Deformable liposomal codelivery of vorinostat and simvastatin promotes antitumor responses through remodeling tumor microenvironment.

The tumor microenvironment (TME) and its major component tumor-associated macrophages (TAM) play a pivotal role in the development of non-small cell lung cancer (NSCLC). An epigenetic drug-based combinatory therapeutic strategy was proposed and a deformable liposome system (D-Lipo) was developed for vorinostat and simvastatin codelivery for remodeling the TME. The application of deformable liposomes in systemic cancer drug delivery has been underexplored and its potential in cancer therapy is largely unknown. This work revealed that D-Lipo exhibited an enhanced intratumor infiltration ability. The proposed therapeutic strategy was characterized by a chemo-free regimen and TME remodeling function. D-Lipo efficiently inhibited the growth of the xenografted lung tumor. The anti-tumor mechanisms involved the repolarization of TAM from the M2 to M1 phenotype, anti-angiogenesis, and the consequent TME remodeling. As a result, the amounts of the anti-tumor M1 macrophages and the cytotoxic CD8+ T cells increased, while the amounts of the pro-tumor M2 macrophages and regulatory T cells (Tregs) reduced. It provides a promising avenue for epigenetic drug-based combination therapy for treating solid tumors.

Nanotechnology-Based Histone Deacetylase Inhibitors for Cancer Therapy.

Histone deacetylase inhibitors (HDACi) have been approved and achieved success in hematologic malignancies. But its application in solid tumors still confronts big challenges and is hampered by low treatment efficacy. Nanotechnology has been widely applied in cancer therapy, and nanomedicine could improve drug stability, prolong the circulation half-life, and increase intratumoral drug accumulation. Therefore, nanomedicine is a promising strategy to enhance HDACi therapy efficacy. The review provides a summary of the advances of HDACi nanomedicines with a focus on the design principles of the targeting delivery systems for HDACi.

Decoy Oligodeoxynucleotides, Polysaccharides, and Targeted Peptide-Functionalized Gold Nanorods for the Combined Treatment of Rheumatoid Arthritis.

Adv. Healthcare Mater. 2018, 7, 1800982 The above article, published online on 04 November 2018 in Wiley Online Library (https://wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, and Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. The retraction has been agreed due to errors in data presentation and non-reproducibility of the results. N. Zhang, S. S. Zhang, C. Y. Xu, L. L. Fu, T. B. Liu, Y. X. Zhao, Adv. Healthcare Mater. 2018, 7, 1800982, DOI:10.1002/adhm.201800982.

Decoy Oligodeoxynucleotides, Polysaccharides, and Targeted Peptide-Functionalized Gold Nanorods for the Combined Treatment of Rheumatoid Arthritis.

Autoimmune diseases like rheumatoid arthritis (RA) possess complicated pathogenesis. Therefore, RA is hard to treat by monotherapies in clinical setting. All-in-one treatments that target inflamed joints and act efficiently are highly needed. Gold compounds are old anti-RA therapies and are fabricated into gold nanorods (GNRs) that serve as anti-RA therapeutics as well as nanocarriers for anti-inflammatory nucleic acid drug-NF-κB-decoy oligodeoxynucleotides (dODNs). A targeted peptide to vascular cell adhesion molecule-1 (VCAM-1) (PVCAM-1 ) is modified onto the GNRs to facilitate enhanced accumulation of GNRs in inflamed tissues and enhanced cellular uptake of GNRs by inflamed cells. dODNs loaded and PVCAM-1 modified GNRs (GNRs-dODN-PVCAM-1 ) are covered by polysialic acid (PSA) to protect GNRs-dODN-PVCAM-1 in vivo. Simultaneous GNRs, dODN, and thermotherapy show synergic effect on the reduction of TNF-α and IL-6 in inflamed macrophages and blood vessel cells. The simultaneous triple therapy (GNRs-dODN-PSA-PVCAM-1 +laser) demonstrates excellent anti-inflammatory efficacy in vitro and in vivo.

Antiglioma via regulating oxidative stress and remodeling tumor-associated macrophage using lactoferrin-mediated biomimetic codelivery of simvastatin/fenretinide.

Effective treatment of malignant glioma still remains a formidable challenge due to lack of the effective BBB-permeable drugs and efficient brain delivery methods, and the pharmacotherapy options are very limited. Therefore, to develop an effective therapeutic strategy is a pressing need. In this work, a noncytotoxic drug combination (i.e., simvastatin and fenretinide) was revealed to be potent for treating glioma, which was co-encapsulated into a TPGS-TAT-embedded lactoferrin nanoparticle system for achieving brain-targeted biomimetic delivery via the LRP-1 receptor. It was shown that the lactoferrin nanoparticle repolarized the tumor-associated macrophages from the M2 phenotype to M1 via regulating the STAT6 pathway, as well as induced the ROS-mediated mitochondrial apoptosis by inhibiting the Ras/Raf/p-Erk pathway in the glioma cells. The antiglioma efficacy was further demonstrated in both the subcutaneous and orthotopic glioma models. The repolarization of tumor-associated macrophages not only prompted the ROS generation but also induced the innate immunity (e.g., antitumor cytokine release). This delivery and therapeutic strategy provides a novel modality for the glioma treatment.

Multifunctional gold nanorods and docetaxel-encapsulated liposomes for combined thermo- and chemotherapy.

Personalized and precise nanomedicines are highly demanded for today's medical needs. Liposomes are ideal candidates for the construction of multifunctional drug delivery systems. In this study, a liposome was used to improve the clinical issues of docetaxel (Doc), a potent antimitotic chemotherapy for prostate cancer (PC). RLT, a low-density lipoprotein receptor (LDLR)-binding peptide, and PEG were conjugated to the liposomes, and gold nanorods (GNRs) were also incorporated into the liposomes. The GNRs/Doc-liposome-RLT (GNRs/DocL-R) was tested in PC-3 cells and in PC-3 tumor-bearing nude mice. Results showed that GNRs/DocL-R possessed a diameter approximately 163.15±1.83 nm and a zeta potential approximately -32.8±2.16 mV. GNRs/DocL-R showed enhanced intracellular entrance, increased accumulation in the implanted tumor region, and the highest tumor inhibition in vitro and in vivo. Therefore, the multifunctional GNRs/DocL-R was a potential cancer treatment via combined chemo- and thermotherapy.

Preparation, pharmacokinetics and pharmacodynamics of ophthalmic thermosensitive in situ hydrogel of betaxolol hydrochloride.

Conventional ophthalmic formulations often eliminate rapidly after administration and cannot provide and maintain an adequate concentration of the drug in the precorneal area. To solve those problems, a thermosensitive in situ gelling and mucoadhesive ophthalmic drug delivery system was prepared and evaluated, the system was composed of poloxamer analogs and polycarbophil (PCP) and betaxolol hydrochloride (BH) was selected as model drug. The concentrations of poloxamer 407 (P407) (22% (w/v)) and poloxamer 188 (P188) (3.5% (w/v)) were identified through central composite design-response surface methodology (CCD-RSM). The BH in situ hydrogel (BH-HG) was liquid solution at low temperature and turned to semisolid at eye temperature. BH-HG showed good stability and biocompatibility, which fulfilled the requirements of ocular application. In vitro studies indicated that addition of PCP enhanced the viscosity of BH-HG and the release results of BH from BH-HG demonstrated a sustained release behavior of BH because of the gel dissolution. In vivo pharmacokinetics and pharmacodynamics studies indicated that the BH-HG formulation resulted in an improved bioavailability and a significantly lower intraocular pressure (IOP). The results suggested BH-HG could be potentially used as an in situ gelling system for ophthalmic delivery to enhance the bioavailability and efficacy.