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The clinical application of nanomedicines faces the dilemma of improved safety but restricted efficacy due to the poor intratumoral bioavailability of chemotherapeutics. We here design an enzyme-silenced nanosponge that shares a long-term lifespan to reversibly exhale/inhale doxorubicin (DOX) for continuous intercellular relay delivery and improved intratumoral retention. The nanosponge is composed of a cationic lipid overlaying a hyaluronic acid derivative polyampholyte core for enveloping of DOX and hyaluronidase-1-targeted siRNA (siHyal1), and a lipoprotein shell decorated with fusion peptide 4F-tLyP-1 that was fused with apolipoprotein A-I (apoA-I) mimetic peptide 4F and tLyP-1 for tumor homing and extravasation into the tumor interstitium. Triggered by the intra/intercellular pH variation, the nanosponge core could reversibly swell in endo/lysosome (pH 5.0) for DOX release. Owing to the deprotonation, the nanosponge core shrinks back in cytoplasm (pH 7.4) for DOX reloading and continues the behavior after being secreted to the extracellular matrix (pH 6.8) via Golgi apparatus, which dramatically improves intratumoral DOX retention and availability. Concurrently, the intratumoral lifespan of the nanosponge is prolonged by siHyal1-specific silencing, ensuring spatiotemporal consistency of carrier and drug when shuttling multilayer tumor cells. As a result, the nanosponge achieves efficient tumor inhibition in 99.1% of tumor spheroids and 80.1% of orthotopic tumor models. Collectively, this study provides an intelligent nanosponge design for active intercellular relay drug delivery, achieving improved intratumoral bioavailability of drugs and amplified chemotherapy on solid tumors.

rHDL is a synthesized drug delivery nanoplatform exhibiting excellent biocompatibility, which possesses most of the advantages of HDL. rHDL shows almost no toxicity and can be degraded to non-toxic substances in vivo. The severe limitation of the application of various antitumor agents is mainly due to their low bioavailability, high toxicity, poor stability, etc. Favorably, antitumor drug-loaded rHDL nanoparticles (NPs), which are known as an important drug delivery system (DDS), help to change the situation a lot. This DDS shows an outstanding active-targeting ability towards tumor cells and improves the therapeutic effect during antitumor treatment while overcoming the shortcomings mentioned above. In the following text, we will mainly focus on the various applications of rHDL in tumor targeted therapy by describing the properties, preparation, receptor active-targeting ability and antitumor effects of antineoplastic drug-loaded rHDL NPs.

In order to combine the drug with the tissue-engineered bone scaffold and make the drugs on the scaffolds stable to achieve sustained-release stepwise function, a new method for preparing coaxial drug-loaded tissue engineering bone scaffolds using coaxial three-dimensional printing technology is proposed, in which inner layer material can carry drugs and the outer material can adjust the drug sustained-release rate. The coupling mechanism of both shape control and property control in the process of coaxial three-dimensional printing micro-structural unit is presented. Design-Expert software is introduced for experimental design. The influences of extrusion speed, filling speed, and delamination height on the forming quality are analyzed, and a coaxial gradient composite scaffold model with controllable micro-structure is established. The macro-structure, mechanical properties, in vitro degradation rate, and drug release rate of the scaffolds were analyzed. The experimental results show that the proposed forming technology and process parameter optimization can effectively improve the forming quality of the coaxial scaffold. At the same time, this design of the coaxial structure can effectively slow down the degradation rate of the scaffold and enables stable and long-time drug release. Furthermore, the presented method provides a new technical approach for the further implementation of implantable drug delivery systems for the effective treatment of bone tuberculosis.

Angiogenesis is the hallmark of melanoma that nurtures the tumor microenvironment (TME) for rapid tumor progression. Vessel normalization could benefit melanoma treatment through TME reconstruction, while its limited duration and extent are still the drag. Herein, two kinds of look-like nanodrugs, called Gemini-like nanodrugs (GLnano), were constructed separately with the same scaffold of antiangiogenic low molecular weight heparin (LMWH) and mixed upon administration in vivo . For one, doxorubicin (DOX) was encapsulated into LMWH-chrysin nanodrug (LCY) with DSPE-PEG-anisamide decoration (D-LCA nanodrugs) for active targeting and direct cell killing toward melanoma cells. For another, matrix metalloproteinases (MMPs)-sensitive peptide was conjugated to LMWH to encapsulate celecoxib (Cel) (C-Lpep nanodrugs), disassembling in TME by MMPs and releasing Cel for M2-to-M1 reprogramming of tumor-associated macrophages. Our results showed that GLnano could remarkably elongate the vessel normalization window up to 12 days with the highest pericyte coverage of nearly 75%, compared to only 4 days by LCY monotherapy. Furthermore, GLnano could spontaneously form the "treatment-delivery" loop to promote nanodrugs toward deep tumor regions, leading to a potent tumor inhibition, metastasis prevention, and overall TME improvements.

Introduction: Herein, a hyaluronic acid (HA)-coated redox-sensitive chitosan-based nanoparticle, HA(HECS-ss-OA)/GA, was successfully developed for tumor-specific intracellular rapid delivery of gambogic acid (GA). Materials and methods: The redox-sensitive polymer, HECS-ss-OA, was prepared through a well-controlled synthesis procedure with a satisfactory reproducibility and stable resulted surface properties of the assembled cationic micelles. GA was solubilized into the inner core of HECS-ss-OA micelles, while HA was employed to coat outside HECS-ss-OA/GA for CD44-mediated active targeting along with protection from cation-associated in vivo defects. The desirable redox-sensitivity of HA(HECS-ss-OA)/GA was demonstrated by morphology and particle size changes alongside in vitro drug release of nanoparticles in different simulated reducing environments. Results: The results of flow cytometry and confocal microscopy confirmed the HA-receptor mediated cellular uptake and burst drug release in highly reducing cytosol of HA(HECS-ss-OA)/GA. Consequently, HA(HECS-ss-OA)/GA showed the highest apoptosis induction and cytotoxicity over the non-sensitive (HA(HECS-cc-OA)/GA) and HA un-coated (HECS-ss-OA/GA) controls against A549 NSCLC model both in vitro and in vivo. Furthermore, a diminished systemic cytotoxicity was observed in HA(HECS-ss-OA)/GA treated mice compared with those treated by HA un-coated cationic ones and GA solution., Competing Interests: The authors report no conflicts of interest in this work.

We discuss the bioinspired surface modifications of nanographene oxide for biocompatibility and biostability concerns, and summarize the biomedical applications of graphene oxide derivatives., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Several obstacles are currently impeding the successful treatment of breast cancer, namely impaired drug accumulation into the tumor site, toxicity to normal cells and narrow therapeutic index of chemotherapy, multidrug resistance (MDR) and the metastatic spread of cancer cells through the blood and lymphatic vessels. In this regard, we designed a novel multifunctional nano-sized drug delivery system based on LyP-1 peptide-modified low-molecular-weight heparin-quercetin conjugate (PLQ). This nanosystem was developed for targeted co-delivery of multiple anticancer drugs to p32-overexpressing tumor cells and peritumoral lymphatic vessels, using LyP-1 peptide as active targeting ligand, with the aim to achieve a targeted combinatorial chemo/angiostatic therapy and MDR reversal. The cellular uptake of PLQ nanoparticles by p32-overexpressing breast cancer cells was significantly higher than nonfunctionalized nanoparticles. Besides, the anti-angiogenic activity of PLQ nanoparticles was proven by the effective inhibition of the bFGF-induced neovascularization in subcutaneous Matrigel plugs. More importantly, PLQ/GA nanoparticles with better targeting ability toward p32-positive tumors, displayed a high antitumor outcome by inhibition of tumor cells proliferation and angiogenesis. Immunohistochemistry and western blot assay showed that PLQ/GA nanoparticles significantly disrupted the lymphatic formation of tumor, and inhibited the P-glycoprotein (P-gp) expression in MCF-7 tumor cells, respectively. In conclusion, PLQ/GA nanoparticles provide a synergistic strategy for effective targeted co-delivery of chemotherapeutic and antiangiogenic agents and reversing MDR and metastasis in breast cancer., Statement of Significance: Herein, we successfully developed a novel amphiphilic nanomaterial, LyP-1-LMWH-Qu (PLQ) conjugate, consisting of a tumor-targeting moiety LyP-1, a hydrophobic quercetin (a multidrug resistance [MDR]-reversing drug) inner core, and a hydrophilic low-molecular-weight heparin (an antiangiogenic agent) outer shell for encapsulating and delivering a hydrophobic chemotherapeutic agent (gambogic acid). This versatile nanoplatform with multiple targeted features, i.e., dual chemo/angiostatic effects, destruction ability of the peritumoral lymphatic vessels, and reversal of MDR, resulted in a significantly stronger antitumor efficacy and lower toxic side effect than those of nontargeted nanoparticles and the free drug solution. Therefore, this versatile nanosystem might provide a novel insight for the treatment and palliation of breast cancer by targeted co-delivery of chemo/antiangiogenic agents and reversing MDR and metastasis., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The quest for an ideal cancer treatment has led to the exploration of a variety of platforms to facilitate highly desirable and efficient drug delivery. As most anticancer drugs possess therapeutic potency to destroy tumor cells, there is a need to steer the compounds to their required sites using site-specific drug delivery vehicles. This has inspired the investigation of various natural particulates and biomaterials for the purpose. Bio-inspired platforms that directly mimic natural components in the body have demonstrated their ability to serve as one of the most versatile and innovative drug delivery systems in cancer therapy and diagnosis. The primary advantage of this innovation lies in the fundamental changes in systemic biodistribution that non-native drug delivery does not possess. This review will try to provide a comprehensive understanding and a succinct evaluation of various intelligent bio-inspired delivery platforms, which have become prominent in recent studies. Recent innovative examples and their advantages and limitations as well as future clinical potential will also be thoroughly discussed.

Background: Lung cancer is the primary cause of cancer-related death worldwide. A redox-sensitive nanocarrier system was developed for tumor-targeted drug delivery and sufficient drug release of the chemotherapeutic agent paclitaxel (PTX) for improved lung cancer treatment., Methods: The redox-sensitive nanocarrier system constructed from a hyaluronic acid-disulfide-vitamin E succinate (HA-SS-VES, HSV) conjugate was synthesized and PTX was loaded in the delivery system. The physicochemical properties of the HSV nanoparticles were characterized. The redox-sensitivity, tumor-targeting and intracellular drug release capability of the HSV nanoparticles were evaluated. Furthermore, in vitro and in vivo antitumor activity of the PTX-loaded HSV nanoparticles was investigated in a CD44 over-expressed A549 tumor model., Results: This HSV conjugate was successfully synthesized and self-assembled to form nanoparticles in aqueous condition with a low critical micelle concentration of 36.3 μg mL -1 . Free PTX was successfully entrapped into the HSV nanoparticles with a high drug loading of 33.5% (w/w) and an entrapment efficiency of 90.6%. Moreover, the redox-sensitivity of the HSV nanoparticles was confirmed by particle size change of the nanoparticles along with in vitro release profiles in different reducing environment. In addition, the HA-receptor mediated endocytosis and the potency of redox-sensitivity for intracellular drug delivery were further verified by flow cytometry and confocal laser scanning microscopic analysis. The antitumor activity results showed that compared to redox-insensitive nanoparticles and Taxol ® , PTX-loaded redox-sensitive nanoparticles exhibited much greater in vitro cytotoxicity and apoptosis-inducing ability against CD44 over-expressed A549 tumor cells. In vivo, the PTX-loaded HSV nanoparticles possessed much higher antitumor efficacy in an A549 mouse xenograft model and demonstrated improved safety profile. In summary, our PTX-loaded redox-sensitive HSV nanoparticles demonstrated enhanced antitumor efficacy and improved safety of PTX., Conclusion: The results of our study indicated the redox-sensitive HSV nanoparticle was a promising nanocarrier for lung cancer therapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Oleanolic acid (OA), a pentacyclic triterpene, is used to safely and economically treat hepatopathy. However, OA, a Biopharmaceutics Classification System IV category drug, has low bioavailability owing to low solubility (<1 μg/mL) and biomembrane permeability. We developed a novel OA nanoparticle (OA-NP)-loaded lactoferrin (Lf) nanodelivery system with enhanced in vitro OA dissolution and improved oral absorption and bioavailability. The OA-NPs were prepared using NP albumin-bound technology and characterized using dynamic light scattering, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, and in vitro dissolution test. The in vivo pharmacokinetics was investigated in Sprague Dawley rats using liquid chromatography-tandem mass spectrometry. OA-NPs (OA:Lf =1:6, w/w%) exhibited spherical morphology, 202.2±8.3 nm particle size, +(27.1±0.32) mV ζ potential, 92.59%±3.24% encapsulation efficiency, and desirable in vitro release profiles. An effective in vivo bioavailability (340.59%) was achieved compared to the free drug following oral administration to rats. The Lf novel nanodelivery vehicle enhanced the dissolution rate, intestinal absorption, and bioavailability of OA. These results demonstrate that Lf NPs are a new strategy for improving oral absorption and bioavailability of poorly soluble and poorly absorbed drugs., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Photodynamic therapy has emerged as a promising strategy for cancer treatment. To ensure the efficient delivery of a photosensitizer to tumor for anticancer effect, a safe and tumor-specific delivery system is highly desirable. Herein, we introduce a novel biomimetic nanoparticle named rHDL/ICG (rHDL/I), by loading amphiphilic near-infrared (NIR) fluorescent dye indocyanine green (ICG) into reconstituted high density lipoproteins (rHDL). In this system, rHDL can mediate photoprotection effect and receptor-guided tumor-targeting transportation of cargos into cells. Upon NIR irradiation, ICG can generate fluorescent imaging signals for diagnosis and monitoring therapeutic activity, and produce singlet oxygen to trigger photodynamic therapy (PDT). Our studies demonstrated that rHDL/I exhibited excellent size and fluorescence stability, light-triggered controlled release feature, and neglectable hemolytic activity. It also showed equivalent NIR response compared to free ICG under laser irradiation. Importantly, the fluorescent signal of ICG loaded in rHDL/I could be visualized subcellularly in vitro and exhibited metabolic distribution in vivo, presenting superior tumor targeting and internalization. This NIR-triggered image-guided nanoparticle produced outstanding therapeutic outcomes against cancer cells, demonstrating great potential of biomimetic delivery vehicles in future clinical practice., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers, and chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor, without apparent toxicity in normal tissues. Combining DCA and p53 gene could be an effective way to treat tumors. The progress towards broad applications of DCA/p53 combination requires the development of safe and efficient vectors that target to specific cells. In this study, we developed a DSPE-PEG-AA (1,2-distearoryl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide) modified reconstituted high-density lipoprotein-based DCA/p53-loaded nanoparticles (DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes), which was fabricated as a drug/gene dual-targeting co-delivery system for potential cancer therapy. Here, DCA-PEI was utilized to effectively condense the p53 plasmid, to incorporate the plasmid into rHDL and to act as an antitumor drug to inhibit tumor cell growth. The DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes exhibited desirable and homogenous particle size, neutral surface charge and low cytotoxicity for normal cells in vitro. The results of confocal laser scanning microscopy (CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug delivery and gene transfection in human lung adenocarcinoma cell line A549. And in vivo investigation on nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes possessed specific tumor targeting and strong antitumor activity. The work described here demonstrated that the DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes might offer a promising tool for effective cancer therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Combination of antiangiogenesis and chemotherapy holds vast promise for effective inhibition of tumor proliferation and invasion. Herein, a multifunctional self-assembled nanosystem consisting of amphiphilic c(RGDyK)-functionalized low-molecular-weight heparin-gambogic acid conjugate (cRHG) is developed, using c(RGDyK) peptide as αv β3 integrin targeting moiety to realize a double-targeted delivery to both tumor cells and angiogenic vasculature. cRHG with a markedly decreased anticoagulant activity can self-assemble into nanosized particles (around 150 nm). cRHG nanoparticles effectively inhibit vascular endothelial growth factor (VEGF)-triggered tube-like formation of HUVEC and neovascularization of subcutaneous Matrigel plugs. More importantly, the targeting ability of cRHG nanoparticles is revealed by their efficient internalization by αv β3 integrin-positive cells (U87MG and HUVEC) in vitro and obvious accumulation of Cy7/cRHG in the tumor site with strong fluorescence signals in both cancer cells and neovasculature. Besides, cRHG maintains the in vitro cytotoxic activity of gambogic acid, while achieving the highest in vivo antitumor activity in U87MG mouse xenograft model and displaying better safety profile than free drugs solutions. Mechanistic investigations reveal the substantial inhibition of hypoxia-inducible factor-1 alpha, VEGF, and CD31 expression by cRHG nanoparticles with remarkable down-regulation of VEGFR2 phosphorylation. These results suggest that cRHG nanoparticles provide a versatile nanoplatform for efficacious combinatorial tumor therapy., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The relevance of personalized medicine, aimed at a more individualized drug therapy, has inspired research into nano-based concerted diagnosis and therapeutics (theranostics). As the intention is to "kill two birds with one stone", scientists have already described the emerging concept as a treasured tailor for the future of cancer therapy, wherein the main idea is to design "smart" nanosystems to concurrently discharge both therapeutic and diagnostic roles. These nanosystems are expected to offer a relatively clearer view of the ingenious cellular trafficking pathway, in-situ diagnosis, and therapeutic efficacy. We herein present a detailed review of versatile nanosystems, with prominent examples of recently developed intelligent delivery strategies which have gained attention in the field of theranostics. These nanotheranostics include various mechanisms programmed in novel platforms to enable predetermined delivery of cargo to specific sites, as well as techniques to overcome the notable challenges involved in the efficacy of theranostics.

Nanoparticles are widely recognized as a vehicle for tumor-targeted therapies. There are many factors that can influence the uptake of nanoparticles, such as the size of the nanoparticles, and/or their shape, elasticity, surface charge and even the cell cycle phase. However, the influence of the cell cycle on the active targeting of a drug delivery system has been unknown until now. In this study, we initially investigated the folate receptor α (FR-α) expression in different phases of HeLa cells by flow cytometric and immunocytochemical methods. The results obtained showed that FR-α expression was cell cycle-dependent, i.e. the S cells' folate receptor expression was the highest as the cell progressed through its cycle. Then, we used folate modified poly(L-amino acid) micelles (FA-PM) as an example to investigate the influence of the cell cycle on the active targeting drug delivery system. The results obtained indicated that the uptake of FA-PM by cells was influenced by the cell cycle phase, and the S cells took up the greatest number of folate conjugated nanoparticles. Our findings suggest that future studies on ligand-mediated active targeting preparations should consider the cell cycle, especially when this system is used for a cell cycle-specific drug.

A new cationic polymer eprosartan-graft-PEI (ESP) containing eprosartan (ES) and polyethylenimine 1.8K was successfully developed and employed as a safe gene vector to assemble a drug (ES) and gene co-delivery complex (ESP/pDNA). Chondroitin sulfate (CS) was then used as a coating polymer to shield the surface charge of ESP/pDNA complexes, as well as a tumor targeting entity to ensure specific delivery of CS/ESP/pDNA complexes. The CS/ESP/pDNA complexes with desirable particle size and zeta potential, exhibited amidase-responsive drug release and CS-mediated endocytosis in vitro. As compared with ESP/pDNA complexes, in vivo imaging results demonstrated decreased reticuloendothelial system uptake and remarkably increased tumor accumulation of CS/ESP/pDNA complexes. All these findings indicated the potential of CS/ESP/pDNA as a promising tumor-targeted drug and gene co-delivery system., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: An amphiphilic polymer N-Octyl-N-Arginine-Chitosan (OACS) was synthesized to coat the Cyclosporine A (CsA) liposomes (CL) to decrease the destruction of liposomes in gastrointestinal tract (GI) tract and improve its oral absorption., Methods: CL and OACS-CsA liposomes (OACS-CL) were prepared by rotary-film evaporation method, and characterized by dynamic light scattering, transmission electron microscopy, atomic force microscope and releasing properties. In-situ single pass perfusion experiment and in-vivo studies in rats were carried out to verify its absorption enhancement., Key Findings: The characterization results showed that its particle size, zeta potential and morphology changed before and after polymer coating. Release experiment indicated that OACS could slow down drug release and protect its degradation in the stomach. In-situ single pass perfusion proved that the absorption of OACS-CL at the jejunum was enhanced about 3 and 22 times compared with commercial preparation of microemulsions (Tianke) and CsA suspensions, respectively. In vivo, AUC0→∞ of three different OACS-CL groups (93.48 ± 2.54, 100.98 ± 13.08 and 99.01 ± 19.02 h·μg/ml, respectively) were higher than those of Tianke (69.34 ± 7.93 h·μg/ml), CL group (54.31 ± 6.70 h·μg/ml) and suspensions (31.14 ± 1.30 h·μg/ml)., Conclusions: Therefore, OACS coated liposomes can be an effective strategy to promote drug's absorption and further reduce the anaphylactic reaction of abundant surfactants in commercial preparations., (© 2015 Royal Pharmaceutical Society.)

A redox-sensitive prodrug, octreotide(Phe)-polyethene glycol-disulfide bond-paclitaxel [OCT(Phe)-PEG-ss-PTX], was successfully developed for targeted intracellular delivery of PTX. The formulation emphasizes long-circulation-time polymer-drug conjugates, combined targeting based on EPR and OCT-receptor mediated endocytosis, sharp redox response, and programmed drug release. The nontargeted redox-sensitive prodrug, mPEG-ss-PTX, and the targeted insensitive prodrug, OCT(Phe)-PEG-PTX, were also synthesized as controls. These polymer-PTX conjugates, structurally confirmed by 1H NMR, exhibited approximately 23,000-fold increase in water solubility over parent PTX and possessed drug contents ranging from 11% to 14%. The redox-sensitivity of the objective OCT(Phe)-PEG-ss-PTX prodrug was verified by in vitro PTX release profile in simulated reducing conditions, and the SSTRs-mediated endocytosis was demonstrated by flow cytometry and confocal laser scanning microscopy analyses. Consequently, compared with mPEG-PTX and OCT(Phe)-PEG-PTX, the OCT(Phe)-PEG-ss-PTX exhibited much stronger cyotoxicity and apoptosis-inducing ability against NCI-H446 tumor cells (SSTRs overexpression), whereas a comparable cytotoxicity of these prodrugs was obtained against WI-38 normal cells (no SSTRs expression). Finally, the in vivo studies on NCI-H466 tumor-bearing nude mice demonstrated that the OCT(Phe)-PEG-ss-PTX possessed superior tumor-targeting ability and antitumor activity over mPEG-PTX, OCT(Phe)-PEG-PTX and Taxol, as well as minimal collateral damage. This targeted redox-sensitive polymer-PTX prodrug system is promising in tumor therapy.

In this study, a novel PTX prodrug, octreotide(Phe)-polyethene glycol-paclitaxel [OCT(Phe)-PEG-PTX], was successfully synthesized and used for targeted cancer therapy. A nontargeting conjugate, mPEG-PTX, was also synthesized and used as a control. Chemical structures of OCT(Phe)-PEG-PTX and mPEG-PTX were confirmed using (1) H nuclear magnetic resonance and circular dichroism. The drug contents in both the conjugates were 12.0% and 14.0%, respectively. Compared with the parent drug (PTX), OCT(Phe)-PEG-PTX, and mPEG-PTX prodrugs showed a 20,000- and 30,000-fold increase in water solubility, respectively. PTX release from mPEG-PTX and OCT(Phe)-PEG-PTX exhibited a pH-dependent profile. Moreover, compared with mPEG-PTX, OCT(Phe)-PEG-PTX exhibited significantly stronger cytotoxicity against NCI-H446 cells (SSTR overexpression) but comparable cytotoxicity against WI-38 cells (no SSTR expression). Results of confocal laser scanning microscopy revealed that the targeting prodrug labeled with fluorescence probe was selectively taken into tumor cells via SSTR-mediated endocytosis. In vivo investigation of prodrugs in nude mice bearing NCI-H446 cancer xenografts confirmed that OCT(Phe)-PEG-PTX prodrug exhibited stronger antitumor efficacy and lower systemic toxicity than mPEG-PTX and commercial Taxol. These results suggested that OCT(Phe)-PEG-PTX is a promising anticancer drug delivery system for targeted cancer therapy., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Tumor-targeted drug delivery and microenvironment-responsive drug release are attractive strategies in cancer treatment. Our previous study demonstrated that redox-sensitive micelles based on hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates exhibited excellent drug-loading capacities (34.1%) for paclitaxel (PTX) and rapid drug release in response to reducing agent, glutathione. In the present study, the physicochemical and biological properties of PTX-loaded HA-ss-DOCA (PTX-HA-ss-DOCA) micelles were investigated further. The micelles have an average size of about 120 nm and a zeta potential of about -36 mV. Transmission electron microscopy and wide-angle X-ray diffraction analysis demonstrated redox-sensitive degradation of micelles in the presence of glutathione. Moreover, the encapsulated payload was effectively released from HA-ss-DOCA micelles into cytoplasm and then rapidly transported into nuclei. In vitro cytotoxicity and cell apoptosis assay further revealed that HA significantly improved the tumor-specific drug delivery of HA-ss-DOCA micelles via receptor-mediated endocytosis, while efficient intracellular drug release and transportation lead to marked inhibition of tumor cell growth, as compared to Taxol(®) and insensitive micelles. More importantly, PTX-HA-ss-DOCA micelles demonstrated superior in vivo antitumor activity compared with Taxol(®) and insensitive control, and decreased systemic toxicity. Herein we present data which provide valuable insight into the design and development of tumor-specific drug delivery systems., (Copyright © 2015. Published by Elsevier B.V.)

Reconstituted high density lipoprotein (rHDL) is an excellent and highly biocompatible nanovector mimicking the physical, chemical as well as physiological properties of native high density lipoprotein (HDL), and is originally widely used as the substitute in HDL related studies. Over the past decades, rHDL has increasingly been exploited into vehicles for targeted delivery of numerous drugs, therapeutic genes, etc., and is playing a more and more important role in drug delivery design for regenerative medicine. As such, a systematic review of this promising carrier will be of great importance for subsequent studies. In this article, the term "rHDL-based nanoparticles (rHDLbased NPs)" is employed to refer to rHDL and its modified form. This review highlights four aspects of rHDL-based NPs: current applications in regenerative medicine, preparation methods, conventional evaluation methods, and future trends on co-delivery of drugs for synergic effects.

Cell-penetrating peptides (CPPs) have been previously shown to be powerful transport vector tools for the delivery of a large variety of cargoes through the cell membrane, as well as other physiological membranes. And since they're relatively cell-, receptor- and energy-independent, CPPs have unique advantages in facilitating drugs entry into cells. This paper briefly reviews the discovery, mechanism and classification of CPPs, and especially focuses on the specific limitations of CPPs and their potential applications for tumor-targeted delivery of biologically active molecules, imaging agents and carriers.

The study is aimed to develop a versatile reticular polyethylenimine (PEI) derivative eprosartan-g-PEI (ESP) conjugate-mediated targeted drug and gene codelivery system for tumor therapy. Eprosartan (ES), an angiotensin II type 1 receptor blocker (ARB), which has been proven to exert beneficial effects on tumor progression, vascularization, and metastasis as the conventional antihypertensive drug, was conjugated with PEI-1.8K chains into ESP via a bis-amide bond of pH-sensitivity to overcome high cytotoxicity and nontargeted gene delivery of PEI-25K. P53 gene was encapsulated in the ESP to form the codelivery system of ESP/p53 complexes, and this system was comprehensively characterized. In vitro ESP/p53 complexes had a significant effect on inhibiting angiogenesis by reducing the expression and secretion of VEGF. In vivo the effective antitumor activity of ESP/p53 complexes was observed on nude mice bearing PANC-1 xenografts, and the microvessel density (MVD) examination demonstrated that ESP/p53 complex-produced antitumor efficacy was closely correlated with the efficient angiogenesis repression. These findings disclosed that the multifunctional ESP/p53 complexes might be a promising dual anticancer drug and gene codelivery system.

We described here the mechanisms by which small interfering RNA (siRNA) molecules incorporated in reconstituted high density lipoprotein (rHDL) were efficiently transferred into the cytoplasm of cells to perform target-specific therapy of tumor angiogenesis. Using fluorescent-tagged apolipoprotein A-I (apoA-I) and cholesterol-conjugated siRNA (Chol-siRNA), it was confirmed with FACS and confocal microscopic measurements that Chol-siRNA-loaded rHDL nanoparticles (rHDL/Chol-siRNA complexes) were successfully established and apoA-I certainly was attached to the surface of Chol-siRNA-loaded lipoplexes (Lipos/Chol-siRNA complexes). Stably assembled rHDL/Chol-siRNA complexes demonstrated proper nanosize, quasi-spherical shape and improved nuclease protection over naked Chol-siRNA. It was also interesting to note that rHDL provided a highly effective approach to transfer Chol-siRNA across the membrane directly into the cytoplasm via the scavenger receptor BI (SR-BI)-mediated non-endocytotic mechanism, thereby bypassing endo-lysosomal trapping. We also showed clear evidence that the in vitro implementation of rHDL for Chol-siRNA-VEGF (Chol-siRNA targeting vascular endothelial growth factor gene) delivery markedly promoted RNA interference (RNAi)-mediated degradation of VEGF mRNA, resulting in down-regulation of secreted VEGF protein. In vivo fluorescence imaging indicated that near-infrared (NIR) dye Cy5 labeled Chol-siRNA-loaded rHDL nanoparticles (rHDL/Cy5-Chol-siRNA complexes) displayed long circulation time, SR-BI positive tumor-selective targeting, and efficient cytosolic delivery capabilities. Furthermore, intravenous administration of Chol-siRNA-VEGF-loaded rHDL nanoparticles (rHDL/Chol-siRNA-VEGF complexes) significantly enhanced anti-tumor efficacy against breast cancer, decreased VEGF expression level, and inhibited formation of intratumoral microvessels at the tumor tissue. It was concluded that rHDL possessed therapeutic potential and versatility in mediating Chol-siRNA-VEGF direct cytosolic delivery for target-specific anti-angiogenic therapy in breast cancer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Gastro-floating tablets of cephalexin were developed to prolong the residence time in major absorption sites. Gastro-floating tablets were prepared and optimized using hydroxypropyl methylcellulose (HPMC K100M) as matrix and sodium bicarbonate as a gas-forming agent. The properties of the tablets in terms of floating lag time, floating time and in vitro release were evaluated. Furthermore, in vivo pharmacokinetic study in fed and fasted beagle dogs was performed. The gastro-floating tablets had short floating lag time and exhibited a satisfactory sustained-release profile in vitro. Compared with conventional capsules, the gastro-floating tablets presented a sustained-release behavior with a relative bioavailability of 99.4%, while the reference sustained-release tablets gave a relative bioavailability of only 39.3%. Meanwhile, the food had significant effect on the pharmacokinetics of sustained-release tablets. It was concluded that the gastro-floating tablets had a sustained-release effect in vitro and in vivo, as well as desired pharmacokinetic properties in both fed and fasted conditions., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In the present study, we prepared an inclusion complex of methotrexate (MTX) with β-cyclodextrin (β-CD) in order to decrease its photosensitivity and enhance its aqueous solubility. Then we incorporated this inclusion complex in a self-microemulsifying drug delivery system (SMEDDS) overall to increase its oral bioavailability. The inclusion complex has been prepared by freeze drying method and characterized by differential scanning calorimetry (DSC), ultraviolet (UV), and infrared (IR) spectroscopy assays. The proper molecular ratio of MTX/β-CD was found to be of 1:7, and the water-solubility of MTX was increased in an average of 10-fold. The photostability studies showed that the MTX became stable on exposure to light. Construction of pseudoternary diagrams were investigated to prepare a MTX/β-CD inclusion complex loaded SMEDDS which was characterized by measuring the particle size and the zeta-potential. The optimum formulation of SMEDDS was a system consisting of ethyl oleate, tween 80, and propylene glycol with a mean droplet size of 39.42 nm. In vitro drug release in different pH media showed that the release profile of MTX from the MTX/β-CD loaded SMEDDS was influenced by the pH of the release medium and presented the characteristics of a sustained release profile. Finally, in-vivo studies showed an enhancement of the bioavailability of MTX from the MTX/β-CD loaded SMEDDS form of 1.57-fold. We concluded that the β-CD inclusion complex loaded SMEDDS improved the chemical and physiological properties of MTX and could be a promising means for the delivery of MTX and other unstable and lipophilic drugs by oral route.

Glycyrrhetinic acid-graft-hyaluronic acid (HGA) conjugate was synthesized as a carrier for intravenous administration of paclitaxel (PTX), which combined hyaluronic acid (HA) and glycyrrhetinic acid (GA) as the active targeting ligands to liver tumor. In the present study, physicochemical characteristics, cellular uptake efficiency, and in vivo fates of HGA conjugates were investigated. HGA nanoparticles could readily load PTX with high efficiency up to 31.16 wt.% and entrapment efficiency to 92.02%. Moreover, PTX-loaded HGA nanoparticles exhibited more significant cytotoxicity to HepG2 cells than B16F10 cells due to simultaneously over-expressing HA and GA receptors. Meanwhile, the cellular uptake of nanoparticles was clearly enhanced in HepG2 and B16F10 cells compared to a normal fibroblast cell (HELF cells). In particular, more HGA nanoparticles were taken up by HepG2 cells than by B16F10 cells, which might be attributed to the affinity of multiple ligands of HA and GA to HepG2 cells. Furthermore, liver and tumor targeting activity of HGA nanoparticles was also confirmed by in vivo imaging analysis. The fluorescence signals of DiR-labeled HGA nanoparticles in tumor and liver were 2.88 and 1.83 folds stronger than that of the control, respectively. These results indicate HGA nanoparticles can be a potential drug carrier with "double target sites" for liver cancer therapy., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In this study, a ligand-PEG-lipid conjugate, octreotide-polyethene glycol-deoxycholic acid (OCT(Phe)-PEG-DOCA, or OPD) was successfully synthesized and used as a targeting molecule for N-deoxycholic acid-O, N-hydroxyethylation chitosan (DAHC) micelles for efficient cancer therapy. DAHC micelles exhibited good loading capacities for doxorubicin (DOX), a model anti-cancer drug, and the modification of OPD showed no significant effect on drug load while slightly increasing the particle size and partly shielding the positive charges on the surface of micelles. Accelerated release rate of DOX from micelles were also observed after OPD modification and the release profile exhibited pH-sensitive properties. Compared with DAHC-DOX micelles, OPD-DAHC-DOX micelles exhibited significantly stronger cytotoxicity to MCF-7 cells (SSTRs overexpression) but with hardly any difference from WI-38 cells (no SSTRs expression). The results of flow cytometry and confocal laser scanning microscopy further revealed that OPD-DAHC-DOX micelles could be selectively taken into tumor cells by SSTRs-mediated endocytosis. In vivo investigation of micelles on nude mice bearing MCF-7 cancer xenografts confirmed that OPD-DAHC micelles possessed much higher tumor-targeting capacity than the DAHC control and exhibited enhanced anti-tumor efficacy and decreased systemic toxicity. These results suggest that OPD-DAHC micelles might be a promising anti-cancer drug delivery carrier for targeted cancer therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Amphiphilic low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate, as a drug carrier for cancer therapy, was found to have markedly low toxicity and to form self-assembled nanoparticles for simultaneous delivery of paclitaxel (PTX) and all-trans-retinoid acid (ATRA) in our previous study. In the present study, PTX-loaded LHR nanoparticles were prepared and demonstrated a spherical shape with particle size of 108.9 nm. Cellular uptake analysis suggested rapid internalization and nuclear transport of LHR nanoparticles. In order to investigate the dynamic behaviors and targeting ability of LHR nanoparticles on tumor-bearing mice, near-infrared fluorescent (NIFR) dye DiR was encapsulated into the nanoparticles for ex vivo optical imaging. The results indicated that LHR nanoparticles could enhance the targeting and residence time in tumor site. Furthermore, in vivo biodistribution study also showed that the area under the plasma concentration time curve (AUC (0→inf)) values of PTX and ATRA for PTX-loaded LHR nanoparticles in tumor were 1.56 and 1.62-fold higher than those for PTX plus ATRA solution. Finally, PTX-loaded LHR nanoparticles demonstrated greater tumor growth inhibition effect in vivo without unexpected side effects, compared to PTX solution and PTX plus ATRA solution. These results suggest that PTX-loaded LHR nanoparticles can be considered as promising targeted delivery system for combination cancer chemotherapy to improve therapeutic efficacy and minimize adverse effects., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A targeted intracellular delivery system of paclitaxel (PTX) was successfully developed based on redox-sensitive hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates. The conjugates self-assembled into nano-size micelles in aqueous media and exhibited excellent drug-loading capacities (34.1%) and entrapment efficiency (93.2%) for PTX. HA-ss-DOCA micelles were sufficiently stable at simulated normal physiologic condition but fast disassembled in the presence of 20 mm reducing agent, glutathione. In vitro drug release studies showed that the PTX-loaded HA-ss-DOCA micelles accomplished rapid drug release under reducing condition. Intracellular release of fluorescent probe nile red indicated that HA-ss-DOCA micelles provide an effective approach for rapid transport of cargo into the cytoplasm. Enhanced cytotoxicity of PTX-loaded HA-ss-DOCA micelles further confirmed that the sensitive micelles are more potent for intracellular drug delivery as compared to the insensitive control. Based on flow cytometry and confocal microscopic analyses, observations revealed that HA-ss-DOCA micelles were taken up to human breast adenocarcinoma cells (MDA-MB-231) via HA-receptor mediated endocytosis. In vivo investigation of micelles in tumor-bearing mice confirmed that HA-ss-DOCA micelles possessed much higher tumor targeting capacity than the insensitive control. These results suggest that redox-sensitive HA-ss-DOCA micelles hold great potential as targeted intracellular delivery carriers of lipophilic anticancer drugs., (Copyright © 2011. Published by Elsevier Ltd.)

For a long time, people have been looking forward to being able to clinically deliver bio-drugs systemically by a noninvasive method. Here, we show that a synthetic peptide, TD (ACSSSPSKHCG) was efficient in transferring human growth hormone (GH) across various kinds of membranes and the blood-brain barrier (BBB) in vivo via rectal administration, resulting in elevation of GH level in serum, acetylcholine and O-choline acetyltransferase activities and GH /IGF-1 contents in brain tissues, manifesting great therapeutic effects on chronic age-related dementia in mice and ameliorating neuronal damage in the brain. Furthermore, the effects of Aβ and TD/GH on LDH release, apoptosis and its relevant gene expression, involving bcl-2 and bax/caspase-3, were observed in a human neuroblastoma cell line (SH-SY5Y). Results indicated that GH decreased LDH release, apoptosis, and bax/caspase-3 activity, and increased bcl-2 expression compared with Aβ treatment, moreover, TD/GH may enhance the effects due to existence of TD, which might be dependent on TD assisted cross-membrane delivery of GH. The transdermal/transmembrane-enhancing activity of the TD peptide was also manifested on porcine abdominal skin in vivo and the murine embryonic fibroblast cell line (3T3 cell) in vitro, which was further shown through interaction between TD and lecithin (one constituent of the cell membrane) by ESI-MS. In conclusion, TD/GH counteracted brain defects in aged mice in vivo and cell apoptosis induced by Aβ in vitro might explain several underlying mechanisms by which GH could ameliorate learning and memory deficits in aged mice. Mixed TD/GH transmembrane delivery might be a promising therapy of Alzheimer's disease., (© 2010 Wiley-Liss, Inc. and the American Pharmacists Association)

A novel albumin derivative octyl modified serum albumin (OSA) which can form a core-shell structure in aqueous media by self-assembling due to core segregation and a combination of intermolecular forces has been synthesized. The chemical structure and physical properties of OSA were characterized by FTIR, (1)H NMR and TG. The degree of substitution (DS) was in the range of 52.4-69.7% and 48.9-65.8% determined by elemental analysis and fluorescamine assay, respectively. With the increase in the DS of octyl group, the critical micelle concentration (CMC) decreased from 30.1 to 14.7 mg/L because of the increasing hydrophobicity. In the light of the hydrophobic core as a microreservoir for poorly water-soluble drugs, paclitaxel (PTX) was successfully loaded into OSA micelles by the dialysis method with a high drug-loading (33.1 wt%) and entrapment efficiency (90.5%) due to the synergistic effect of micellar encapsulation and binding interaction between drug and OSA. Compared with PTX-loaded unmodified BSA preparation, PTX-loaded OSA micelles are characterized by small size, narrow size distribution, great drug-loading capacity and enhanced stability. The size of PTX-loaded micelles was in the range of 123.3-152.8 nm and smaller than their corresponding blank micelles. Hemolysis and cytotoxicity studies showed that OSA was safer than Tween-80 and Cremophor EL as an injectable pharmaceutic adjuvant for PTX. In terms of the greater drug-loading capacity and safer character, the novel albumin derivative OSA is a prospective injectable delivery system for PTX.

Three-dimensional printing technology has fundamentally revolutionized the product development processes in several industries. Three-dimensional printing enables the creation of tailored prostheses and other medical equipment, anatomical models for surgical planning and training, and even innovative means of directly giving drugs to patients. Polymers and their composites have found broad usage in the healthcare business due to their many beneficial properties. As a result, the application of 3D printing technology in the medical area has transformed the design and manufacturing of medical devices and prosthetics. Polymers and their composites have become attractive materials in this industry because of their unique mechanical, thermal, electrical, and optical qualities. This review article presents a comprehensive analysis of the current state-of-the-art applications of polymer and its composites in the medical field using 3D printing technology. It covers the latest research developments in the design and manufacturing of patient-specific medical devices, prostheses, and anatomical models for surgical planning and training. The article also discusses the use of 3D printing technology for drug delivery systems (DDS) and tissue engineering. Various 3D printing techniques, such as stereolithography, fused deposition modeling (FDM), and selective laser sintering (SLS), are reviewed, along with their benefits and drawbacks. Legal and regulatory issues related to the use of 3D printing technology in the medical field are also addressed. The article concludes with an outlook on the future potential of polymer and its composites in 3D printing technology for the medical field. The research findings indicate that 3D printing technology has enormous potential to revolutionize the development and manufacture of medical devices, leading to improved patient outcomes and better healthcare services. [ABSTRACT FROM AUTHOR]

Nanocarriers capable of circumventing various biological barriers between the site of administration and the therapeutic target hold great potential for cancer treatment. Herein, a redox-sensitive, hyaluronic acid-decorated graphene oxide nanosheet (HSG) is developed for tumor cytoplasm-specific rapid delivery using near-infrared (NIR) irradiation controlled endo/lysosome disruption and redox-triggered cytoplasmic drug release. Hyaluronic acid (HA) modification through redox-sensitive linkages permits HSG a range of advantages over the standard graphene oxide, including high biological stability, enhanced drug-loading capacity for aromatic molecules, HA receptor-mediated active tumor targeting, greater NIR absorption and thermal energy translation, and a sharp redox-dependent response for accelerated cargo release. Results of in vivo and in vitro testing indicate a high loading of doxorubicin (DOX) onto HSG. Selective delivery to HA-receptor overexpressing tumors is achieved through passive and active targeting with minimized unfavorable interactions with blood components. Cytoplasm-specific DOX delivery is then achieved through NIR controlled endo/lysosome disruption along with redox-triggered release of DOX in glutathione rich areas. HSG's specificity is resulted in enhanced cytotoxicity of chemotherapeutics with minimal collateral damage to healthy tissues in a xenograft animal tumor model. HSG is validated the programmed delivery of therapeutic agents in a spatiotemporally controlled manner to overcome multiple biological barriers results in specific and enhanced cancer treatment. [ABSTRACT FROM AUTHOR]

Context: Gambogic acid (GA) can inhibit the growth of various cancer cells. However, the low bioavailability caused by insolubility, limits its clinical application. L-arginine is always used with GA to form a complex to obtain the higher solubility. Moreover, guanidyl group from arginine, which can facilitate the cellular uptake, was identified. Objective: In this study, L-arginine and chitosan (CS) were used for the first time to prepare N-octyl-N-arginine CS (OACS), a novel amphiphilic carrier for GA with solubility- and absorption-enhancing functions; the characterization of the GA loaded OACS micelles (GA-OACS) and its absorption-enhancing effect were also investigated. Materials and methods: GA-OACS were prepared by the dialysis method. The formed micelles were characterized and evaluated by atomic force microscope (AFM), dynamic light scattering, differential scanning calorimeter (DSC), solubility test, in vitro release and in situ intestinal perfusion. Results: The GA-OACS micelles were successfully prepared attaining a 35.3% drug loading and 82.2% entrapment efficiency. GA-OACS had a homogeneous particle size of 160.3 nm; +21.8 mv zeta potential with smooth continuous surface was observed by using AFM. DSC diagram suggested that GA was encapsulated in the micelles. Meanwhile, GA encapsulated in micelles exhibited a desirable slow release in vitro experiment. The solubility of GA in OACS micelles was increased up to 3.16 ± 0.13 mg/mL, 2320 times than that of free GA. The single pass perfusion showed that the absorption of GA-OACS micelles was enhanced 3.6-fold, 2.1-fold and 2.2-fold for jejunum, ileum and colon, respectively. Discussion and conclusion: OACS provided excellent ability of drug loading, increasing solubility and enhanced absorption for GA, which indicated that OACS micelles as an oral drug delivery carrier may have potential research and application values. [ABSTRACT FROM AUTHOR]

A programmed drug-delivery system that can transport different anticancer therapeutics to their distinct targets holds vast promise for cancer treatment. Herein, a core-shell-based 'nanodepot' consisting of a liposomal core and a crosslinked-gel shell (designated Gelipo) is developed for the sequential and site-specific delivery (SSSD) of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and doxorubicin (Dox). As a small-molecule drug intercalating the nuclear DNA, Dox is loaded in the aqueous core of the liposome, while TRAIL, acting on the death receptor (DR) on the plasma membrane, is encapsulated in the outer shell made of crosslinked hyaluronic acid (HA). The degradation of the HA shell by HAase that is concentrated in the tumor environment results in the rapid extracellular release of TRAIL and subsequent internalization of the liposomes. The parallel activity of TRAIL and Dox show synergistic anticancer efficacy. The half-maximal inhibitory concentration (IC50) of TRAIL and Dox co-loaded Gelipo (TRAIL/Dox-Gelipo) toward human breast cancer (MDA-MB-231) cells is 83 ng mL-1 (Dox concentration), which presents a 5.9-fold increase in the cytotoxicity compared to 569 ng mL-1 of Dox-loaded Gelipo (Dox-Gelipo). Moreover, with the programmed choreography, Gelipo significantly improves the inhibition of the tumor growth in the MDA-MB-231 xenograft tumor animal model. [ABSTRACT FROM AUTHOR]

Highlights: A combined assembly strategy from hydrophobicity-driving and reversible borate bridges is proposed for high drug-loading efficiency and superior stability. Intestinal environment-triggered drug delivery system represents an effective treatment for local infection due to the site-specific targeting and shuttling of drugs. The reduced dosage brought by the drug-loading micelles could solve the problem of drug residue in breeding industry. Stimuli-triggered drug delivery systems hold vast promise in local infection treatment for the site-specific targeting and shuttling of drugs. Herein, chitosan conjugates (SPCS) installed with sialic acid (SA) and phenylboronic acid (PBA) were synthesized, of which SA served as targeting ligand for coccidium and reversible-binding bridge for PBA. The enhanced drug-loading capacity of SPCS micelles was attributed to a combination assembly from hydrophobicity-driving and reversible borate bridges. The drug-loaded SPCS micelles shared superior biostability in upper gastrointestinal tract. After reaching the lesions, the borate bridges were snipped by carbohydrates under a higher pH followed by accelerated drug release, while SA exposure on micellar surface facilitated drug cellular internalization to eliminate parasites inside. The drug-micelles revealed an enhanced anti-coccidial capacity with a higher index of 185.72 compared with commercial preparation. The dual-responsive combination of physicochemical assembly could provide an efficient strategy for the exploitation of stable, safe and flexible anti-infectious drug delivery systems. [ABSTRACT FROM AUTHOR]

Abstract: A new series of amphiphilically modified chitosan molecules with long alkyl chains as hydrophobic moieties and glycol groups as hydrophilic moieties (N-octyl-O-glycol chitosan, OGC) was synthesized for use as drug carriers. The chemical structure was characterized by Fourier transform infrared, 1H nuclear magnetic resonance, and elemental analysis. OGC could easily self-assemble to form nanomicelles in an aqueous environment and exhibited a low critical micellar concentration of 5.3–32.5mg/L. The biocompatibility and low toxicity of OGC as excipient for the dosage forms aimed at i.v. administration were confirmed by hemolysis, acute toxicity and histopathological studies. Furthermore, the possibility of solubilizing paclitaxel (PTX), a water-insoluble antitumor drug, with OGC micelles was also explored. PTX was successfully loaded into OGC micelles by using a simple dialysis process. The drug-loading capacity of OGC and stability of drug-loaded micelles were significantly affected by the degree of substitution of alkyl chains. Moreover, a series of safety studies including hemolysis, hypersensitivity, maximum tolerated dose, acute toxicity, and organ toxicity revealed that the PTX-loaded OGC micelles had advantages over the commercially available injectable preparation of PTX (Taxol®), in terms of low toxicity levels and increased tolerated dose. Additionally, cytotoxicity studies showed that the PTX-loaded OGC micelles were comparable to the commercial formulation, but the blank micelles were far less toxic than the Cremophor EL vehicle. These results suggest that OGC is a promising carrier for injectable PTX micelles. [Copyright &y& Elsevier]

The inverse correlation between high-density lipoprotein (HDL) levels in vivo and the risk of Alzheimer's disease (AD) has become an inspiration for HDL-inspired AD therapy, including plain HDL and various intelligent HDL-based drug delivery systems. In this review, we will focus on the two endogenous HDL subtypes in the central nervous system (CNS), apolipoprotein E-based HDL (apoE-HDL) and apolipoprotein A-I-based HDL (apoA-I-HDL), especially their influence on AD pathophysiology to reveal HDL's potential as biomarkers for risk prediction, and summarize the relevant therapeutic mechanisms to propose possible treatment strategies. We will emphasize the latest advances of HDL as therapeutics (plain HDL and HDL-based drug delivery systems) to discuss the potential for AD therapy and review innovative techniques in the preparation of HDL-based nanoplatforms to provide a basis for the rational design and future development of anti-AD drugs. [Display omitted] • High-density lipoprotein affects the progression of Alzheimer's disease through multiple mechanisms. • High-density lipoprotein demonstrates potential as biomarkers for risk prediction of Alzheimer's disease. • The advances of high-density lipoprotein as potential therapeutics for Alzheimer's disease therapy are summarized. [ABSTRACT FROM AUTHOR]

Abstract Chemo-immunotherapy represents an appealing approach to improving cancer treatment. Simultaneously administrating chemotherapeutics with immunoadjuvants can elicit potent tumor death and immune responses. Herein, high density lipoprotein (HDL) inspired immune lipoprotein was proposed for relay drug delivery and amplifying antitumor therapy. Lipophilic AS1411 aptamer-immunoadjuvant CpG fused sequences (Apt-CpG-DSPE) were conjugated to facilitate decoration onto HDLs; and doxorubicin (Dox) was successively intercalated into the consecutive base pairs of Apt-CpG to complete immune HDL nanodrug imHDL/Apt-CpG-Dox. For relay drug delivery, imHDL/Apt-CpG-Dox underwent site-specific structure collapse in tumor intercellular substances inspired from HDL biofunctions (sequential module I); subsequently, dissociated Apt-CpG-Dox was endocytosed into tumor cells mediated by the recognition of AS1411 and nucleolin (sequential module II), translocating Dox to nucleus and enabling tumor ablation and antigens release. The liberated CpG motif further evoked antigen recognition, induced vast secretion of pro-inflammatory cytokines and potentiated host antitumor immunity. Our studies demonstrated that HDL biomimetic platform based relay drug delivery strategy outperformed the monotherapy counterparts in malignant tumor models, eventually generating an augmented antitumor efficacy. [ABSTRACT FROM AUTHOR]

Metastatic cancer is difficult to defeat with current treatments due to lack of etiological therapeutics and efficient delivery platforms. Employing tumor microenvironment in programming intelligent nanosystems has attracted considerable attention for combinative antitumor therapy. Herein, we proposed a core-shell based drug depot consisting of micellar core and crosslinked-gel shell for site-specific shuttling of paclitaxel (PTX) and KIAA1199 specific shRNA (shKIAA). Poly (e-caprolactone) were grafted with branched polyethylenimine (PEI-PCL) as micellar core, into which hydrophobic PTX was embedded; while shKIAA, a reliable RNAi regimen for metastatic cell inhibition was condensed with PEI through electrostatic interaction; and then photo-crosslinked hyaluronic acid (m-HA) was further coated as shell. The nanoscale drug depot shared HAase-triggered charge switching and desirable release profile. Upon reaching tumor region, HA shell was degraded by concentrated HAase, and facilitated drug shuttling to individual subcellular targeting site. Rapid intracellular trafficking of micellar core achieved endo/lysosomal escape and cytoplasmic liberation. The half-maximal inhibitory concentration (IC 50 ) of “nanodepot” toward human breast cancer cell line MDA-MB-231 was 0.016 μg/mL (PTX concentration), approximately 3-fold decrease compared to that of monotherapy group (0.043 μg/mL). The tumor weight inhibition (TWI) is 83.30% in xenografted MDA-MB-231 tumor model and metastasis was effectively inhibited in 4T1 orthotopic tumors. Moreover, knockdown of KIAA1199 via sustainable RNAi affected a broad range of cellular functions including apoptosis, migration and invasion. Collectively, tumor environment differentiated spatiotemporal co-delivery fashion holds a great promise for combinative treatment with enhanced efficacy on metastatic cancer cases. [ABSTRACT FROM AUTHOR]

Herein, thioglycolic acid modified N-octyl-O, N′-glycol chitosan (N-mercapto acetyl-N′-octyl-O, N″-glycol chitosan, abbreviated as SH-OGC) was synthesized to improve the oral bioavailability of paclitaxel (PTX). PTX was readily solubilized into the hydrophobic inner core of SH-OGC. Pharmacokinetic studies demonstrated that the bioavailability of PTX was greatly enhanced when delivered by SH-OGC compared to Taxol ® or non-sulfhydrylated OGC micelles. Caco-2 cell experiments confirmed PTX or rhodamine-123-loaded SH-OGC demonstrated effective cellular accumulation via caveola-mediated endocytosis along with the inhibition of P-gp efflux. Furthermore, Caco-2 transport studies demonstrated that the mechanistic basis of SH-OGC efficacy was attributed to P-gp inhibition, enhanced permeability of tight junctions and clathrin-mediated transcytosis across the endothelium. In addition, SH-OGC exhibited increased intestinal retention through thiol-mediated mucoadhesion compared with OGC according to results of mucoadhesion evaluation on freshly excised rat intestine. In summary, SH-OGC micelles may present as a promising delivery vehicle for enhancing the oral bioavailability of P-gp substrates. [ABSTRACT FROM AUTHOR]

Multi-walled carbon nanotube (MWNT) with its versatility has exhibited tremendous superiority in drug delivery. Despite plenty of researches on MWNT based delivery systems, precision-guided assistances to maximize their profitable properties are still lacking in substantive progress. We developed here a dual-targeting and co-delivery system based on MWNT for antiangiogenesis therapy in lung cancer which aimed at renin-angiotensin system (RAS) dysregulation by synergistically conducting angiotensin II type 1 receptor (AT 1 R) and type 2 receptor (AT 2 R) pathway. In this work, iRGD peptide connected to polyethyleneimine (PEI) was linked to MWNT skeleton, accompanying with candesartan (CD) conjugated to MWNT mediated by cystamine (SS). The functionalized MWNT is assembled with plasmid AT 2 (pAT 2 ) to form iRGD-PEI-MWNT-SS-CD/pAT 2 complexes. iRGD and CD act as pilots for complexes to dually target symbolic ανβ3-integrin and AT 1 R both overexpressed on tumor angiogenic endothelium and lung cancer cell. CD as chemotherapy showed synergistic downregulation of VEGF when combining of pAT 2 and efficiently inhibited angiogenesis. iRGD-PEI-MWNT-SS-CD/pAT 2 complexes greatly appreciated drug activities by changing drug distribution and exhibited remarkable tumor growth suppression in A549 xenograft nude mice. Our work presents that such dual-targeting strategy highly improves the delivery performance of MWNT and open a new avenue for RAS related lung cancer therapy. [ABSTRACT FROM AUTHOR]

Many nanoparticle matrixes have been demonstrated to be efficient in brain targeting, but there are still certain limitations for them. To overcome the shortcomings of the existing nanoparticulate systems for brain-targeted delivery, a lipoprotein resembling protein-free nanostructured lipid carrier (PS80-NLC) loaded with curcumin was constructed and assessed for in vitro and in vivo performance. Firstly, single factor at a time approach was employed to investigate the effects of various formulation factors. Mean particle sizes of ≤100 nm, high entrapment efficiency (EE, about 95%) and drug loading (DL, >3%) were obtained for the optimized formulations. In vitro release studies in the presence of plasma indicated stability of the formulation under physiological condition. Compared with NLC, PS80-NLC showed noticeably higher affinity for bEnd.3 cells (1.56 folds greater than NLC) but with lower uptake in macrophages. The brain coronal sections showed strong and widely distributed fluorescence intensity of PS80-NLC than that of NLC in the cortex. Ex vivo imaging studies further confirmed that PS80-NLC could effectively permeate BBB and preferentially accumulate in the brain (2.38 times greater than NLC). The considerable in vitro and in vivo performance of the safe and biocompatible PS80–NLC makes it a suitable option for further investigations in brain targeted drug delivery. [ABSTRACT FROM AUTHOR]

Since its approval by the FDA, Abraxane™ has been established as a clinical standard of paclitaxel (PTX)-based therapy against a variety of cancers. Despite success, Abraxane™ is still limited by suboptimal biodistribution, unfavorable pharmacokinetics and chronic toxicities from chloroform used during preparation. Accordingly, a PTX-loaded nanosuspension based on human serum albumin (HSA) with PEG modifiers (PTX-PEG-HSA) has been developed to optimize the in-vivo biodistribution, pharmacokinetics and safety of PTX over traditional PTX-HSA nanosuspensions prepared using the accepted method for Abraxane™. Results of in-vivo pharmacokinetic (PK) studies indicated PTX-PEG-HSA achieved prolonged blood circulation, illustrated by an 8.8-fold and 4.8-fold increase in area-under-the-curve (AUC) of PTX over Taxol® and PTX-HSA, while the mean residence time (MRT) of PTX in PTX-PEG-HSA was increased by 3.2-fold and 1.5-fold, respectively. HSA mediated active targeting further suppressed non-specific distribution of PTX to normal tissues, which permitted enhanced antitumor efficacy in S180 mice over Taxol® and PTX-HSA. Safety of intravenously administered PTX-PEG-HSA was confirmed through lower hemolytic activity, a 2.2-fold and 1.2-fold increase in LD 50 (113.4 mg/kg) over Taxol® and PTX-HSA alongside the absence of local venous irritation. Studies herein suggest the therapeutic and clinical applicability of PTX-PEG-HSA for tumor specific therapy. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop a novel featured and flexible methotrexate (MTX) formulation, in which MTX was physically entrapped and chemically conjugated in the same drug delivery system. A series of poloxamer–MTX (p–MTX) conjugates was synthesized, wherein MTX was grafted to poloxamer through an ester bond. p–MTX conjugates could self-assemble into micelle-like structures in aqueous environment and the MTX end was in the inner-core of micelles. Moreover, free MTX could be physically entrapped into p–MTX micelles hydrophobic core region to increase the total drug loading. Importantly, the resulting MTX-loaded p–MTX micelles showed a biphasic release of MTX, with a relative fast release of the entrapped MTX (about 6–7 h) followed by a sustained release of the conjugated MTX. The pharmacokinetics study showed that the mean residence time (MRT) was extended in the case of MTX-loaded p–MTX micelles, indicating a delayed MTX elimination from the bloodstream and prolonged in vivo residence time. Besides, the area under curve (AUC) of MTX-loaded p–MTX micelles was greater than free MTX, indicating a drug bioavailability improvement. Overall, MTX-loaded p–MTX micelles might be a promising nanosized drug delivery system for the cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Protein stabilized polymeric nanoparticles for optimal multi-drug shielding and compatibility. • Relay delivery of chemotherapeutics and genetic drugs in tumour cells for tackling chemotherapy promoted metastasis. • Advanced therapeutic efficacy of primary tumour shrinkage and complete metastatic nodule elimination. The pro-metastatic potential of chemotherapy limits its therapeutic benefits against invasive cancer. Herein, a protein stabilized polymeric nanoparticle inspired relay drug delivery platform was developed to address post-chemotherapeutic metastasis. An ROS-responsive Phenylboronic acid (PBA)-Rich cationic polymer (RPP) bridges Doxorubicin (Dox) coordination and Snail-targeted siRNA (siSnail) compression, and natural apolipoprotein A-I (apoA-I) is attracted by surface electron-deficient PBA moieties for nanoparticle shaping, drug biostability, and tumour-penetration. The spatially-separated structure enables a timing-controlled relay drug delivery in tumour cells, where Dox gives a prior release phase by acidity, and RPP polymer is subsequently disintegrated by concentrated ROS for rapid siSnail liberation. In dual therapy, Dox pre-treatment upregulated pro-metastatic factors and aggravated metastasis, but subsequent liberation by siSnail silenced the central metastatic regulator of Epithelial-mesenchymal transition (EMT). The terminal nanoparticles exhibited advanced therapeutic efficacy, achieving primary tumour shrinkage (tumour weight inhibition, TWI of ~86.15%) and complete metastatic nodule elimination. This work promises to improve the clinical benefits of chemotherapy against invasive cancer. [ABSTRACT FROM AUTHOR]

Octreotide (OCT) was recently found to have a high binding affinity for the somatostatin receptor expressed on tumor cells. In this study, OCT-polyethylene glycol-stearic acid (OCT-Phe-PEG-A) was used as a targeting molecule for N-octyl-O, N-carboxymethyl chitosan (OCC) micelles loaded with doxorubicin (DOX). For in vivo fluorescence imaging, the fluorescent probe Cyanine 7 (Cy7) was successfully loaded into OCC micelles with or without OCT modification (Cy7-OCC, Cy7-OCC-OCT), and their physicochemical properties were compared with DOX-loaded micelles (DOX-OCC and DOX-OCC-OCT). All micelles were less than 120 nm with spherical shape and zeta potential of around −30 mV. Enhanced tumor-targeting capacity of OCC-OCT micelles was observed in BALB/c nude mice bearing MCF-7 cancer xenografts as compared with the OCC micelles. Moreover, pharmacodynamic studies demonstrated that DOX-OCC-OCT presented a strongest inhibition of tumor growth and lowest systemic toxicity compared with the DOX solution and DOX-OCC micelles. All the results indicated that OCC-OCT micelles might be a promising tumor-targeting carrier for cancer therapy. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:126-135, 2013 [ABSTRACT FROM AUTHOR]