Jie Gao

Polymer-lipid hybrid nanoparticles conjugated with anti-EGF receptor antibody for targeted drug delivery to hepatocellular carcinoma.

AIMSnThe aim of this study was to obtain adriamycin-loaded polymer-lipid hybrid nanoparticles conjugated with anti-EGF receptor antibody (PLNP-Mal-EGFR) for hepatocellular carcinoma (HCC) chemotherapy.nnnMATERIALS & METHODSnThe nanoparticles were characterized by dynamic light scattering and fluorescence spectroscopy. The in vitro and in vivo distribution and anti-tumor activity of the nanoparticles were evaluated.nnnRESULTS & CONCLUSIONnPLNP-Mal-EGFR showed significantly enhanced cellular cytotoxicity against HCC cells overexpressing EGFR compared with nontargeted nanoparticles (polymer-lipid hybrid nanoparticles [containing DSPE-PEG-Mal] and polymer-lipid hybrid nanoparticles [containing DSPE-mPEG] combined with anti-EGFR Fab´). PLNP-Mal-EGFR and nontargeted nanoparticles could significantly reduce the proportion of side-population cells in HCC cells. The in vivo accumulation of PLNP-Mal-EGFR was obviously higher than that of nontargeted nanoparticles in SMMC-7721 HCC cells overexpressing EGFR. Notably, PLNP-Mal-EGFR showed significantly enhanced anti-tumor activity against HCC in vivo compared with nontargeted nanoparticles and free adriamycin. Therefore, PLNP-Mal-EGFR may serve as an effective therapeutic approach for HCC chemotherapy.

iRGD-conjugated DSPE-PEG2000 nanomicelles for targeted delivery of salinomycin for treatment of both liver cancer cells and cancer stem cells

AIMSnTo develop novel iRGD (internalizing Arg-Gly-Asp peptide)-conjugated DSPE-PEG2000 nanomicelles (M-SAL-iRGD) for delivery of salinomycin to both liver cancer cells and cancer stem cells (CSCs).nnnMATERIALS & METHODSnThe characterization, antitumor activity and mechanism of action of M-SAL-iRGD were evaluated.nnnRESULTS & CONCLUSIONnM-SAL-iRGD possessed a small size of around 10 nm, and drug encapsulation efficacy higher than 90%. M-SAL-iRGD showed significantly increased cytotoxic effect toward both nontargeted M-SAL (salinomycin-loaded DSPE-PEG2000 nanomicelles) and salinomycin in both liver cancer cells and CSCs. The tissue distribution and antitumor assays in mice bearing liver cancer xenograft confirmed the superior penetration tumor efficacy and antitumor activity of M-SAL-iRGD. M-SAL-iRGD represent a potential effective nanomedicine against liver cancer.

Novel dual-control poly(N-isopropylacrylamide-co-chlorophyllin) nanogels for improving drug release.

AIMnHow to overcome insufficient drug release is an important issue in the drug-delivery system.nnnMATERIALS & METHODSnHere, a novel temperature and UV dual-control poly(N-isopropylacrylamide [PNIPAM]-co-chlorophyllin) nanogel was prepared via the surfactant-free emulsion polymerization.nnnRESULTSnThe introduction of hydrophilic chlorophyllin to the PNIPAM chain backbone led to a narrow size of poly[NIPAM-co-CHLN nanogel (D ∼180 nm) confirmed by atomic force microscopy and transmission electron microscopy. This nanogel had a lower critical solution temperature (∼35°C), observed by dynamic laser light scattering. After the phase transition, the size under UV light (50 nm) was much smaller than that induced by temperature (90 nm). The inhomogeneous collapse was attributed to the temperature-gradient generated from the gel surface to the core with a surrounding dense PNIPAM layer. The obstacles that strongly inhibited 5-fluorouracil release was successfully overcome by light irradiation via a large drug diffusion coefficient.nnnCONCLUSIONnConsequently, the novel dual functional nanogel is potent for improving the drug-release profile.

Codelivery of salinomycin and chloroquine by liposomes enables synergistic antitumor activity in vitro.

AIMnTo improve the suboptimal therapeutic efficacy of salinomycin (SAL) toward liver cancer cells using chloroquine (CQ) combination by the liposomes co-delivering SAL and CQ (SCNL).nnnMATERIALS & METHODSnThe synergy of these two drugs was evaluated in liver cancer cells (HepG2) and liver cancer stem cells (LCSCs) by median-effect analysis. SCNL with optimized ratio were developed. The cytotoxic effect and basal autophagy flux (measure of autophagic degradation activity) of various formulations were evaluated.nnnRESULTS & CONCLUSIONnCQ could significantly increase the cytotoxic effect of SAL in HepG2 cells, but not in HepG2-LCSCs, due to the greater basal autophagy flux in HepG2 cells. This combination therapy is promising for liver cancer treatment by eradicating liver cancer cells and LCSCs.

Co-delivery of doxorubicin and PEGylated C16-ceramide by nanoliposomes for enhanced therapy against multidrug resistance

AIMnTo develop novel nanoliposomes (Lip-ADR-Cer) codelivering doxorubicin (ADR) and PEGylated C16 ceramide (PEG-ceramide C16) to overcome multidrug resistance.nnnMATERIALS & METHODSnThe antitumor activity and mechanism of Lip-ADR-Cer were evaluated.nnnRESULTS & CONCLUSIONnThe IC50 of Lip-ADR-Cer after 48-h treatment with the MCF-7/ADR and HL-60/ADR cancer cells, both being ADR resistant, was 2.2- and 1.4-fold effective respectively versus the general nanoliposomes with no PEG-ceramide C16 (Lip-ADR). The antitumor assay in mice bearing MCF-7/ADR or HL-60/ADR xenograft tumors confirmed the superior antitumor activity of Lip-ADR-Cer over Lip-ADR. We found that the improved therapeutic effect of Lip-ADR-Cer may be attributed to both of the cytotoxic effect of PEG-ceramide C16 and glucosylceramide synthase overexpression in multidrug resistance cells.

Cancer nanoimmunotherapy using advanced pharmaceutical nanotechnology

Immunotherapy is a promising option for cancer treatment that might cure cancer with fewer side effects by primarily activating the hosts immune system. However, the effect of traditional immunotherapy is modest, frequently due to tumor escape and resistance of multiple mechanisms. Pharmaceutical nanotechnology, which is also called cancer nanotechnology or nanomedicine, has provided a practical solution to solve the limitations of traditional immunotherapy. This article reviews the latest developments in immunotherapy and nanomedicine, and illustrates how nanocarriers (including micelles, liposomes, polymer-drug conjugates, solid lipid nanoparticles and biodegradable nanoparticles) could be used for the cellular transfer of immune effectors for active and passive nanoimmunotherapy. The fine engineering of nanocarriers based on the unique features of the tumor microenvironment and extra-/intra-cellular conditions of tumor cells can greatly tip the triangle immunobalance among host, tumor and nanoparticulates in favor of antitumor responses, which shows a promising prospect for nanoimmunotherapy.

A dual brain-targeting curcumin-loaded polymersomes ameliorated cognitive dysfunction in intrahippocampal amyloid-β1-42-injected mice

Due to the impermeability of the blood–brain barrier and the nonselective distribution of drugs in the brain, the therapeutic access to intractable neurological disorders is challenging. In this study, dual brain-targeting polymersomes (POs) functionalized by transferrin and Tet-1 peptide (Tf/Tet-1-POs) promoted the transportation of curcumin into the brain and provided neuroprotection. The modification of the ligands that bind to the surface of POs was revealed by X-ray photoelectron spectroscopy analysis. The cell uptake of a coculture model of mouse brain capillary endothelial cells with neurons showed that the Tf/Tet-1-POs had significant transportation properties and possessed affinity for neurons. The pharmacokinetic analysis showed that the blood–brain barrier permeability–surface efficiency of the Tf/Tet-1-POs was 0.28 mL/h/g and that the brain tissue uptake rate (% ID/g) was 0.08, which were significant compared with the controls (P<0.05). The curcumin-encapsulated Tf/Tet-1-POs provided neuroprotection and ameliorated cognitive dysfunction in intrahippocampal amyloid-β1–42-injected mice. These results suggest that the dual brain-targeting POs are more capable of drug delivery to the brain that can be exploited as a multiple noninvasive vehicle for targeting therapeutics.

Nanomedicine strategies for sustained, controlled, and targeted treatment of cancer stem cells of the digestive system

Cancer stem cells (CSCs) constitute a small proportion of the cancer cells that have self-renewal capacity and tumor-initiating ability. They have been identified in a variety of tumors, including tumors of the digestive system. CSCs exhibit some unique characteristics, which are responsible for cancer metastasis and recurrence. Consequently, the development of effective therapeutic strategies against CSCs plays a key role in increasing the efficacy of cancer therapy. Several potential approaches to target CSCs of the digestive system have been explored, including targeting CSC surface markers and signaling pathways, inducing the differentiation of CSCs, altering the tumor microenvironment or niche, and inhibiting ATP-driven efflux transporters. However, conventional therapies may not successfully eradicate CSCs owing to various problems, including poor solubility, stability, rapid clearance, poor cellular uptake, and unacceptable cytotoxicity. Nanomedicine strategies, which include drug, gene, targeted, and combinational delivery, could solve these problems and significantly improve the therapeutic index. This review briefly summarizes the ongoing development of strategies and nanomedicine-based therapies against CSCs of the digestive system.

Nanomedicine-Mediated Combination Drug Therapy in Tumor

REVIEW ARTICLE Nanomedicine-Mediated Combination Drug Therapy in Tumor Dazhong Chen, Fangyuan Xie, Duxin Sun, Chuan Yin, Jie Gao and Yanqiang Zhong Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China

Therapeutic PEG-ceramide nanomicelles synergize with salinomycin to target both liver cancer cells and cancer stem cells

AIMnSalinomycin (SAL)-loaded PEG-ceramide nanomicelles (SCM) were prepared to target both liver cancer cells and cancer stem cells.nnnMATERIALS & METHODSnThe synergistic ratio of SAL/PEG-ceramide was evaluated to prepare SCM, and the antitumor activity of SCM was examined both in vitro and in vivo.nnnRESULTSnSAL/PEG-ceramide molar ratio of 1:4 was chosen as the synergistic ratio, and SCM showed superior cytotoxic effect and increased apoptosis-inducing activity in both liver cancer cells and cancer stem cells. In vivo, SCM showed the best tumor inhibitory effect with a safety profile.nnnCONCLUSIONnThus, PEG-ceramide nanomicelles could serve as an effective and safe therapeutic drug carrier to deliver SAL into liver cancer, opening up the avenue of using PEG-ceramide as therapeutic drug carriers.