxygen consumption and inhibited HIF1α and P-glycoprotein (Pgp) expression in vitro. In addition, the dual-drug-loaded liposomes increased tumor targeting and intratumoral blood oxygen saturation, which suggested that the tumor reoxygenation effect of MET facilitated the exertion of its synergistic activity with DOX against MCF7/ADR xenografts. In general, our study represents a feasible strategy to boost the therapeutic effect in treating multi-drug-resistant cancer by improving the hypoxic tumor microenvironment.

Doxorubicin derivative loaded acetal-PEG-PCCL micelles for overcoming multidrug resistance in MCF-7/ADR cells.

Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor. Significance: Chemotherapy is one of the main treatments for breast cancer but is plagued by multidrug resistance (MDR). DOX-TPP-loaded micelles can enhance the specific concentration of drugs in the tumor and improve the efficacy and overcome MDR. Methods: In this study, DOX-TPP-loaded micelles based on acetal-PEG-PCCL were prepared and their physicochemical properties were characterized. The cellular uptake and ability to induce apoptosis of the micelles was confirmed by flow cytometry in MCF-7/ADR cells. In addition, cytotoxicity of the micelles was studied in MCF-7 cells and MCF-7/ADR cells. Confocal is used to study the subcellular distribution of DOX. Free DOX-TPP or DOX-TPP-loaded acetal-PEG-PCCL micelles were administered via intravenous injection in the tail vain for the biodistribution study in vivo. Results: The diameter of micelles was about 102.4 nm and their drug-loading efficiency is 61.8%. The structural characterization was confirmed by 1H NMR. The micelles exhibited better antitumor efficacy compared to free doxorubicin in MCF-7/ADR cells by MTT assay. The apoptotic rate and the cellular uptake of micelles were significantly higher than free DOX and DOX-TPP. Micelles can efficiently deliver mitochondria-targeting DOX-TPP to tumor cells. The result of bio-distribution showed that the micelles had stronger tumor infiltration ability than free drugs. Conclusions: In this study, mitochondriotropic DOX-TPP was conjugated to the nanocarrier acetal-PEG-PCCL via ionic interaction to form a polymer, which spontaneously formed spherical micelles. The cytotoxicity and cellular uptake of the micelles are superior to free DOX and exhibit mitochondrial targeting and passive tumor targeting, indicating that they have potential prospects.

AIE/FRET-based versatile PEG-Pep-TPE/DOX nanoparticles for cancer therapy and real-time drug release monitoring.

On account of the biological significance of self-assembling peptides in blocking the cellular mass exchange as well as impeding the formation for actin filaments resulting in program cell death, stimuli-responsive polypeptide nanoparticles have attracted more and more attention. In this work, we successfully fabricated doxorubicin-loaded polyethylene glycol-block-peptide (FFKY)-block-tetraphenylethylene (PEG-Pep-TPE/DOX) nanoparticles, where the aggregation-induced emission luminogens (AIEgen, TPE-CHO) can become a fluorescence resonance energy transfer (FRET) pair with the entrapped antitumor drug DOX to detect the release of drugs dynamically. This is the first successful attempt to detect and quantify the change of FRET signals in A549 cells via three methods to monitor the cellular uptake of nanoprobes and intracellular drug molecule release intuitively. As we proposed here, the combination of free DOX and the self-assembling peptide could achieve the synergistic anticancer efficacy. The multifunctional PEG-Pep-TPE/DOX nanoparticles may provide a new opportunity for combination cancer therapy and real-time detection of the drug release from stimuli-responsive nanomedicine.

Effectiveness of platelet-rich plasma injection in patients with temporomandibular joint osteoarthritis: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The aim of this study was to investigate the effectiveness of platelet-rich plasma (PRP) injection after arthrocentesis or arthroscopy in patients with temporomandibular joint osteoarthritis. STUDY DESIGN: Electronic databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched for reports up to July 30, 2018. We included all published or unpublished randomized controlled trials (RCTs). The primary outcome was pain reduction, and the secondary outcome was the improvement of maximal mouth opening. Weighted mean differences were utilized for random-effect meta-analysis. RESULTS: Five RCTs were enrolled in the meta-analysis, comparing PRP injection to placebo (hyaluronic acid [HA] injection, saline injection, or no injection). The results revealed that PRP injection was more effective than placebo in pain reduction, but no in the improvement of maximal mouth opening, in the long term. In the subgroup analysis, PRP injection yielded better outcome only in pain reduction comparing to HA injection (Weighted mean difference 1.34, 95% confidence interval [CI] 0.95-1.73). CONCLUSIONS: This meta-analysis demonstrated that PRP injection provided adjuvant efficacy to arthrocentesis or arthroscopy in pain reduction for temporomandibular joint osteoarthritis in the long term. Furthermore, PRP injection significantly reduced pain better compared with HA injection, saline injection, or no injection.

Ulcerative colitis-specific delivery of keratinocyte growth factor by neutrophils-simulated liposomes facilitates the morphologic and functional recovery of the damaged colon through alleviating the inflammation.

Keratinocyte growth factor (KGF) was effective to treat ulcerative colitis. However, its poor stability and unspecific distribution toward inflamed bowel were two important obstacles hindering its consistent efficacy. Herein, KGF was firstly encapsulated into the liposomes (KGF-Lips) to improve its stability. Thereafter, the neutrophil membrane vesicle (NEM) was extracted from the activated neutrophil which was isolated from the healthy mice and then activated by lipopolysaccharide. Subsequently, NEM was inlaid in KGF-Lips to construct a neutrophil-like liposome (KGF-Neus). KGF was easily encapsulated into KGF-Neus with a high encapsulation efficiency of 95.3 ±â€¯0.72%. Controlling NEM/lipid ratio at 1:50, KGF-Neus displayed the spherical morphology with Dh of 154.8 ±â€¯2.7 nm, PDI of 0.18, and zeta potential of -2.37 ±â€¯0.14 mV. Moreover, KGF-Neus exhibited good stability of Dh and significantly improved the chemical stability of KGF. Owing to NEM-associated proteins, KGF-Neus were specifically internalized by the inflammatory HUVECs. Moreover, KGF-Neus were specifically homed to the inflamed bowel in dextran sulfate sodium-induced mice after intravenous injection, resulting in the effective recovery of the morphology and function of the bowel. The therapeutic mechanisms of KGF-Neus were highly associated with alleviation of inflammation in colitis. Overall, the neutrophil-like liposome may be an excellent carrier for the colitis-targeted delivery of KGF.

Homing of ICG-loaded liposome inlaid with tumor cellular membrane to the homologous xenografts glioma eradicates the primary focus and prevents lung metastases through phototherapy.

Currently, phototherapy initiated by local irradiation with a near-infrared (NIR) laser has emerged as a promising strategy for cancer treatment owing to its low toxicity. However, a key problem for effective phototherapy is how to specifically deliver a sufficient dose of photosensitizers to a tumor focus. Herein, indocyanine green (ICG), a United States Food and Drug Administration (US FDA)-approved photosensitizer, was first encapsulated in an inner aqueous compartment of liposome (ICG-LIP) to improve its stability. Thereafter, tumor cell membranes were isolated from native glioma cells and subsequently inlaid in the bilayer lipid membrane of ICG-LIP to construct cell-like liposomes (ICG-MCLs). ICG was easily encapsulated into the ICG-MCLs with a very high encapsulation efficiency, reaching 78.01 ± 0.72% and its concentration in the final formulation reached 200 µg mL-1. The ICG-MCLs displayed a spherical morphology with a hydrodynamic diameter (Dh) of 115.0 ± 0.5 nm, a PDI of 0.14, and a zeta potential of -11.2 ± 0.9 mV. Moreover, ICG-MCLs exhibited a good stability in terms of particle size and significantly improved the chemical stability of ICG in pH 7.4 PBS at 37 °C. In addition, the temperature of the ICG-MCLs rapidly increased to 63 °C after 10 min irradiation and this was maintained for a longer time. Owing to the cancer cell membrane associated protein, the ICG-MCLs were specifically internalized by homogenous glioma C6 cells in vitro, which resulted in the strong red fluorescence of ICG in cytoplasm. Moreover, in vivo imaging showed that the ICG-MCLs were effectively homed to the tumor site of C6 glioma-bearing Xenograft nude mice through vein injection, which resulted in the temperature of the tumor site rapidly rising, allowing the killing of tumor cells after local NIR irradiation. After treatment with the ICG-MCLs, the primary tumor focus was completely eradicated and lung metastases were effectively inhibited. In conclusion, liposomes inlaid with tumor cellular membranes may serve as an excellent nanoplatform for homologous-targeting phototherapy using ICG.

Glioma-Targeted Delivery of a Theranostic Liposome Integrated with Quantum Dots, Superparamagnetic Iron Oxide, and Cilengitide for Dual-Imaging Guiding Cancer Surgery.

Herein, a theranostic liposome (QSC-Lip) integrated with superparamagnetic iron oxide nanoparticles (SPIONs) and quantum dots (QDs) and cilengitide (CGT) into one platform is constructed to target glioma under magnetic targeting (MT) for guiding surgical resection of glioma. Transmission electron microscopy and X-ray photoelectron spectroscopy confirm the complete coencapsulation of SPIONs and QDs in liposome. Besides, CGT is also effectively encapsulated into the liposome with an encapsulation efficiency of ∼88.9%. QSC-Lip exhibits a diameter of 100 ± 1.24 nm, zeta potential of -17.10 ± 0.11 mV, and good stability in several mediums. Moreover, each cargo shows a biphasic release pattern from QSC-Lip, a rapid initial release within initial 10 h followed by a sustained release. Cellular uptake of QSC-Lip is significantly enhanced by C6 cells under MT. In vivo dual-imaging studies show that QSC-Lip not only produces an obvious negative-contrast enhancement effect on glioma by magnetic resonance imaging but also makes tumor emitting fluorescence under MT. The dual-imaging of QSC-Lip guides the accurate resection of glioma by surgery. Besides, CGT is also specifically distributed to glioma after administration of QSC-Lip under MT, resulting in an effective inhibition of tumors. The integrated liposome may be a potential carrier for theranostics of tumor.

pH-sensitive polymeric nanoparticles of mPEG-PLGA-PGlu with hybrid core for simultaneous encapsulation of curcumin and doxorubicin to kill the heterogeneous tumour cells in breast cancer.

Most breast tumours are heterogeneous and not only contain the bulk of differentiated tumour cells but also a small population of highly tumorigenic and intrinsically drug-resistant cancer stem cells (CSCs). Herein, a pH-sensitive nanoparticle with simultaneous encapsulation of curcumin and doxorubicin (CURDOX-NPs) was prepared by using monomethoxy (polyethylene glycol)-b-P (D,L-lactic-co-glycolic acid)-b-P (L-glutamic acid) polymer to simultaneously target the differentiated tumor cells and CSCs. CURDOX-NPs had a mean diameter of 107.5 nm and zeta potential of -13.7 mV, determined by DLS. Drug-loading efficiency for curcumin and doxorubicin was reaching to 80.30% and 96.2%, respectively. Moreover, a cascade sustained-release profiles with the faster release of CUR followed by a slower release of DOX was observed in normal pH7.4 condition. Moreover, a pH-sensitive release profile for each cargo was seen in pH5.0 condition. The anti-tumour effect of CURDOX-NPs on CSCs-enriching MCF-7/ADR mammospheres was confirmed by in vitro. Moreover, a significant regression of tumour growth after treatment with CURDOX-NPs was also observed in Xenograft mice model. The percentage of CSCs in tumour significantly decreased from 39.9% in control group to 6.82% after treatment with CURDOX-NPs. The combinational delivery of CUR and DOX may a potentially useful therapeutic strategy for refractory breast cancer.

Ratiometric delivery of two therapeutic candidates with inherently dissimilar physicochemical property through pH-sensitive core-shell nanoparticles targeting the heterogeneous tumor cells of glioma.

Currently, combination drug therapy is one of the most effective approaches to glioma treatment. However, due to the inherent dissimilar pharmacokinetics of individual drugs and blood brain barriers, it was difficult for the concomitant drugs to simultaneously be delivered to glioma in an optimal dose ratio manner. Herein, a cationic micellar core (Cur-M) was first prepared from d-α-tocopherol-grafted-ε-polylysine polymer to encapsulate the hydrophobic curcumin, followed by dopamine-modified-poly-γ-glutamic acid polymer further deposited on its surface as a anion shell through pH-sensitive linkage to encapsulate the hydrophilic doxorubicin (DOX) hydrochloride. By controlling the combinational Cur/DOX molar ratio at 3:1, a pH-sensitive core-shell nanoparticle (PDCP-NP) was constructed to simultaneously target the cancer stem cells (CSCs) and the differentiated tumor cells. PDCP-NP exhibited a dynamic diameter of 160.8 nm and a zeta-potential of -30.5 mV, while its core-shell structure was further confirmed by XPS and TEM. The ratiometric delivery capability of PDCP-NP was confirmed by in vitro and in vivo studies, in comparison with the cocktail Cur/DOX solution. Meanwhile, the percentage of CSCs in tumors was significantly decreased from 4.16% to 0.95% after treatment with PDCP-NP. Overall, PDCP-NP may be a promising carrier for the combination therapy with drug candidates having dissimilar physicochemical properties.