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Electrospun polymeric micro/nanofibrous scaffolds have been investigated extensively as drug delivery platforms capable of controlled and sustained release of therapeutic agents in situ . Such scaffolds exhibit excellent physicochemical and biological properties and can encapsulate and release various drugs in a controlled fashion. This article reviews recent advances in the design and manufacture of electrospun scaffolds for long-term drug release, placing particular emphasis on polymer selection, types of incorporated drugs and the latest drug-loading techniques. Finally, applications of such devices in traumatic or disease states requiring effective and sustained drug action are discussed and critically appraised in their biomedical context. [ABSTRACT FROM AUTHOR]

Near infrared (NIR) light allows deep tissue penetration and high spatial resolution due to the reduced scattering of long-wavelength photons. NIR light-activatable polymer nanoparticles are widely exploited for enhanced cancer imaging (diagnosis) and therapy owing to their superior photostability, photothermal conversion efficiency (or high emission rate), and minimal toxicity to cells and tissues. This review surveys the most recent advances in the synthesis of different NIR-absorbing and emissive polymer nanoformulations, and their applications for cancer imaging, photothermal therapy, theranostics and combination therapy by delivering multiple small molecule chemotherapeutics. Photo-responsive drug delivery systems for NIR light-triggered drug release are also discussed with particular emphasis on their molecular designs and formulations as well as photo-reaction mechanisms. Finally, outlook and challenges are presented regarding potential clinical applications of NIR light-activatable nanoformulations. [ABSTRACT FROM AUTHOR]

A new method for 3D in silico screening of large virtual combinatorial chemistry spaces is described. The software PharmShape screens millions of individual compounds applying a multi-conformational pharmacophore and shape based approach. Its extension, PharmShapeCC, is capable of screening trillions of compounds from tens of thousands of combinatorial libraries. Key elements of PharmShape and PharmShapeCC are customizable pharmacophore features, a composite inclusion sphere, library core intermediate clustering, and the determination of combinatorial library consensus orientations that allow for orthogonal enumeration of libraries. The performance of the software is illustrated by the prospective identification of a novel CXCR5 antagonist and examples of finding novel chemotypes from synthesizing and evaluating combinatorial hit libraries identified from PharmShapeCC screens for CCR1, LTA4 hydrolase, and MMP-13. [ABSTRACT FROM AUTHOR]

Novel multiresponsive microgels based on poly( N-isopropylacrylamide) were synthesized to contain triphenylmethane leucohydroxide, and used to construct etalons. The optical properties of the resultant etalons were investigated, and their response to ultraviolet and visible irradiation, solution pH changes, and the presence of a mimic of the nerve agent Tabun characterized. We clearly show that the optical properties of the device depended dramatically on these stimuli. This investigation illustrates the versatility of the microgel-based etalon structure, and showcases the clear utility of such devices for remote actuation, color tunable optics, sensing, and potential remotely triggered drug delivery applications. [ABSTRACT FROM AUTHOR]

Abstract: pH-sensitive polymeric nanoparticles are promising for oral drug delivery, especially for peptide/protein drugs and poorly water-soluble medicines. This review describes current status of pH-sensitive polymeric nanoparticles for oral drug delivery and introduces the mechanisms of drug release from them as well as possible reasons for absorption improvement, with emphasis on our contribution to this field. pH-sensitive polymeric nanoparticles are prepared mainly with polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of drug release are the result of carriers’ dissolution, swelling or both of them at specific pH. The possible reasons for improvement of oral bioavailability include the following: improve drug stability, enhance mucoadhesion, prolong resident time in GI tract, ameliorate intestinal permeability and increase saturation solubility and dissolution rate for poorly water-soluble drugs. As for the advantages of pH-sensitive nanoparticles over conventional nanoparticles, we conclude that (1) most carriers used are enteric-coating materials and their safety has been approved. (2) The rapid dissolution or swelling of carriers at specific pH results in quick drug release and high drug concentration gradient, which is helpful for absorption. (3) At the specific pH carriers dissolve or swell, and the bioadhesion of carriers to mucosa becomes high because nanoparticles turn from solid to gel, which can facilitate drug absorption. [Copyright &y& Elsevier]

With the advent of nanotechnology, DNA molecules have been transformed from solely genetic information carriers to multifunctional materials, showing a tremendous potential for drug delivery and disease diagnosis. In drug delivery systems, DNA is used as a building material to construct drug carriers through a variety of DNA self-assembly methods, which can integrate multiple functions to complete in vivo and in situ tasks. In this study, ladder-shaped drug carriers are developed for drug delivery on the basis of a DNA nanoladder. We first demonstrate the overall structure of the nanoladder, in which a nick is added into each rung of the nanoladder to endow the nanoladder with the ability to incorporate a drug loading site. The structure is designed to counteract the decrement of stability caused by the nick and investigated in different conditions to gain insight into the properties of the nicked DNA nanoladders. As a proof of concept, we fix the biotin in every other nick as a loading site and assemble the protein (streptavidin) on the loading site to demonstrate the feasibility of the drug-carrying function. The protein can be fixed stably and can be extended to different biological and chemical drugs by altering the drug loading site. We believe this design approach will be a novel addition to the toolbox of DNA nanotechnology, and it will be useful for versatile applications such as in bioimaging, biosensing, and targeted therapy. [ABSTRACT FROM AUTHOR]

Antibodies are not only an important class of biotherapeutic drugs, but also are targeting moieties for achieving active targeting drug delivery. Meanwhile, the rapidly increasing application of antibodies and Fc-fusion proteins has inspired the emerging development of downstream processing technologies. Thus, IgG Fc affinity ligands have come into being and have been widely exploited in antibody purification strategies. Given the high binding affinity and specificity to IgGs, binding stability in physiological medium conditions, and favorable toxicity and immunogenicity profiles, Fc affinity ligands are gradually applied to antibody delivery, non-covalent antibody–drug conjugates or antibody-mediated active-targeted drug delivery systems. In this review, we will briefly introduce IgG affinity ligands that are widely used at present and summarize their diverse applications in the field of antibody-involved drug delivery. The challenges and outlook of these systems are also discussed. [ABSTRACT FROM AUTHOR]

Peptides are considered as a new generation of drugs due to their high structural and functional diversity. However, the development of peptide drugs is always limited by their poor stability and short circulation time. Carriers are applied for peptide drug delivery, but there may be problems like poor loading efficiency and undesired xenobiotic toxicity. Peptide self-assembly is an effective approach to improve the stability and control the release of peptide drugs. In this study, two self-assembling anticancer peptides are designed by appending a pair of glutamic acid and asparagine to either the N-terminus or the C-terminus of a lytic peptide. This simple, yet rational sequence modification was made to change the amphiphilic pattern and secondary structural content of the parent peptide, thereby modulating its self-assembly process. It was found that the N-terminus modified peptide favors the formation of nanofibrils and the peptide with C-terminal modification formed micelles. Although both nanostructures showed prolonged action profiles and improved serum stability compared to the parent peptide, the morphology of the nanostructures is highly critical to manipulate the release profile of the free peptide from the assembly and regulate their bioactivity. We believe the self-assembly approach demonstrated in this study can be applied to a variety of therapeutic peptide drugs to improve their stability and therapeutic activity for the development of carrier-free drug delivery system. [ABSTRACT FROM AUTHOR]

A near infrared (NIR) light-responsive supramolecular hydrogel consisting of α-cyclodextrin and poly(ethylene glycol)-modified dendrimer-encapsulated platinum nanoparticles was developed. Upon NIR irradiation, this hydrogel underwent a photothermo-sensitive degradation to release the entrapped therapeutic agents in an on-demand and dose-tunable fashion. [ABSTRACT FROM AUTHOR]

Abstract: Multidrug resistance (MDR) in tumor cells is a significant obstacle for successful cancer chemotherapy. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is a key factor contributing to the development of tumor drug resistance. Verapamil (VRP), a P-gp inhibitor, has been reported to be able to reverse completely the resistance caused by P-gp. For optimal synergy, the drug and inhibitor combination may need to be temporally colocalized in the tumor cells. Herein, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel (PTX), along with VRP, using DOMC-FA micelles to overcome tumor drug resistance. The floate-functionalized dual agent loaded micelles resulted in the similar cytotoxicity to PTX-loaded micelles/free VRP combination and co-administration of two single-agent loaded micelles, which was higher than that of PTX-loaded micelles. Enhanced therapeutic efficacy of dual agent micelles could be ascribe to increased accumulation of PTX in drug-resistant tumor cells. We suggest that the synergistic effect of folate receptor-mediated internalization and VRP-mediated overcoming MDR could be beneficial in treatment of MDR solid tumors by targeting delivery of micellar PTX into tumor cells. As a result, the difunctional micelle systems is a very promising approach to overcome tumor drug resistance. [Copyright &y& Elsevier]

Abstract: Camptothecin (CPT) is a potent, broad spectrum antitumor agent that inhibits the activity of DNA topoisomerase I. Due to its poor solubility and stability and consequent delivery challenges, its clinical use is nevertheless limited. We aim to use nanocrystal formulation as a way to circumvent the difficult solubilization practice. Specifically, camptothecin nanocrystals were prepared with a sonication–precipitation method without additional stabilizing surfactants. Particle characteristics, cellular cytotoxicity, and animal antitumor effect were examined. CPT nanocrystals were tested to be more potent to MCF-7 cells than CPT solution in vitro. When tested in MCF-7 xenografted BALB/c mice, the CPT nanocrystals exhibited significant suppression of tumor growth. The drug concentration in the tumor was five times more at 24h by using the nanocrystal treatment than by using the drug salt solution. Storage stability study indicated that the nanocrystals were stable for at least six months. Overall, CPT nanocrystals were considered to be potentially feasible to overcome formulation challenges for drug delivery and to be used in clinic. [Copyright &y& Elsevier]

Abstract: Spherical mesocellular foam (MCF) with a continuous 3-D pore system was synthesized using Pluronic 123 triblock polymer (P123) as a surfactant coupled with cetyltrimethyl ammonium bromide (CTAB) as a co-surfactant. The feasibility of the prepared MCF nanoparticles for oral drug delivery was studied. A model drug, telmisartan (TEL), was loaded onto MCF via a procedure involving a combination of adsorption equilibrium and solvent evaporation. The drug-release rate and the drug loading efficiency of spherical MCF were compared with those of fibrous SBA-15. Investigations using nitrogen adsorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), wide-angle X-ray scattering (WXRS), differential scanning calorimetry (DSC) and HPLC demonstrated the successful incorporation of TEL into the MCF host. It is found that spherical MCF has a high drug loading efficiency up to 42.9% (drug weight/total weight) and higher than that of SBA-15 with a pore diameter of 6.5nm. It is shown that a fast release rate of TEL was obtained from MCF compared with SBA-15 and pure crystalline TEL using enzyme-free simulated gastric fluid (pH 1.2) and intestinal fluid (pH 6.8). We believe that the present study will help in the design of oral drug delivery systems for the dissolution enhancement of water-insoluble drugs. [ABSTRACT FROM AUTHOR]

Chemotherapy post cancer surgery has important clinical significance for reducing the chance of recurrent-metastasis. However, postoperative chemotherapy efficacy is hampered by poor targeting capability and dose-limiting toxicity of chemo-drugs. Herein, we report a bio-mimetic platelet membrane-cloaked paclitaxel nanocrystal system (PPNCs), which consists of spherical paclitaxel nanocrystals (PNCs) as a high-dose drug core, polyethylene glycol-conjugated paclitaxel (PEG-PTX) as an amphiphilic molecule to adjust the surface hydrophilicity of PNCs and the shell of platelet membrane that can target surgical coagulation site. The in vitro characterization of PPNCs exhibited uniform particle size distribution, high drug loading, and good stability, which are crucial for effective drug delivery. At cell levels, PPNCs showed greater cellular uptake and higher cytotoxicity in 4T1 breast cancer cells than bare PNCs. In vivo , the nanoparticles could deliver high-dose chemo-drugs and target the coagulation site caused by surgery or vascular disrupting agents, resulting in enhanced anti-tumor efficacy and reduced systemic toxicities. In general, the PPNCs system can be served as a promising and efficient drug delivery system for postoperative chemotherapy. The bio-mimetic platelet membrane-cloaked paclitaxel nanocrystal system (PPNCs) could carry high-dose chemo-drugs and target the coagulation site caused by surgery or vascular disrupting agents, resulting in enhanced anti-tumor efficacy and reduced systemic toxicities. Unlabelled Image • The bio-mimetic PPNCs consists of three components, drug nanocrystals, pegylated paclitaxel and platelet membrane shell. • PPNCs exhibited uniform particle size distribution, high drug loading, and good stability. • PPNCs retained the expression of specific platelet membrane proteins, collagen binding capacity with little risk of thrombi. • PPNCs could target the coagulation site caused by surgery or VDA, resulting in better anti-tumor effect and improved safety. [ABSTRACT FROM AUTHOR]

The surface chemistry and size of nanoparticles can greatly impact their interaction with biological pathways and alter efficacy. However, the interplay between surface modification and particle size has not been well investigated especially for oral delivery. It is necessary to maximize the bioavailability of loading therapeutics. Here, we prepared different sized mesoporous silica nanoparticles (100–500 nm) and conjugated them with polyethylenimine-coated carbon dots (PCD) for effective transepithelial absorption. The nanoparticles were also coated with polyethylene glycol (PEG) polymers for improved mucus permeability. These mesoporous silica nanoparticles conjugated to PCD and coated in PEG (MSN@PCD@PEG) were used to study the influence of particle size and surface chemistry on transepithelial transport and bioavailability. Results demonstrated that the MSN@PCD@PEG with a diameter 250 nm had the highest transepithelial transport and oral bioavailability compared to other formulations. Drug release, endocytosis pathways, transepithelial transport and degradation of these different nanocarriers were systematically studied in order to investigate effects of size variety. The findings indicated that nanoparticle-based oral drug delivery can be potentially improved by adjusting physicochemical properties. We believe that understanding the importance of surface chemistry and particle size in the oral delivery will improve nanoparticle engineering and oral application. [ABSTRACT FROM AUTHOR]

A distinctive and personalized nanocarrier is described here for controlled and targeted antitumor drug delivery and real-time bioimaging by combining a redox/enzyme dual-responsive disulfide-conjugated carbon dot with mesoporous silica nanoparticles (MSN-SS-CD HA ). The carbon dot with controlling and targeting abilities was prepared through a polymerizing reaction by applying citric acid and HA as starting materials (named CD HA ). The as-prepared MSN-SS-CD HA exhibited not only superior photostability and excellent biocompatibility, but also the ability to target A549 cells with overexpression of CD44 receptors. Upon loading the antitumor drug, doxorubicin (DOX), into the mesoporous channels of MSN nanoparticles, CD HA with a diameter size of 3 nm completely blocked the pore entrance of DOX-encapsulated MSN nanoparticles with a pore size of about 3 nm, thus preventing the premature leakage of DOX and increasing the antitumor activity until being triggered by specific stimuli in the tumor environment. The results of the cell imaging and cytotoxicity studies demonstrated that the redox/enzyme dual-responsive DOX-encapsulated MSN-SS-CD HA nanoparticles can selectively deliver and control the release of DOX into tumor cells. Ex vivo fluorescence images showed a much stronger fluorescence of MSN-SS-CD HA -DOX in the tumor site than in normal tissues, greatly facilitating the accumulation of DOX in the target tissue. However, its counterpart, MSN-SH-DOX exhibited no or much lower tumor cytotoxicity and drug accumulation in tumor tissue. In addition, MSN-SS-CD was also used as a control to investigate the ability of MSN-SS-CD HA to target A549 cells. The results obtained indicated that MSN-SS-CD HA possessed a higher cellular uptake through the CD44 receptor-mediated endocytosis compared with MSN-SS-CD in the A549 cells. Such specific redox/enzyme dual-responsive targeted nanocarriers are a useful strategy achieving selective controlled and targeted delivery of therapeutic reagents with real-time bioimaging, and may also facilitate the development of drug delivery systems for a number of clinical applications. [ABSTRACT FROM AUTHOR]

Three biologically active macromolecules including bovine lactoferrin, hyaluronic acid and infliximab spontaneously form 50 nm-sized nanoparticles. The nanoparticles are equivalent to carrier-free drug delivery system, which differ from conventional drug delivery system. Moreover, inflixmab and bovine lactoferrin can still maintain the structural integrity and biological activity. The nanoparticles show better therapeutic effect than INF for hTNF-α transgenic mice. [Display omitted] Infliximab (INF) is intravenously used for the clinical treatment of rheumatoid arthritis. However, it can cause serious side effects, which are mainly associated with systemic exposure and high doses. Here, we developed a modified hydrophobic ion-pairing complexes (INF HIPC) through the sequential introduction of bovine lactoferrin (BLF) and hyaluronic acid (HA) with opposite charges into the INF solution. INF and BLF were found to be not only integrally responsible for the structural integrity of HIPC but also were determined to have respective biological activities by binding human tumor necrosis factor-alpha (hTNF-α) or promoting the proliferation of osteoblasts. The INF HIPC had good stability, high drug-loading efficiency, and long-term retention effects. Whether via knee joint injection or intravenous injection, INF HIPC resulted in lower hTNF-α levels and less cartilage destruction than INFs in the transgenic mouse model. At the same time, INF HIPC could reduce toxicity based on body weight changes in transgenic mice. Our findings provide a simple and promising avenue to develop advanced delivery systems for other antibodies and macromolecules. [ABSTRACT FROM AUTHOR]

Combination therapy is one of the important treatment strategies for cancer at present. However, the outcome of current combination therapy based on the co-administration of conventional dosage forms is suboptimal, due to the short half-lives of chemodrugs, their deficient tumor selectivity and so forth. Nanotechnology-based targeted delivery systems show great promise in addressing the associated problems and providing superior therapeutic benefits. In this review, we focus on the combination of therapeutic strategies between different nanomedicines or drug-loaded nanocarriers, rather than the co-delivery of different drugs via a single nanocarrier. We introduce the general concept of various targeting strategies of nanomedicines, present the principles of combination antitumor therapy with dual-nanomedicines, analyze their advantages and limitations compared with co-delivery strategies, and overview the recent advances of combination therapy based on targeted nanomedicines. Finally, we reviewed the challenges and future perspectives regarding the selection of therapeutic agents, targeting efficiency and the gap between the preclinical and clinical outcome. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) not only support tumorigenesis and tumor metastasis by reciprocal cellular cross-talk with cancer cells, but also remodel the extracellular matrix (ECM) and architecture of tumor microenvironment. This leads to poor tumor penetration of traditional chemotherapeutic nanomedicines and resulting drug resistance. In this study, we use a novel tumor stroma-targeted nanovehicle (FH-SSL-Nav) to specifically eradicate CAFs, promote tumor penetration of nanomedicines and cut off the stroma's support to cancer cells. FH-SSL-Nav exhibited excellent and comprehensive tumor microenvironment modulation including downregulation ECM deposition, decreasing interstitial fluid pressure (IFP) and facilitating blood perfusion. As a result, more chemotherapeutic drug delivery systems penetrated deep into tumor spheroids in vitro and tumor tissues in vivo . Furthermore, chemotherapeutic drug resistance induced by microenvironment was partly reversed by FH-SSL-Nav. In a human Hep G2 xenograft nude mouse model, FH-SSL-Nav greatly improved the tumor suppression of cancer cell-targeted liposomal doxorubicin (7pep-SSL-DOX) with low dose and low toxicity. Since Nav and DOX exhibited no synergy against Hep G2 cells, it was clear that the improved antitumor efficacy was basically due to the comprehensive tumor microenvironment priming by FH-SSL-Nav. [ABSTRACT FROM AUTHOR]

The transport of nanocarriers is supposed to be based on EPR effect which is affected by diverse factors, so the modulation of EPR effect seems very significant for nanocarriers including targeted drug delivery systems (TDDSs). Besides, it is extremely unclear how the EPR effect impacts the fate of different types of TDDSs. To make the most advantage of EPR effect for TDDSs, it is definitely necessary to clarify these key issues. Here, we construct and characterize various TDDSs, including sterically-stabilized liposomes (SSL), RGD functionalized SSL (RGD-SSL) and novel 7PEP functionalized SSL (7PEP-SSL), loaded with doxorubicin (DOX), DIR or DID. Here, we modulate the permeability of tumor vessels by thalidomide (THD) in a sarcoma-bearing EPR mouse model via monitoring endogenous deoxygenated hemoglobin in circulation, and then we confirm the effect of THD on tumor vessel permeability by vessel density, vessel maturity, VEGF expression and so on. Importantly, we investigate and find the impacts of EPR effect on the antitumor efficacy, in vivo distribution and intratumoral microdistribution of the three TDDSs. Interestingly, the EPR effects affect different TDDSs differently. The elevated EPR effect enhances the tumor accumulation of SSL and RGD-SSL but fails to increase their efficacy. The RGD-SSL exhibits the best efficacy with the least fluctuation, demonstrating the advantage of angiogenesis targeted systems. 7PEP-SSL seems the biggest beneficiary of EPR effect, suggesting the significance of EPR modulation for cells targeted systems. Generally, this study demonstrates the feasibility of modulating EPR effect bidirectionally by THD as well as the impacts of EPR effect on different type of testing TDDSs based on this animal model. It certainly provides novel insight into the design and potential use of TDDSs. [ABSTRACT FROM AUTHOR]

The study was designed to identify the safety and antitumor activity of teniposide self-microemulsified drug delivery system (TEN-SMEDDS) previously developed, and to provide evidence for the feasibility and effectiveness of TEN-SMEDDS for application in clinic. The TEN-SMEDDS could form fine emulsion with mean diameter of 279 ± 19 nm, Zeta potential of −6.9 ± 1.4 mV, drug loading of 0.04 ± 0.001% and entrapment efficiency of 98.7 ± 1.6% after dilution with 5% glucose, respectively. The safety, including hemolysis, hypersensitivity, vein irritation and toxicity in vivo , and antitumor activity were assessed, VUNON as a reference. Sulforhodamine B assays demonstrated that the IC50 of TEN-SMEDDS against C6 and U87MG cells were higher than that of VUMON. But the effect of TEN-SMEDDS on the cell cycle distribution and cell apoptotic rate was similar to that of VUMON as observed by flow cytometry. Likewise, the antitumor activity of TEN-SMEDDS was considerable to that of VUMON. Finally, the TEN-SMEDDS exhibited less body weight loss, lower hemolysis and lower myelosuppression as compared with VUMON. In conclusion, promising TEN-SMEDDS retained the antitumor activity of teniposide and was less likely to cause some side effects compared to VUMON. It may be favorable for the application in clinic. [ABSTRACT FROM AUTHOR]

The biomimetic delivery system (BDS) based on special types of endogenous cells like macrophages and T cells, has been emerging as a novel strategy for cancer therapy, due to its tumor homing property and biocompatibility. However, its development is impeded by complicated construction, low drug loading or negative effect on the cell bioactivity. The present report constructed a BDS by loading doxorubicin (DOX) into a mouse macrophage-like cell line (RAW264.7). It was found that therapeutically meaningful amount of DOX could be loaded into the RAW264.7 cells by simply incubation, without significantly affecting the viability of the cells. Drug could release from the BDS and maintain its activity. RAW264.7 cells exhibited obvious tumor-tropic capacity towards 4T1 mouse breast cancer cells both in vitro and in vivo, and drug loading did not alter this tendency. Importantly, the DOX loaded macrophage system showed promising anti-cancer efficacy in terms of tumor suppression, life span prolongation and metastasis inhibition, with reduced toxicity. In conclusion, it is demonstrated that the BDS developed here seems to overcome some of the main issues related to a BDS. The DOX loaded macrophages might be a potential BDS for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Alpha7 nicotinic acetylcholine receptor (α7 nAChR), a ligand-gated ion channel, is increasingly emerging as a new tumor target owing to its expression specificity and significancy for cancer. In an attempt to increase the targeted drug delivery to the α7 nAChR-overexpressing tumors, herein, α-conotoxin ImI, a disulfide-rich toxin with highly affinity for α7 nAChR, was modified on the PEG-DSPE micelles (ImI-PMs) for the first time. The DLS, TEM and HPLC detections showed the spherical nanoparticle morphology about 20 nm with negative charge and high drug encapsulation. The ligand modification did not induce significant differences. The immunofluorescence assay confirmed the expression level of α7 nAChR in MCF-7 cells. In vitro and in vivo experiments demonstrated that the α7 nAChR-targeted nanomedicines could deliver more specifically and faster into α7 nAChR-overexpressing MCF-7 cells. Furthermore, fluo-3/AM fluorescence imaging technique indicated that the increased specificity was attributed to the ligand-receptor interaction, and the inducitivity for intracellular Ca 2+ transient by ImI was still remained after modification. Moreover, paclitaxel, a clinical frequently-used anti-tumor drug for breast cancer, was loaded in ImI-modified nanomedicines to evaluate the targeting efficacy. Besides of exhibiting greater cytotoxicity and inducing more cell apoptosis in vitro , paclitaxel-loaded ImI-PMs displayed stronger anti-tumor efficacy in MCF-7 tumor-bearing nu/nu mice. Finally, the active targeting system showed low systemic toxicity and myelosuppression evidenced by less changes in body weight, white blood cells, neutrophilic granulocyte and platelet counts. In conclusion, α7 nAChR is also a promising target for anti-tumor drug delivery and in this case, α-conotoxin ImI-modified nanocarrier is a potential delivery system for targeting α7 nAChR-overexpressing tumors. [ABSTRACT FROM AUTHOR]

Cyclosporine A (CyA) is a poorly soluble peptide and the available preparation is the surfactant based Sandimmum Neoral ® . In this study, we developed a novel pH-sensitive nanomatrix system of CyA with medical-grade nanoporous silica and Eudragit ® to enhance the oral absorption of CyA as well as to improve the potential nephrotoxicity caused by the pronounced initial plasma peak of Neoral ® . The nanomatrixs were prepared by an absolutely simple conventional process. The scanning electron microscopy (SEM), X-ray powder diffraction analysis (XRD), differential thermal analysis (DSC) and specific surface area and pore size analysis were used to analyze the physicochemical characterization of the nanomatrix. The nanomatrix, consisted of CyA, Eudragit ® S100 and Sylysia 350 (1/5/5, w/w/w %), not only increased the dissolution of CyA in vitro but also exhibited excellent enteric behavior. The characterization of CyA nanomatrix showed the CyA was highly dispersed in the nanomatrix in a molecular or amorphous state and partly filled into the nanopores of Sylysia 350. The results of comparative pharmacokinetic study showed that the optimized nanomatrix had a relative bioavailability of 90.8% with Neoral ® but a lower C max than that of Neoral ® . In conclusion, the novel nanomatrix of CyA, composed of pharmaceutical excipients of biological safety and easily prepared, is expected to become a promising marketed product for the oral delivery of CyA. [ABSTRACT FROM AUTHOR]

To meet the needs of targeted drug delivery and medical imaging, uniform mesoporous carbon spheres (UMCS) were functionalized using hyperbranched polyethyleneimine (PEI) covalently linked with fluorescein isothiocyanate (FITC) and folic acid (FA). Folate-receptor-positive KB cancer cells internalized five times more nanoparticles than A549 cells deficient in folate receptors in vitro using flow cytometry and confocal microscopy. The in vivo distribution results also confirmed that the FA–PEI–FITC–UMCS nanoparticles could target the FA-positive tumors. In addition, the specifically targeted hybrid carbon nanoparticles exhibited non-cytotoxic and controlled intracellular release (pH dependent) of the loaded agents. The in vivo antitumor effect of the paclitaxel (PTX)-loaded nanoparticles was investigated in Kunming mice harboring a hepatic H22 tumor. PTX-loaded FA–PEI–UMCS nanoparticles displayed superior antitumor effects compared to other PTX formulations, and the tumor growth inhibition rate was 86.53% compared with the control group (saline) for the enhanced targeted accumulation of NPs in tumor cells. [ABSTRACT FROM AUTHOR]

Since they were first reported in 1980, site-specific drug delivery nanocarriers have progressed greatly with the development of nanotechnology and biotechnology, especially in the anti-tumor field. Currently, some of the ligand peptides like RGD have become hot targeting molecules with extensive academic studies and some receptor-medicated nanocarriers are now in clinical trials. Homing peptides have been the preferred ligands thus far due to their low molecular weight, low antigenicity, high modification ratios and low interference in vivo. The major benefit of receptor-mediated nanocarriers over passive ones may be their accumulation within tumors for longer period of time due to their binding to and/or their uptake by cancer cells, preventing them from fast redistribution into systemic circulation. The studies on receptor-mediated nanocarriers are very dynamic currently, advancing gradually from these against non-therapeutic targets to these against therapeutic targets. And recently, more studies were focused on these systems against multiple receptors and the combination therapies with receptor-mediated nanocarriers. However, we still face great challenges, especially in the understanding of receptors, the key issue for receptor-mediated delivery. This review presents the past and ongoing studies on various types of drug delivery systems based on receptor mediation, discusses the prospective and challenges, and introduces the possible trend of study in the future. [ABSTRACT FROM AUTHOR]

Bovine serum albumin (BSA) nanoparticle is a promising drug carrier system. Oridonin (ORI)-loaded galactosylated BSA nanoparticle (ORI-GB-NP) was prepared for liver targeting delivery of ORI. This work was designed to investigate the in vitro release, i n vivo pharmacokinetics and tissue distribution of ORI-GB-NP. ORI-GB-NP was prepared by the desolvation method. The particle size of ORI-GB-NP was 172.0 ± 8.3 nm with narrow size distribution. The in vitro release of ORI-GB-NP exhibited biphasic drug release pattern with an initial burst release and consequently sustained release. Pharmacokinetic analysis displayed that ORI-GB-NP and ORI-loaded BSA nanoparticle (ORI-BSA-NP) could enhance the drug plasma level and prolong the circulation time in contrast with ORI solution. Meanwhile, compared with ORI-BSA-NP, ORI-GB-NP could deliver more ORI to liver and simultaneously reduce the toxicity of ORI to heart, lung and kidney. In conclusion, ORI-GB-NP could be a promising drug delivery system for liver cancer therapy. [ABSTRACT FROM AUTHOR]

Receptor change induced by ligand binding is a new issue to face in the field of targeted delivery. Receptor clustering, the main pattern of receptor changes, decreases the affinity between ligand and receptor due to the redistribution of receptor position. In an attempt to respond to such challenge, we designed and constructed three RGD-modified nanocarriers with different ligand intervals: stealth liposomes modified with the monomeric RGD (moRGD-LP), dimeric RGD (diRGD-LP) and a special dimeric RGD with a linker between two cyclic RGD motifs (P-diRGD-LP). The αvβ3-positive and -negative tumor cells (Melanoma B16 and MCF-7) were used as the cell models. As a result, P-diRGD-LP demonstrated strongest interaction with B16 cells in surface plasmon resonance study and highest cellular uptake in B16 cells in real-time confocal analysis. The enhanced endocytosis of P-diRGD-LP was found to be αvβ3-mediated and P-diRGD-LP increased the involvement of the clathrin-dependent pathway. Importantly, P-diRGD-LP demonstrated the best targeting effect in B16-tumor bearing mice in both in vivo and ex vivo near-infrared fluorescent images, about 2.4-fold that of moRGD-LP and 2.8-fold that of diRGD-LP at 3 h. Further, we validated integrin αvβ3 clustering on B16 cells via a single-molecule imaging by a total internal reflection fluorescence microscopy. Finally, the 3D models of αvβ3 clustering suggested a receptor interval within 41.916–65.779 Å, while the molecular computation revealed an RGD ligand interval of 20.944 Å, 42.753 Å and 78.196 Å for diRGD-LP, P-diRGD-LP and moRGD-LP, respectively, confirming the best matching between clustered αvβ3 and P-diRGD-LP. In conclusion, P-diRGD-LP could achieve higher targeting to αvβ3-positive tumor via the enhanced interaction based on the better ligand-receptor compatibility. The design of targeted nanocarriers against receptor clustering might provide new insight into the nanotechnology-based anticancer therapy. [ABSTRACT FROM AUTHOR]

A liver-targeting drug delivery system for doxorubicin ( DOX), that is, DOX-loaded self-assembled nanoparticles based on galactosylated O-carboxymethyl chitosan-graft-stearic acid conjugates (Gal- OS/ DOX), has been prepared. The objective of the present study was to investigate the preparation, in vitro release, in vivo pharmacokinetics, and tissue distribution of Gal- OS/ DOX nanoparticles. The drug-loaded nanoparticles were spherical in shape with mean size of 181.9 nm. In vitro release profiles indicated that the release of DOX from Gal- OS/ DOX nanoparticles behaved with a sustained and pH-dependent drug release. Pharmacokinetics study revealed Gal- OS/ DOX nanoparticles exhibited a higher AUC value and a prolonged residence time of drug in the blood circulation than those of DOX solution. Furthermore, Gal- OS/ DOX nanoparticles increased the uptake of DOX in liver and spleen, but decreased uptake in heart, lung, and kidney in the tissue distribution study. These results suggested that the Gal- OS/ DOX nanoparticles could prolong blood circulation time, enhance the liver accumulation, and reduce the side effect especially the cardiotoxicity of DOX. In conclusion, Gal- OS/ DOX nanoparticles could be a promising drug delivery system for liver cancer therapy. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:987-993, 2014 [ABSTRACT FROM AUTHOR]

Abstract: Based on the hydrophobic interaction with biomembranes, PFVYLI (PFV), a hydrophobic penetration peptide (HPP), was initially introduced to modify doxorubicin-loaded stealth-sustained liposomes (PFV-SSLs-DOX) against different breast cancer cell phenotypes irrespective of their receptor expression or antigen presence. The physicochemical characteristics of PFV-SSLs were determined with approximately 100 nm size, satisfactory distribution and high encapsulation. In addition, drug release experiments demonstrated that modification with PFV has a negligible influence on the release profile of liposomes. Surface plasmon resonance (SPR) analysis revealed that PFV-modified liposomes could increase the binding proportion of PFV-SSLs with a model cell membrane. It was demonstrated that modification with PFV highly facilitated the intracellular delivery of DOX-loaded liposomes and enhanced cytotoxicity via a hydrophobic interaction. An endocytosis inhibition assay revealed a combination of cellular internalization mechanisms for PFV-SSLs involving lipid raft and clathrin-mediated endocytosis in a temperature-dependent manner. The PFV-modified liposomes displayed more lasting accumulation in the tumor and better tumor growth inhibition with relatively low systemic and cardiac toxicity. In conclusion, PFV-SSLs might be a promising delivery system for the delivery of different therapeutic or imaging agents to heterogeneous tumors. More significantly, this study provides a new perspective on developing HPP-modified drug delivery system for antitumor therapy. [Copyright &y& Elsevier]

Our previous study had reported that cholesterol-grafted poly(amidoamine) (rPAA-Chol polymer) was able to self-assemble into cationic nanoparticles and act as a potential carrier for siRNA transfection. In this study, the core–shell type lipid/rPAA-Chol hybrid nanoparticles (PEG-LP/siRNA NPs and T7-LP/siRNA NPs) were developed for improving in vivo siRNA delivery by modifying the surface of rPAA-Chol/siRNA nanoplex core with a lipid shell, followed by post-insertion of polyethylene glycol phospholipid (DSPE-PEG) and/or peptide (HAIYPRH, named as T7) modified DSPE-PEG-T7. The integrative hybrid nanostructures of LP/siRNA NPs were evidenced by dynamic light scattering (DLS), confocal laser scanning microscope (CLSM), cryo-transmission electron microscope (Cryo-TEM) and surface plasmon resonance (SPR) assay. It was demonstrated that the T7 peptide modified LP/siRNA NPs (T7-LP/siRNA NPs) exhibited uniform and spherical structures with particle size of 99.39 ± 0.65 nm and surface potential of 42.53 ± 1.03 mV, and showed high cellular uptake efficiency and rapid endosomal/lysosomal escape ability in MCF-7 cells. Importantly, in vitro gene silencing experiment demonstrated that both of pegylated and targeted LP/siEGFR NPs exhibited significantly stronger downregulation of EGFR protein expression level in MCF-7 cells, compared to that of the physical mixture of siRNA lipoplexes and rPAA-Chol/siRNA nanoplexes. In vivo tumor therapy on nude mice bearing MCF-7 tumors further confirmed that the targeted T7-LP/siEGFR NPs exhibited the greatest inhibition on tumor growth via transferrin receptor-mediated targeting delivery, without any activation of immune responses and significant body weight loss following systemic administration. These findings indicated that the core-shell type T7-LP/siRNA nanoparticles would be promising siRNA delivery systems for in vivo tumor-targeted therapy. [ABSTRACT FROM AUTHOR]

Amoitone B, a novel compound chemically synthesized as the analogue of cytosporone B, has been proved to own superior affinity with Nur77 than its parent compound and exhibit notable anticancer activity. However, its application is seriously restricted due to the water-insolubility and short biological half-time. The aim of this study was to construct an effective delivery system for Amoitone B to realize sustained release, thus prolong drug circulation time in body and improve the bioavailability. Nanostructured lipid carriers (NLC) act as a new type of colloidal drug delivery system, which offer the advantages of improved drug loading and sustained release. Amoitone B-loaded NLC (AmB-NLC) containing glyceryl monostearate (GMS) and various amounts of medium chain triglycerides (MCT) were successfully prepared by emulsion-evaporation and low temperature-solidification technology with a particle size of about 200 nm and a zeta potential value of about −20 mV. The results of X-ray diffraction and DSC analysis showed amorphous crystalline state of Amoitone B in NLC. Furthermore, the drug entrapment efficacy (EE) was improved compared with solid lipid nanoparticles (SLN). The EE range was from 71.1% to 84.7%, enhanced with the increase of liquid lipid. In vitro drug release studies revealed biphasic drug release patterns with burst release initially and prolonged release afterwards and the release was accelerated with augment of liquid lipid. These results demonstrated that AmB-NLC could be a promising delivery system to control drug release and improve loading capacity, thus prolong drug action time in body and enhance the bioavailability. [ABSTRACT FROM AUTHOR]

Abstract: Oridonin (ORI), a diterpenoid compound with promising antitumor activity, was proved to possess potent antileukemia efficacies in vitro and in vivo recently. However, the development and application of ORI was limited by its poor solubility and rapid plasma clearance. The purpose of this study was to solve these problems. PEGylated oridonin linked with succinic acid (SA) as spacer moiety (PEG-SA-ORI conjugate) was synthesized. mPEG amines with four specifications of molecular weight (MW) were utilized. All polymeric conjugates showed satisfactory aqueous solubility and in vitro studies implied that the drug solubility and release features of conjugates were relevant to PEGs. The drug solubility increased more when the MW of PEG was lower, while more significant sustained-release effect was shown with higher PEG MW. Moreover, the release behaviors of conjugates showed a pH-sensitive property. In vivo pharmacokinetic studies demonstrated that the elimination half-life was prolonged in comparison with ORI solution. PEGylation could be a promising method to obtain better efficacy in the field of drug delivery system. [Copyright &y& Elsevier]

Abstract: The interaction of nanocarriers with cells including their transcellular behavior is vital not only for a drug delivery system, but also for the safety of nanomaterials. In an attempt to clarify how the structures of polymers impact the transport mechanisms of their nanocarriers in epithelial cells, three amphiphilic polymers (PEEP–PCL, PEG–PCL and PEG–DSPE) with different hydrophilic or hydrophobic blocks were synthesized or chosen to form different micelle systems here. The endocytosis, exocytosis, intracellular colocalization, paracellular permeability and transcytosis of these micelle systems were compared using Förster resonance energy transfer analysis, real-time confocal images, colocalization assay, transepithelial electrical resistance study, and so on. All micelle systems were found intact during the studies with cells. The endocytosis and exocytosis studies with undifferentiated MDCK cells and the transcytosis study with differentiated MDCK monolayers all indicated the fact that PEG–DSPE micelles achieved the most and fastest transport, followed by PEG–PCL and PEEP–PCL in order. These might be because DSPE has higher hydrophobicity than PCL while PEG has lower hydrophilicity than PEEP. Different in hydrophilic or hydrophobic structures, all kinds of micelles demonstrated similar pathways during endocytosis and exocytosis, both caveolae- and clathrin-mediated but with difference in degree. The colocalization studies revealed different behaviors in intracellular trafficking among the three polymer micelles, suggesting the decisive role of hydrophilic shells on this process. Finally, all micelle systems did not impact the paracellular permeability of test cell monolayer. In conclusion, the hydrophilic and hydrophobic structures of test micelles could influence their transport ability, intracellular trafficking and the transport level under each pathway in MDCK cells. [Copyright &y& Elsevier]

Highlights: [•] The entrapment efficiency of peptide loaded nanostructured lipid carriers (NLCs) could reach to 95%. [•] The porous nanoparticle-aggregate particles (PNAPs) powders could remain in lungs for a longer time than octreotide acetate (OA) solution and reach a sustained release. [•] The bioavailability was markedly enhanced by pulmonary deliver PNAPs compared with pulmonary deliver OA solutions and subcutaneous inject OA solution. [•] As far as we know, this is the first report on the anti-hepatic ischemia–reperfusion injury (HIRI) effects through intrapulmonary administration. [ABSTRACT FROM AUTHOR]

The targeting ability of pentapeptide (Thr-Lys-Pro-Pro-Arg) grafted nanostructured lipid carriers (Pen-NLCs) to macrophages was investigated in both in vitro and in vivo studies. The results showed the improvement of the anti-inflammatory effect by using this drug delivery system. Firstly, a pentapeptide-polyethylene glycol2000-stearate was synthesized and formulated into Pen-NLCs. Non-grafted nanostructured lipid carriers (Bare-NLCs) and Pen-NLCs were 190.0±1.0 and 203.0±8.5nm in size, −8.1±2.1 and 2.3±1.2mV in zeta potential respectively. Meanwhile, they had comparable entrapment efficiency and drug loading efficiency. In vitro and in vivo cellular uptake studies showed increased internalization of Pen-NLCs by macrophages when compared to pure drugs and Bare-NLCs. Animal studies in a carrageenan-treated air pouch model were used to further investigate the anti-inflammatory effects of Pen-NLCs. Through intravenous administration, a single dose of DXM loaded Pen-NLCs showed the strongest inhibition of inflammatory indexes of air pouch fluid weight, leukocyte infiltration, granulation tissue weight and nitric oxide concentration in comparison with free drugs and DXM loaded Bare-NLCs. In conclusion, this study demonstrated the potential of Pen-NLCs as promising drug carriers for anti-inflammatory treatments. [ABSTRACT FROM AUTHOR]

The present study aimed at developing a drug delivery system targeting the densest site of tuberculosis infection, the alveolar macrophages (AMs). Rifampicin (RFP)-loaded solid lipid nanoparticles (RFP-SLNs) with an average size of 829.6 ± 16.1 nm were prepared by a modified lipid film hydration method. The cytotoxicity of RFP-SLNs to AMs and alveolar epithelial type II cells (AECs) was examined using MTT assays. The viability of AMs and AECs was above 80 % after treatment with RFP-SLNs, which showed low toxicity to both AMs and AECs. Confocal Laser Scanning Microscopy was employed to observe the interaction between RFP-SLNs and both AMs and AECs. After incubating the cells with RFP-SLNs for 2 h, the fluorescent intensity in AMs was more and remained longer (from 0.5 to 12 h) when compared with that in AECs (from 0.5 to 8 h). In vitro uptake characteristics of RFP-SLNs in AMs and AECs were also investigated by detection of intracellular RFP by High performance liquid chromatography. Results showed that RFP-SLNs delivered markedly higher RFP into AMs (691.7 ng/mg in cultured AMs, 662.6 ng/mg in primary AMs) than that into AECs (319.2 ng/mg in cultured AECs, 287.2 ng/mg in primary AECs). Subsequently, in vivo delivery efficiency and the selectivity of RFP-SLNs were further verified in Sprague-Dawley rats. Under pulmonary administration of RFP-SLNs, the amount of RFP in AMs was significantly higher than that in AECs at each time point. Our results demonstrated that solid lipid nanoparticles are a promising strategy for the delivery of rifampicin to alveolar macrophages selectively. [ABSTRACT FROM AUTHOR]

Abstract: Interstitial fluid pressure (IFP) in tumor is much higher than that in normal tissue and it constitutes a great obstacle for the delivery of chemodrugs, which makes it a potential target for cancer therapy. In this study, imatinib, a molecular targeting drug, was loaded in sterically stabilized liposomes (SSL-IMA) to reduce the tumor IFP, in an attempt to deliver more liposomal doxorubicin (SSL-DOX) into tumor tissue. In a mouse B16 melanoma model, intravenous injection of 20 mg/kg SSL-IMA achieved the most reduction of tumor IFP and the effect lasted for at least 50 h with the least hematotoxicity. However, intragastric administration of 100 mg/kg free IMA did not decrease the tumor IFP significantly. Mechanisms of the reduction of tumor IFP by SSL-IMA were proved to be the inhibition of PDGF receptor beta, the inhibition of tumor fibroblasts as well as the anti-angiogenesis effect of SSL-IMA. Then it was demonstrated by in vivo imaging that the decrease of tumor IFP by SSL-IMA led to a more and longer intratumoral distribution of the lipid vehicles. The improved delivery was proved again in the anti-tumor study. The combination of SSL-IMA and SSL-DOX inhibited tumor growth and induced apoptosis of tumor cells the most, at a low dose in which neither SSL-DOX nor SSL-IMA showed obvious anti-tumor efficacy. Since no synergy against B16 cells was found between SSL-IMA and SSL-DOX, it was clear that the improved combinational therapy was basically due to the decrease of tumor IFP by SSL-IMA. In conclusion, reducing tumor IFP by SSL-IMA seems to be a promising strategy to potentiate chemotherapies. [Copyright &y& Elsevier]

Abstract: 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 31.16wt.% 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 &y& Elsevier]

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]

Abstract: A novel approach was applied to fabricate mesoporous silica nanoparticles (MSNs) with different pore size in this study. The pore size of MSNs can be modulated conveniently from 3nm to 10nm by controlling the etching time of MSNs with the NaBH4 solution. The as-synthesized MSNs were investigated as carriers for loading and delivery of the model drug paclitaxel (PTX). The characteristics, drug loading capacity, in vitro drug release behavior, anti-tumor activity and the mechanism of cell uptake were systematically studies. The resultant MSNs showed uniform and mono-dispersed sphere with high drug loading capacity (12–21%). The in vitro drug release exhibited that the released rate of PTX from MSNs could be controlled by the pore size and the larger the pore size, the faster the release rate of PTX. The in vitro anti-tumor studies demonstrated that PTX-loaded MSNs produced higher cytotoxicity than free PTX. Besides, the PTX-loaded MSNs with largest pore size showed the highest anti-tumor activity. These results indicated that these MSNs could provide a promising platform for delivering water-insoluble drugs, controlling the release rate of drugs and increasing the anti-tumor activity. [Copyright &y& Elsevier]

Abstract: Tumor metastasis is responsible for 90% of cancer-associated deaths and highly metastatic cancers are more prone to form metastasis foci and acquire the drug resistance. Here, a nanocarrier system (TMT-LS) has been constructed by modification of stealth liposomes with a metastatic cancer specific peptide, using the unmodified stealth liposomes (LS) as the control. The active targeted nanocarriers presented satisfactory particle size (about 100 nm) and drug release characteristics in vitro. Highly metastatic cancer cells (MDA-MB-435S and MDA-MB-231) and non-metastatic cancer cells (MCF-7) were applied as tumor cell models. The highly metastatic cancer cells were found to endocytose more TMT-LS in a faster way than TS, through a receptor-mediated pathway proved by specific receptor inhibition. Co-localization technique indicated the integrity of nanocarriers in cytoplasm. The significant targeting of TMT-LS to highly metastatic tumors was demonstrated in vivo and ex vivo in an orthotopic model as well as in a double tumor-bearing animal model with both metastatic and non-metastatic tumors in the same mouse. Importantly, the active targeted drug delivery system was found to penetrate deeper into tumor mass and have a longer retention within the malignant tissue. Further, TMT-LS greatly facilitated the efficacy of doxorubicin loaded in terms of inhibiting xenograft tumor growth and inducing cancer cell apoptosis, with only minor side effects. Together, the specific nanocarriers hold great potential in the development of nanomedicine for diagnosis and therapy of metastatic tumor. [Copyright &y& Elsevier]

Abstract: In this study, oridonin-loaded nanoparticles coated with galactosylated chitosan (ORI-GC-NP) were prepared for tumor targeting and their characteristics were evaluated for the morphologies, particle size and zeta potential. Oridonin-loaded nanoparticles (ORI-NP) without galactosylated chitosan were prepared as a control. The entrapment efficiency of ORI-GC-NP and ORI-NP were 72.15% and 85.31%, respectively. The in vitro drug release behavior from nanoparticles displayed biphasic drug release pattern with initial burst release and consequently sustained release. Next, the pharmacokinetics and tissue distribution of ORI-GC-NP, ORI-NP and ORI solution were carried out. Pharmacokinetic analysis showed that ORI-GC-NP and ORI-NP could prolong the drug plasma levels compared with ORI solution. Meanwhile, the distribution of ORI-GC-NP to liver was higher than that of ORI-NP and free drug. In conclusion, ORI-GC-NP, as a promising intravenous drug delivery system for ORI, could be developed as an alternative to the conventional ORI preparations. [Copyright &y& Elsevier]

Abstract: Due to the absence of safe and effective carriers for in vivo delivery, the applications of small interference RNA (siRNA) in clinic for therapeutic purposes have been limited. In this study, a biodegradable amphiphilic tri-block copolymer (mPEG2000-PLA3000-b-R15) composed of monomethoxy poly(ethylene glycol), poly(d,l-lactide) and polyarginine was synthesized and further self-assembled to cationic polymeric nanomicelles for in vivo siRNA delivery, with an average diameter of 54.30 ± 3.48 nm and a zeta potential of approximately 34.8 ± 1.77 mV. The chemical structures of the copolymers were well characterized by 1H NMR spectroscopy and FT-IR spectra. In vitro cytotoxicity and hemolysis assays demonstrated that the polymeric nanomicelles showed greater cell viability and haemocompatibility than those of polyethyleneimine (PEI) or R15 peptide. In vitro experiments demonstrated that EGFR targeted siRNA formulated in micelleplexes exhibited approximately 65% inhibition of EGFR expression on MCF-7 cells in a sequence-specific manner, which was comparable to Lipofectamine™ 2000. The results of intravenous administration showed Micelleplex/EGFR-siRNA significantly inhibited tumor growth in nude mice xenografted MCF-7 tumors, with a remarkable inhibition of EGFR expression. Furthermore, no positive activation of the innate immune responses and no significant body weight loss was observed during treatment suggested that this polymeric micelle delivery system is non-toxic. In conclusion, the present nanomicelles based on cationic mPEG2000-PLA3000-b-R15 copolymer would be a safe and efficient nanocarrier for in vivo delivery of therapeutic siRNA. [Copyright &y& Elsevier]

Purpose: Both combretastatin A-4 (CA-4) and doxorubicin (DOX) was loaded in different form in a targeted nanomedicine in order to achieve the active delivery of these two drugs followed by sequentially suppressing tumor vasculature and tumor cells. Methods: Octreotide-modified stealth liposomes loaded with CA-4 and DOX (Oct-L[CD]) were prepared and characterized. Then in vitro release, cellular uptake, in vitro antitumor effect, pharmacokinetics, in vivo sequential killing effect, in vivo antitumor efficacy against somatostatin receptor (SSTR) positive cells, as well as the action mechanism of such system, were studied. Results: A rapid release of CA-4 followed by a slow release of DOX was observed in vitro. The active targeted liposomes Oct-L[CD] showed a specific cellular uptake through ligand-receptor interaction and a higher antitumor effect in vitro against SSTR-positive cell line. The in vivo sequential killing effect of such system was found as evidenced by the fast inhibition of blood vessels and slow apoptosis-inducing of tumor cells. Oct-L[CD] also exhibited the strongest antitumor effect in MCF-7 subcutaneous xenograft models. Conclusions: Oct-modified co-delivery system may have great potential as an effective carrier for cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract: 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 &y& Elsevier]

Abstract: In this study, uniform mesoporous carbon spheres (UMCS) with 3-D pore system and fibrous ordered mesoporous carbon (FOMC) with 2-dimensional hexagonal mesoporous structure were studied as drug carriers for oral drug delivery system. Lovastatin (LOV), which has low water solubility, was chosen as a model drug. Drug release rate and degree of drug loading of UMCS and FOMC were compared. The effects of different pore channel structures and pore sizes on LOV uptake and release were systematically investigated. Cytotoxicity of UMCS and FOMC on human colon carcinoma (Caco-2) cells were also studied. The results indicate that UMCS has a higher degree of drug loading (up to 36.26% drug weight/total weight) compared with FOMC. The dissolution rate of LOV from UMCS was found to be markedly increased compared with pure crystalline LOV, and the dissolution rate of LOV from FOMC was relatively sustained compared with UMCS, and both UMCS and FOMC exhibited a weak cytotoxicity at tested concentrations (10–800μg/ml). [Copyright &y& Elsevier]

Nanosuspension drug delivery has obtained great success in the preparation of insoluble drugs. The nanosuspension technology can confer a series of special characteristics to the drugs, such as the enhanced dissolution rate and saturation solubility. This mini review first described the differences between the nanocrystals and nanosuspensions. Next, the product techniques, the stable measures, the special features, and the routes of administration of the nanosuspensions were reviewed and compared. Finally, some existing shortcomings of the nanosuspensions were mentioned and the perspectives of the nanosuspensions were also made. [ABSTRACT FROM AUTHOR]

Abstract: 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 &y& Elsevier]