Therapeutic Carriers Research Articles

Surface modification of PLGA nanoparticles by carbopol to enhance mucoadhesion and cell internalization

Mucoadhesive poly (lactic-co-glycolic acid) (PLGA) nanoparticles having a modified shell-matrix derived from polyvinyl alcohol (PVA) and Carbopol (CP), a biodegradable polymer coating, to improve the adhesion and cell transfection properties were developed. The optimum formulations utilized a CP concentration in the range of 0.05–0.2%w/v, and were formed using modified emulsion-solvent evaporation technique. The resulting CP-PLGA nanoparticles were characterized in terms of their physical and chemical properties. The absorbed CP on the PLGA shell-matrix was found to affect the particle size and surface charge, with 0.05% CP giving rise to smooth spherical particles (0.05CP-PLGA) with the smallest size (285.90nm), and strong negative surface charge (−25.70mV). The introduction of CP results in an enhancement of the mucoadhesion between CP-PLGA nanoparticles and mucin particles. In vitro cell internalization studies highlighted the potential of 0.05CP-PLGA nanoparticles for transfection into SiHa cells, with uptake being time dependent. Additionally, cytotoxicity studies of CP-PLGA nanoparticles against SiHa cancer cells indicated that low concentrations of the nanoparticles were non-toxic to cells (cell viability >80%). From the various formulations studied, 0.05CP-PLGA nanoparticles proved to be the optimum model carrier having the required mucoadhesive profile and could be an alternative therapeutic efficacy carrier for targeted mucosal drug delivery systems with biodegradable polymer.

Folate-decorated anticancer drug and magnetic nanoparticles encapsulated polymeric carrier for liver cancer therapeutics

Nanoparticulate system with theranostic applications has attracted significant attention in cancer therapeutics. In the present study, we have developed a novel composite PLGA NP co-encapsulated with anticancer drug (sorafenib) and magnetic NP (SPION). We have successfully developed nanosized folate-conjugated PEGylated PLGA nanoparticles (SRF/FA–PEG–PLGA NP) with both anticancer and magnetic resonance property. We have showed that FA-conjugated NP exhibits sustained drug release and enhanced cellular uptake in BEL7402 cancer cells. The targeted NP effectively suppressed the tumor cell proliferation and has improved the anticancer efficacy than that of free drug or non-targeted one. Additionally, enhanced MRI properties demonstrate this formulation has good imaging agent characteristics. Finally, SRF/FA–PEG–PLGA NP effectively inhibited the colony forming ability indicating its superior anticancer effect. Together, these multifunctional nanoparticles would be most ideal to improve the therapeutic response in cancer and holds great potential to be a part of future nanomedicine. Our unique approach could be extended for multiple biomedical applications.

Polymeric nanoparticle-based delivery of microRNA-199a-3p inhibits proliferation and growth of osteosarcoma cells.

Our prior screening of microRNAs (miRs) identified that miR-199a-3p expression is reduced in osteosarcoma cells, one of the most common types of bone tumor. miR-199a-3p exhibited functions of tumor cell growth inhibition, suggesting the potential application of miR-199a-3p as an anticancer agent. In the study reported here, we designed and developed a lipid-modified dextran-based polymeric nanoparticle platform for encapsulation of miRs, and determined the efficiency and efficacy of delivering miR-199a-3p into osteosarcoma cells. In addition, another potent miR, let-7a, which also displayed tumor suppressive ability, was selected as a candidate miR for evaluation. Fluorescence microscopy studies and real-time polymerase chain reaction results showed that dextran nanoparticles could deliver both miR-199a-3p and let-7a into osteosarcoma cell lines (KHOS and U-2OS) successfully. Western blotting analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that dextran nanoparticles loaded with miRs could efficiently downregulate the expression of target proteins and effectively inhibit the growth and proliferation of osteosarcoma cells. These results demonstrate that a lipid-modified dextran-based polymeric nanoparticle platform may be an effective nonviral carrier for potential miR-based anticancer therapeutics.

Highly effective antiangiogenesis via magnetic mesoporous silica-based siRNA vehicle targeting the VEGF gene for orthotopic ovarian cancer therapy.

Therapeutic antiangiogenesis strategies have demonstrated significant antitumor efficacy in ovarian cancer. Recently, RNA interference (RNAi) has come to be regarded as a promising technology for treatment of disease, especially cancer. In this study, vascular endothelial growth factor (VEGF)-small interfering RNA (siRNA) was encapsulated into a magnetic mesoporous silica nanoparticle (M-MSN)-based, polyethylenimine (PEI)-capped, polyethylene glycol (PEG)-grafted, fusogenic peptide (KALA)-functionalized siRNA delivery system, termed M-MSN_VEGF siRNA@PEI-PEG-KALA, which showed significant effectiveness with regard to VEGF gene silencing in vitro and in vivo. The prepared siRNA delivery system readily exhibited cellular internalization and ease of endosomal escape, resulting in excellent RNAi efficacy without associated cytotoxicity in SKOV3 cells. In in vivo experiments, notable retardation of tumor growth was observed in orthotopic ovarian tumor-bearing mice, which was attributed to significant inhibition of angiogenesis by systemic administration of this nanocarrier. No obvious toxic drug responses were detected in major organs. Further, the magnetic core of M-MSN_VEGF siRNA@PEI-PEG-KALA proved capable of probing the site and size of the ovarian cancer in mice on magnetic resonance imaging. Collectively, the results demonstrate that an M-MSN-based delivery system has potential to serve as a carrier of siRNA therapeutics in ovarian cancer.

Self‐assembled UCST‐Type Micelles as Potential Drug Carriers for Cancer Therapeutics

A methoxy‐poly(ethylene glycol)‐block‐poly(acrylamide‐co‐acrylonitrile) (mPEG‐b‐P(AAm‐co‐AN)) amphiphilic copolymer exhibiting upper critical solution temperature (UCST) behavior is synthesized, and micelles from this copolymer are fabricated. It is found that the thermal responses of these micelles are tunable through balancing the hydrophobic/hydrophilic blocks in the copolymer. The size of the doxorubicin (DOX)‐loaded micelles is dependent on the hydrophobic interaction as well as hydrogen bonding between polymer and drug molecules. As a proof of concept, the drug release behavior is studied in vitro, and the cumulative release of DOX increases at temperature above the UCST of blank micelles. 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) assays indicate that these polymers are non‐toxic towards human hepatic carcinoma cells (Bel 7402 cells) as well as human embryonic hepatocytes (L02 cells). DOX‐loaded micelles could effectively enter Bel 7402 cells in 2 h, and display much lower half inhibitory concentration compared with free DOX. These micelles may be exploited as a promising drug carrier for cancer therapeutics. image

Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer

Ultrasound induced microbubble cavitation can cause enhanced permeability across natural barriers of tumors such as vessel walls or cellular membranes, allowing for enhanced therapeutic delivery into the target tissues. While enhanced delivery of small (<1nm) molecules has been shown at acoustic pressures below 1MPa both in vitro and in vivo, the delivery efficiency of larger (>100nm) therapeutic carriers into cancer remains unclear and may require a higher pressure for sufficient delivery. Enhanced delivery of larger therapeutic carriers such as FDA approved pegylated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NP) has significant clinical value because these nanoparticles have been shown to protect encapsulated drugs from degradation in the blood circulation and allow for slow and prolonged release of encapsulated drugs at the target location. In this study, various acoustic parameters were investigated to facilitate the successful delivery of two nanocarriers, a fluorescent semiconducting polymer model drug nanoparticle as well as PLGA-PEG-NP into human colon cancer xenografts in mice. We first measured the cavitation dose produced by various acoustic parameters (pressure, pulse length, and pulse repetition frequency) and microbubble concentration in a tissue mimicking phantom. Next, in vivo studies were performed to evaluate the penetration depth of nanocarriers using various acoustic pressures, ranging between 1.7 and 6.9MPa. Finally, a therapeutic microRNA, miR-122, was loaded into PLGA-PEG-NP and the amount of delivered miR-122 was assessed using quantitative RT-PCR. Our results show that acoustic pressures had the strongest effect on cavitation. An increase of the pressure from 0.8 to 6.9MPa resulted in a nearly 50-fold increase in cavitation in phantom experiments. In vivo, as the pressures increased from 1.7 to 6.9MPa, the amount of nanoparticles deposited in cancer xenografts was increased from 4- to 14-fold, and the median penetration depth of extravasated nanoparticles was increased from 1.3-fold to 3-fold, compared to control conditions without ultrasound, as examined on 3D confocal microscopy. When delivering miR-122 loaded PLGA-PEG-NP using optimal acoustic settings with minimum tissue damage, miR-122 delivery into tumors with ultrasound and microbubbles was 7.9-fold higher compared to treatment without ultrasound. This study demonstrates that ultrasound induced microbubble cavitation can be a useful tool for delivery of therapeutic miR loaded nanocarriers into cancer in vivo.

A facile synthesis of novel mesoporous bioactive glass nanoparticles with various morphologies and tunable mesostructure by sacrificial liquid template method

In this paper, two types of mesoporous bioactive glasses (MBGs) including spherical MBGs (SBG) with radial mesostructure and pineal MBGs (PBG) with lamellar mesostructure have been successfully synthesized through a novel sacrificial liquid template method in sol–gel process. The morphologies and structures of the samples were characterized and the results demonstrated that ethyl acetate was added in the hexadecy ltrimethyl ammonium bromide aqueous solution to form micro-emulsion droplets as liquid template; the aqueous ammonia was added as template corrodent and hydrolysis catalyst. The morphology of MBGs could be controlled by the reaction conditions. Meanwhile, the size and the mesostructure of MBGs could be tuned by the aqueous ammonia concentration. The novel MBGs may be a good candidate as therapeutic molecules carriers for bone and dental tissue regeneration.

Optimal structure of particles-based superparamagnetic microrobots: application to MRI guided targeted drug therapy

This paper presents an optimal design strategy for therapeutic magnetic micro carriers (TMMC) guided in real time by a magnetic resonance imaging (MRI) system. As aggregates of TMMCs must be formed to carry the most amount of drug and magnetic actuation capability, different clustering agglomerations could be arranged. Nevertheless, its difficult to predict the hydrodynamic behavior of any arbitrary-shaped object due to the nonlinear hydrodynamic effects. Indeed, the drag effect is related not only to the properties of the bolus but also to its interaction with the fluid viscosity, the free-stream velocity and the container geometry. In this work, we propose a mathematical framework to optimize the TMMC aggregates to improve the steering efficiency in experimental endovascular conditions. The proposed analysis is carried out on various sizes and geometries of microcarrier: spherical, ellipsoid-like, and chain-like of microsphere structures. We analyze the magnetophoretic behavior of such designs to exhibit the optimal configuration. Based on the optimal design of the boluses, experimental investigations were carried out in mm-sized fluidic artery phantoms to demonstrate the steerability of the magnetic bolus using a proof-of-concept setup. The experiments demonstrate the steerability of the magnetic bolus under different velocity, shear-stress, and trajectory constraints with a laminar viscous fluidic environment. Preliminary experiments with a MRI system confirm the feasibility of the steering of these TMMCs in hepatic artery microchannel phantom.

Evaluation of a newly developed HPMC ophthalmic insert with sustainehttp://10.10.23.106:8080/TDXPSLIVEGANG/gateway/elsevierjournal/index.jsp#d release properties as a carrier for thermolabile therapeutics

A novel drug delivery system (DDS) with sustained release properties was developed to allow ocular protein delivery. The DDS developed is aimed at overcoming stability issues during preparation such as denaturation of proteins caused by shear forces applied or due to elevated temperatures and air entrapment potentially causing oxidation of the molecule. The rod-shaped HPMC inserts were loaded with lysozyme and several HPMC types were studied and compared. An aqueous colloidal HPMC solution (hydrogel) was prepared and subsequently dried at 150°C to dehydrate the polymer solution. This partially dehydrated polymer cylinder was loaded with an aqueous glycerol/lysozyme solution at 2°C. A 24 full factorial design was set up to evaluate the effect of the different preparation parameters on water uptake and release properties. As a result, four out of sixteen formulations revealed homogenous distribution for lysozyme in both duplicates. The change in water uptake over time was dependent on the type of HPMC polymer used but not between the chosen HPMC percentages. After 240min, 50% of lysozyme loaded was released depending on the chosen formulation. Lysozyme molecules exhibit slower release from a K100M matrix compared to E10M inserts, albeit the overall effect is relatively limited.

Glycosaminoglycan-functionalized poly-lactide-co-glycolide nanoparticles: synthesis, characterization, cytocompatibility, and cellular uptake.

The efficient delivery of chemotherapeutics to the tumor via nanoparticle (NP)-based delivery systems remains a significant challenge. This is compounded by the fact that the tumor is highly dynamic and complex environment composed of a plurality of cell types and extracellular matrix. Since glycosaminoglycan (GAG) production is altered in many diseases (or pathologies), NPs bearing GAG moieties on the surface may confer some unique advantages in interrogating the tumor microenvironment. In order to explore this premise, in the study reported here poly-lactide-co-glycolide (PLGA) NPs in the range of 100–150 nm bearing various proteoglycans were synthesized by a single-step nanoprecipitation and characterized. The surface functionalization of the NPs with GAG moieties was verified using zeta potential measurements and X-ray photoelectron spectroscopy. To establish these GAG-bearing NPs as carriers of therapeutics, cellular toxicity assays were undertaken in lung epithelial adenocarcinoma (A549) cells, human pulmonary microvascular endothelial cells (HPMEC), and renal proximal tubular epithelial cells. In general NPs were well tolerated over a wide concentration range (100–600 μg/mL) by all cell types and were taken up to appreciable extents without any adverse cell response in A549 cells and HPMEC. Further, GAG-functionalized PLGA NPs were taken up to different extents in A459 cells and HPMEC. In both cell systems, the uptake of heparin-modified NPs was diminished by 50%–65% in comparison to that of unmodified PLGA. Interestingly, the uptake of chondroitin sulfate NPs was the highest in both cell systems with 40%–60% higher uptake when compared with that of PLGA, and this represented an almost twofold difference over heparin-modified NPs. These findings suggest that GAG modification can be explored as means of changing the uptake behavior of PLGA NPs and these NP systems have potential in cancer therapy.

Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the 5(th) most common malignancy which is responsible for more than half million annual mortalities; also, it is the third leading cause of cancer related death. Unfavorable systemic side-effects of chemotherapeutic agents and susceptibility to the degradation of small interfering RNAs (siRNAs), which can knock down a specific gene involved in the disease, have hampered their clinical application. So, it could be beneficial to develop an efficient carrier for the stabilization and specific delivery of drugs and siRNA to cells. Targeted nanoparticles have gained considerable attention as an efficient drug and gene delivery system, which is due to their capability in achieving the highest accumulation of cytotoxic agents in tumor tissue, modifiable drug pharmacokinetic- and bio-distribution, improved effectiveness of treatment, and limited side-effects. Recent studies have shed more light on the advantages of novel drug loaded carrier systems vs free drugs. Most of the animal studies have reported improvement in treatment efficacy and survival rate using novel carrier systems. Targeted delivery may be achieved passively or actively. In passive targeting, no ligand as homing device is used, while targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. However, in active targeting, the therapeutic agent or carrier system is conjugated to a tissue or cell-specific receptor which is over-expressed in a special malignancy using a ligand called a homing device. This review covers a broad spectrum of targeted nanoparticles as therapeutic and non-viral siRNA delivery systems, which are developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and their characteristics and opportunities for the clinical applications of drugs and therapeutic siRNA are discussed in this article. Asialoglycoprotein receptors, low-density lipoprotein, ganglioside GM1 cell surface ligand, epidermal growth factor receptor receptors, monoclonal antibodies, retinoic acid receptors, integrin receptors targeted by Arg-Gly-Asp peptide, folate, and transferrin receptors are the most widely studied cell surface receptors which are used for the site specific delivery of drugs and siRNA-based therapeutics in HCC and discussed in detail in this article.

Design and evaluation of endosomolytic biocompatible peptides as carriers for siRNA delivery.

Gene therapy using RNA interference (RNAi) technology has been explored to treat cancers, by regulating the expression of oncogene. However, even though small interfering RNA (siRNA), which triggers RNAi, may have great therapeutic potential, efforts at using them in vivo have been hampered by the difficulty of effective and safe delivery into cells of interest. In this study, to develop a safe and efficient carrier for in vitro and in vivo siRNA delivery, we designed a peptide library. These peptides are improved variants of a known peptide based siRNA carrier C6. All the modifications improved the transfection efficiency of C6 to some degree. After completing prescreening for activity, several promising candidates were used for further evaluation. Selected peptides C6M3 and C6M6 could form stable complexes with siRNA. These complexes could be greatly uptaken by cells and showed a punctate perinuclear distribution. Moreover, peptide/siRNA complexes achieved high transfection efficiency in vitro without inducing substantial cytotoxicity. We have validated the therapeutic potential of this strategy for cancer treatment by targeting Bcl-2 gene in mouse tumor models, and demonstrated that tumor growth was inhibited. In order to address possible immune side effects of these peptide carriers, biocompatibility study in terms of complement activation and cytokine activation assay were carried out, whereas none of the peptides induced such effects. In conclusion, these results support the potential of these peptides as therapeutic siRNA carrier.

Nano-engineered mesenchymal stem cells as targeted therapeutic carriers

Poor availability in deep-seated solid tumors is a significant challenge that limits the effectiveness of currently used anticancer drugs. Approaches that can specifically enhance drug delivery to the tumor tissue can potentially improve therapeutic efficacy. In our current studies, we used nano-engineered mesenchymal stem cells (nano-engineered MSCs) as tumor-targeted therapeutic carriers. In addition to their exquisite tumor homing capabilities, MSCs overexpress efflux transporters such as P-glycoprotein and are highly drug resistant. The inherent tumor-tropic and drug-resistant properties make MSCs ideal carriers for toxic payload. Nano-engineered MSCs were prepared by treating human MSCs with drug-loaded polymeric nanoparticles. Incorporating nanoparticles in MSCs did not affect their viability, differentiation or migration potential. Nano-engineered MSCs induced dose-dependent cytotoxicity in A549 lung adenocarcinoma cells and MA148 ovarian cancer cells in vitro. An orthotopic A549 lung tumor model was used to monitor the in vivo distribution of nanoengineered MSCs. Intravenous injection of nanoparticles resulted in non-specific biodistribution, with significant accumulation in the liver and spleen while nano-engineered MSCs demonstrated selective accumulation and retention in lung tumors. These studies demonstrate the feasibility of developing nano-engineered MSCs loaded with high concentration of anticancer agents without affecting their tumor-targeting or drug resistance properties.

Abstract 5420: Nano-engineered mesenchymal stem cells as targeted therapeutic carriers

Abstract Poor availability of chemotherapeutics in deep-seated and metastatic cancers results in the development of drug resistance and failed therapeutic outcomes. Approaches that can specifically enhance drug delivery to the tumor tissue can potentially improve therapeutic efficacy while minimizing toxic side effects. In our current studies, we used nano-engineered mesenchymal stem cells (MSCs) as tumor-targeted therapeutic carriers. MSCs possess exquisite tumor homing capabilities. In addition, MSCs overexpress efflux transporters such as P-glycoprotein and are highly drug resistant. The inherent tumor-tropic and drug-resistant properties make MSCs ideal carriers for toxic payload. Since a majority of MSCs first accumulate in the lungs following systemic administration, this technology is particularly suitable for the delivery of anticancer therapeutics to lung tumors. The overall objective of this study was to investigate the efficacy of nano-engineered MSCs in non-small cell lung cancer. We hypothesized that incorporation of drug-loaded, polymeric nanoparticles in MSCs will allow for tumor-targeted and sustained drug delivery. Nanoparticles containing paclitaxel and imaging agent were formulated using poly (DL-lactide-co-glycolide) polymer by solvent evaporation technique and characterized for size, charge, drug loading and in vitro drug release. Nano-engineered MSCs were designed by loading MSCs with nanoparticles containing paclitaxel and an infrared (in vivo) or green fluorescent (in vitro) imaging agent and characterized for nanoparticle uptake using flow cytometry. Nano-engineered MSCs were characterized for in vitro cytotoxicity, differentiation potential and in vivo migratory potential. Human MSCs incubated with nanoparticles showed a steady increase in nanoparticle uptake, with saturation at 4 hours. Nanoparticles encapsulation did not affect the viability or the differentiation potential of MSCs. Nano-engineered MSCs resulted in dose-dependent cytotoxicity in A549 lung adenocarcinoma cells. An orthotopic lung tumor model was used to monitor the in vivo distribution of nano-engineered MSCs. Intravenous injection of A549 cells stably transfected with luciferase in mice resulted in formation of lung tumors that were monitored by bioluminescence imaging. Intravenous injection of nanoparticles alone resulted in non-specific biodistribution, with high accumulation in liver and spleen. Nano-engineered MSCs, in contrast, demonstrated selective accumulation and retention in lung tumors. These results indicate that nano-engineered MSCs can be loaded with high concentration of anticancer agents without affecting their migratory or drug resistance properties. Future studies will examine the anticancer efficacy of nano-engineered MSCs in an orthotopic mouse model of lung cancer. Citation Format: Swayam Prabha, Tanmoy Sadhukha. Nano-engineered mesenchymal stem cells as targeted therapeutic carriers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5420. doi:10.1158/1538-7445.AM2014-5420

Abstract 4107: Efficient delivery of dietary compound modulates mcp-1 in murine prostate cancer cells

Abstract Monocyte chemo-attractant protein (MCP-1) is a chemokine, which recruits monocytes, neutrophils, and lymphocytes in response to trauma and proinflammatory cytokines such as TNF-α. MCP-1 generally is not expressed in healthy individuals, but in response to various stressful stimuli it gets up-regulated, which in turn contributes to increased inflammation. MCP-1 has been implicated in mediating apoptosis by producing a proapoptotic protein designated MCP-induced protein (MCPIP). Resveratrol (RES), a polyphenolic compound found in the skin of red fruits, exhibits anti-inflammatory, anti-oxidative, anti-cancer, and anti-proliferative characteristics. In this study, we hypothesized that the functionalization of RES with detonated nano-diamond (DND, hereafter called fDND) will enhance the effective delivery of RES to tumor cell and impact the modulation of molecular mechanisms in murine prostate cancer (PCa) cells. This hypothesis was tested on mouse PCa cell lines, derived from transgenic adenocarcinoma of mouse prostate (TRAMP), in C57/B6 mice. Interestingly, TRAMP-C1 and TRAMP-C2 form tumor while TRAMP-C3 fails to develop tumor. TRAMP cells were treated with different concentrations of fDND at different time points and analyzed for underlying cellular and molecular mechanisms such as cell viability/proliferation, mitochondrial membrane potential, cytokines and growth factors production. The initial results indicate that the fDND significantly induce molecular signatures in TRAMP-C3 cells in comparison with TRAMPC1 and C2. Interestingly, the level of MCP-1 was significant elevated in TRAMP C1 and C2 cells. Thus, suggesting a major role of MCP-1 in the regulation of cancer progression and clearance. This data also suggest that the functionality of dietary compounds can be enhanced by conjugating or functionalizing them with DND, which can be used as a therapeutic carrier. Citation Format: Manoj K. Mishra, James A. Stokes, Amanee Salaam, Elijah Nyairo, Udai Singh, Derrick Dean. Efficient delivery of dietary compound modulates mcp-1 in murine prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4107. doi:10.1158/1538-7445.AM2014-4107

Core-shell-type magnetic mesoporous silica nanocomposites for bioimaging and therapeutic agent delivery.

Advances in nanotechnology and nanomedicine offer great opportunities for the development of nanoscaled theranostic platforms. Among various multifunctional nanocarriers, magnetic mesoporous silica nanocomposites (M-MSNs) attract prominent research interest for their outstanding properties and potential biomedical applications. This Research News article highlights recent progress in the design of core-shell-type M-MSNs for both diagnostic and therapeutic applications. First, an overview of synthetic strategies for three representative core-shell-type M-MSNs with different morphologies and structures is presented. Then, the diagnostic functions of M-MSNs is illustrated for magnetic resonance imaging (MRI) applications. Next, magnetic targeted delivery and stimuli-responsive release of drugs, and effective package of DNA/siRNA inside mesopores using M-MSNs as therapeutic agent carriers are discussed. The article concludes with some important challenges that need to be overcome for further practical applications of M-MSNs in nanomedicine.

Layer-by-layer assembly of liposomal nanoparticles with PEGylated polyelectrolytes enhances systemic delivery of multiple anticancer drugs

Layer-by-layer (LbL)-engineered nanoparticles (NPs) are a promising group of therapeutic carriers used in an increasing number of biomedical applications. The present study uses a controlled LbL process to create a multidrug-loaded nanoplatform capable of promoting blood circulation time, biodistribution profile and controlling drug release in the dynamic systemic environment. LbL assembly is achieved by sequential deposition of poly-l-lysine (PLL) and poly(ethylene glycol)-block-poly(l-aspartic acid) (PEG-b-PLD) on liposomal nanoparticles (LbL-LNPs). This generates spherical and stable multilayered NPs ∼240nm in size, enabling effective systemic administration. The numerous functional groups and compartments in the polyelectrolyte shell and core facilitate loading with doxorubicin and mitoxantrone. The nanoarchitecture effectively controls burst release, providing different release kinetics for each drug. LbL-LNPs are pH-sensitive, indicating that intracellular drug release can be increased by the acidic milieu of cancer cells. We further demonstrate that the LbL nanoarchitecture significantly reduces the elimination rates of both drugs tested and markedly extends their systemic circulation times, paving the way for efficacious tumor drug delivery. Because this delivery system accommodates multiple drugs, improves drug half-life and diminishes burst release, it provides an exciting platform with remarkable potential for combination therapeutics in cancer therapy.

Facile synthesis of high‐molecular‐weight acid‐labile polypeptides using urethane derivatives

ABSTRACTPolypeptides have received noticeable attention in the biomedical field due to their structural versatility and biomimetic properties. Particularly, polypeptides that are responsive to biological stimuli, such as mildly acidic extracellular and intracellular conditions, have great potential as delivery carriers for therapeutics. However, synthesis of high‐molecular‐weight acid‐labile peptides is often daunting due to highly restrictive polymerization conditions and limitations in preserving acid‐degradable functional groups. For instance, the popular N‐carboxyanhydride (NCA) ring‐opening polymerization (ROP) is efficient, but acid‐labile NCA monomers are difficult to synthesize and store. In this study, acid‐labile polypeptides with high molecular weights were synthesized under mild, permissive conditions using carboxylated urethane derivative monomers which are stable for ease of handling. The polymerization was successful in various organic solvents at room temperature, and did not require additional energy or initiation to drive the formation of NCA intermediates. The polymerization was also rapid enough to be independent of inert atmosphere. The strategy explored here to synthesize high‐molecular‐weight acid‐labile polypeptides offers significant advantages including facile synthesis of acid‐labile urethane derivative monomers that are stable, even in contact with moisture, and fast polymerization under easily achievable conditions. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 280–286

Recent advances in the development of functionalized carbon nanotubes: a versatile vector for drug delivery

Carbon nanotubes (CNTs) possess unique physical and chemical properties and can serve as a platform for transporting a variety of bioactive molecules, such as drugs, proteins, and genes, given appropriate surface modifications. Here, we present an overview of the progress in applying CNTs as therapeutic agent carriers. Drugs can be attached to CNTs either through supramolecular chemistry to form noncovalent assembly or via covalent linkage to the functional groups preinstalled on CNTs. In addition to surface loading, packing of molecules inside the internal cavity of CNTs to protect less stable entities has also been achieved. Besides drugs, the high specific surface area of CNTs can also allow the installation of multiple molecules with different functions, e.g. target recognition and optical imaging, simultaneously to achieve synergistic effects. The drug release process tends to be gradual and sustained after being attached to CNTs, and could be tuned by various factors, such as pH, diameter of CNTs, and target recognition. The content throughout this review is mainly focused on the different protocols of loading drugs onto or into CNTs as well as how to control the drug release.

Endocytosis of PEGylated nanoparticles accompanied by structural and free energy changes of the grafted polyethylene glycol

Nanoparticles (NPs) are in use to efficiently deliver drug molecules into diseased cells. The surfaces of NPs are usually grafted with polyethylene glycol (PEG) polymers, during so-called PEGylation, to improve water solubility, avoid aggregation, and prevent opsonization during blood circulation. The interplay between grafting density σp and grafted PEG polymerization degree N makes cellular uptake of PEGylated NPs distinct from that of bare NPs. To understand the role played by grafted PEG polymers, we study the endocytosis of 8 nm sized PEGylated NPs with different σp and N through large scale dissipative particle dynamics (DPD) simulations. The free energy change Fpolymer of grafted PEG polymers, before and after endocytosis, is identified to have an effect which is comparable to, or even larger than, the bending energy of the membrane during endocytosis. Based on self-consistent field theory Fpolymer is found to be dependent on both σp and N. By incorporating Fpolymer, the critical ligand-receptor binding strength for PEGylated NPs to be internalized can be correctly predicted by a simple analytical equation. Without considering Fpolymer, it turns out impossible to predict whether the PEGylated NPs will be delivered into the diseased cells. These simulation results and theoretical analysis not only provide new insights into the endocytosis process of PEGylated NPs, but also shed light on the underlying physical mechanisms, which can be utilized for designing efficient PEGylated NP-based therapeutic carriers with improved cellular targeting and uptake.