Protein functionalized tramadol-loaded PLGA nanoparticles: preparation,optimization, stability and pharmacodynamic studies

Poly (d,l-lactide-co-glycolide acid) (PLGA) Nanoparticles (NPs) with sustained drug release and enhanced circulation time presents widely explored non-invasive approach for drug delivery to brain. However, blood-brain barrier (BBB) limits the drug delivery to brain. This can be overcome by anchoring endogenous ligand like Transferrin (Tf) and Lactoferrin (Lf) on the surface of NPs, allowing efficient brain delivery via receptor-mediated endocytosis. The aim of the present investigation was preparation, optimization, characterization and comparative evaluation of targeting efficiency of Tf- vs. Lf-conjugated NPs. Tramadol-loaded PLGA NPs were prepared by nanoprecipitation techniques and optimized using 3³ factorial design. The effect of polymer concentration, stabilizer concentration and organic:aqueous phase ratio were evaluated on particle size (PS) and entrapment efficiency (EE). The formulation was optimized based on desirability for lower PS (<150 nm) and higher EE (>70%). Optimized PLGA NPs were conjugated with Tf and Lf, characterized and evaluated for stability study. Pharmacodynamic study was performed in rat after intravenous administration. The optimized formulation had 100 mg of PLGA, 1% polyvinyl alcohol (PVA) and 1:2 acetone:water ratio. The Lf and Tf conjugation to PLGA NPs was estimated to 186 Tf and 185 Lf molecules per NPs. Lyophilization was optimized at 1:2 ratio of NPs:trehalose. The NPs were found stable for 6 months at refrigerated condition. Pharmacodynamic study demonstrated enhanced efficacy of ligand-conjugated NPs against unconjugated NPs. Conjugated NPs demonstrated significantly higher pharmacological effect over a period of 24 h. Furthermore Lf functionalized NPs exhibited better antinociceptive effect as compared to Tf functionalized NPs.     

Preparation,characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting

Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder manifested by cognitive, memory deterioration and variety of neuropsychiatric symptoms. Donepezil is a reversible cholinesterase inhibitor used for the treatment of AD. The purpose of this work is to prepare a nanoparticulate drug delivery system of donepezil using poly(lactic-co-glycolic acid) (PLGA) for sustained release and efficient brain targeting.

Materials and methods: PLGA nanoparticles (NPs) were prepared by the solvent emulsification diffusion–evaporation technique and characterized for particle size, particle-size distribution, zeta potential, entrapment efficiency, drug loading and interaction studies and in vivo studies using gamma scintigraphy techniques.

Results and discussion: The size of drug-loaded NPs (drug polymer ratio 1:1) was found to be 89.67?±?6.43?nm. The TEM and SEM images of the formulation suggested that particle size was within 20–100?nm and spherical in shape, smooth morphology and coating of Tween-80 on the NPs was clearly observed. The release behavior of donepezil exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous sustained release. The biodistribution studies of donepezil-loaded PLGA NPs and drug solution via intravenous route revealed higher percentage of radioactivity per gram in the brain for the nanoparticulate formulation as compared with the drug solution (p?Conclusion: The high concentrations of donepezil uptake in brain due to coated NPs may help in a significant improvement for treating AD. But further, more extensive clinical studies are needed to check and confirm the efficacy of the prepared drug delivery system.     

Ultrafine PEG-coated poly(lactic-co-glycolic acid) nanoparticles formulated by hydrophobic surfactant-assisted one-pot synthesis for biomedical applications

A novel method was developed for the one-pot synthesis of ultrafine poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), using an emulsion solvent evaporation formulation method. Using either cetyltrimethylammonium bromide (CTAB) or poly(ethylene glycol)-distearyl phosphoethanolamine (PEGPE) as an oily emulsifier during the emulsion process, produced PLGA particle sizes of less than 50 nm, constituting a breakthrough in emulsion formulation methods. The yield of ultrafine PLGA NPs increased with PEGPE/PLGA ratio, reaching a plateau at around 85%, when the PEGPE/PLGA ratio reached 3:1. The PEGPE-PLGA NPs exhibited high drug loading content, reduced burst release, good serum stability, and enhanced cell uptake rate compared with traditional PLGA NPs. Sub-50 nm diameter PEG-coated ultrafine PLGA NPs show great potential for in vivo drug delivery systems.     

Development of electrosprayed artesunate-loaded core–shell nanoparticles

Objective: Artesunate (ART) is proven to have potential anti-proliferative activities, but its instability and poor aqueous solubility limit its application as an anti-cancer drug. The present study was undertaken to develop coaxial electrospraying as a novel technique for fabricating nanoscale drug delivery systems of ART as the core–shell nanostructures.

Methods: The core–shell nanoparticles (NPs) were fabricated with coaxial electrospraying and the formation mechanisms of NPs were examined. The physical solid state and drug–polymer interactions of NPs were characterized by X-ray powder diffraction (XRPD) and Fourier transform infrared (FTIR) spectroscopy. The effects of materials and electrospraying process on the particle size and surface morphology of NPs were investigated by scanning electron microscopy (SEM). The drug release from NPs was determined in vitro by a dialysis method.

Results: The ART/poly(lactic-co-glycolic) acid (PLGA) chitosan (CS) NPs exhibited the mean particle size of 303?±?93?nm and relatively high entrapment efficiency (80.5%). The release pattern showed an initial rapid release within two hours followed by very slow extended release. The release pattern approached the Korsmeyer–Peppas model.

Conclusions: The present results suggest that the core–shell NPs containing PLGA and CS have a potential as carriers in the anticancer drug therapy of ART.     

Development and characterization of folate anchored Saquinavir entrapped PLGA nanoparticles for anti-tumor activity

Objective: Saquinavir (SQV) is a US-FDA approved HIV protease inhibitor (HPI) for HIV cure. The purpose of the present investigation was to develop and characterize the anticancer potential of the SQV-loaded folic acid (FA) conjugated PEGylated and non-PEGylated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) (SQV–Fol–PEG–PLGA and SQV–Fol–PLGA) employing PC-3 (human prostate) and MCF-7 (human breast) cancer cell lines.

Materials and methods: Developed NPs were characterized by IR, NMR, DSC, XRD, size, charge and further tested for drug loading and cellular uptake properties.

Result: The entrapment efficiency was found to be 56?±?0.60 and 58?±?0.80 w/v for SQV–Fol–PEG–PLGA and SQV–PLGA NPs, respectively. The obtained results of SQV–Fol–PEG–PLGA showed enhanced cytotoxicity and cellular uptake and were most preferentially taken up by the cancerous cells via folate receptor-mediated endocytosis (RME) mechanism. At 260?µM concentration, SQV–PLGA NPs and SQV–Fol–PEG–PLGA NPs showed 20%, 20% and 23% cell growth inhibition in PC-3 cells, respectively whereas in MCF-7 cells it was 12%, 15% and 14% cell growth inhibition, respectively.

Conclusions: Developed targeted SQV–Fol–PEG–PLGA NPs were superior anticancer potential as compared to non-targeted SQV–PLGA NPs. Thus, these targeted NPs provide another option for anticancer drug delivery scientists.     

SN-38 loading capacity of hydrophobic polymer blend nanoparticles: formulation,optimization and efficacy evaluation

One of the most important problems in nanoencapsulation of extremely hydrophobic drugs is poor drug loading due to rapid drug crystallization outside the polymer core. The effort to use nanoprecipitation, as a simple one-step procedure with good reproducibility and FDA approved polymers like Poly(lactic-co-glycolic acid) (PLGA) and Polycaprolactone (PCL), will only potentiate this issue. Considering that drug loading is one of the key defining characteristics, in this study we attempted to examine whether the nanoparticle (NP) core composed of two hydrophobic polymers will provide increased drug loading for 7-Ethyl-10-hydroxy-camptothecin (SN-38), relative to NPs prepared using individual polymers. D-optimal design was applied to optimize PLGA/PCL ratio in the polymer blend and the mode of addition of the amphiphilic copolymer Lutrol^®F127 in order to maximize SN-38 loading and obtain NPs with acceptable size for passive tumor targeting. Drug/polymer and polymer/polymer interaction analysis pointed to high degree of compatibility and miscibility among both hydrophobic polymers, providing core configuration with higher drug loading capacity. Toxicity studies outlined the biocompatibility of the blank NPs. Increased in vitro efficacy of drug-loaded NPs compared to the free drug was confirmed by growth inhibition studies using SW-480 cell line. Additionally, the optimized NP formulation showed very promising blood circulation profile with elimination half-time of 7.4?h.     

Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application,Spatial Distribution,and Dosimetry

Targeted delivery of nanomedicine/nanoparticles (NM/NPs) to the site of disease (e.g., the tumor or lung injury) is of vital importance for improved therapeutic efficacy. Multimodal imaging platforms provide powerful tools for monitoring delivery and tissue distribution of drugs and NM/NPs. This study introduces a preclinical imaging platform combining X‐ray (two modes) and fluorescence imaging (three modes) techniques for time‐resolved in vivo and spatially resolved ex vivo visualization of mouse lungs during pulmonary NP delivery. Liquid mixtures of iodine (contrast agent for X‐ray) and/or (nano)particles (X‐ray absorbing and/or fluorescent) are delivered to different regions of the lung via intratracheal instillation, nasal aspiration, and ventilator‐assisted aerosol inhalation. It is demonstrated that in vivo propagation‐based phase‐contrast X‐ray imaging elucidates the dynamic process of pulmonary NP delivery, while ex vivo fluorescence imaging (e.g., tissue‐cleared light sheet fluorescence microscopy) reveals the quantitative 3D drug/particle distribution throughout the entire lung with cellular resolution. The novel and complementary information from this imaging platform unveils the dynamics and mechanisms of pulmonary NM/NP delivery and deposition for each of the delivery routes, which provides guidance on optimizing pulmonary delivery techniques and novel‐designed NM for targeting and efficacy.     

Targeted biodegradable nanoparticles for drug delivery to smooth muscle cells

Targeted delivery of therapeutic agents to prevent smooth muscle cell (SMC) proliferation is important in averting restenosis (a narrowing of blood vessels). Since platelet derived growth factor (PDGF) receptors are over-expressed in proliferating SMCs after injury from cardiovascular interventions, such as angioplasty and stent implantation, our hypothesis is that conjugation of PDGF-BB (platelet-derived growth factor BB (homodimer)) peptides to biodegradable poly (D,L-lactic-co-glycolide) (PLGA) nanoparticles (NPs) would exhibit an increased uptake of these NPs by proliferating SMCs. In this study, poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles containing dexamethasone were formulated and conjugated with PDGF-BB peptides. These NPs were stable, biocompatible, and exhibited a sustained drug release over 14 days. Various particle uptake studies using HASMCs (human aortic smooth muscle cells) demonstrated that PDGF-BB peptide-conjugated nanoparticles significantly increased cellular uptake and decreased proliferation of HASMCs compared to control nanoparticles (without conjugation of PDGF-BB peptides). These NPs were internalized primarily by clathrin-mediated endocytosis and macropinocytosis. Our in vitro results suggest that PDGF-BB peptide-conjugated NPs could represent as an effective targeted, sustained therapeutic delivery system to reduce restenosis and neointimal hyperplasia.     

A Comparative In Vivo Study of Albumin‐Coated Paclitaxel Nanocrystals and Abraxane

Nanoparticulate drug carriers exploit the enhanced permeability of tumor vasculature to achieve selective delivery of chemotherapeutic drugs. For this purpose, nanoparticles (NPs) need to circulate with a long half‐life, enter tumors via the permeable vasculature and stay in tumors via favorable interactions with tumor cells. To fulfill these requirements, albumin‐coated nanocrystal formulation of paclitaxel (PTX), Cim‐F‐alb, featuring high drug loading content, physical stability in serum, and surface‐bound albumin in its native conformation is prepared. The pharmacokinetic and biodistribution (PK/BD) profiles of Cim‐F‐alb in a mouse model of B16F10 melanoma show that Cim‐F‐alb exhibits a longer plasma half‐life and a greater PTX deposition in tumors than Abraxane by ≈1.5 and ≈4.6 fold, respectively. Biolayer interferometry analysis indicates that Cim‐F‐alb has less interaction with serum proteins than nanocrystals lacking albumin coating, indicating the protective effect of the surface‐bound albumin against opsonization in the initial deposition phase. With the advantageous PK/BD profiles, Cim‐F‐alb shows greater and longer‐lasting anticancer efficacy than Abraxane at the equivalent dose. This study demonstrates the significance of controlling circulation stability and surface property of NPs in efficient drug delivery to tumors and enhanced anticancer efficacy.     

Intracellular delivery of cysteine protease inhibitor cystatin by polymeric nanoparticles

Two polymers chitosan and poly(lactide-co-glycolide) copolymer (PLGA) were investigated to develop nanoparticles (NPs) for delivery of protein drug substance into tumour cells. Cystatin was selected as a model protein drug due to its high potential to inhibit cysteine proteases, known to trigger the invasive process. Ionotropic gelation of chitosan with tripolyposphate and precipitation of PLGA polymer from a double emulsion system by a solvent diffusion process were used to produce 250-300 nm in diameter NPs. The cellular uptake of NPs was tested on a transformed human breast epithelial cell line, MCF-10A neoT, characterized by an increased expression of cysteine proteases and highly invasive cell phenotype. The influence of NPs on cell viability was evaluated by MTT test showing IC50 400 microg/ml for PLGA and 5 mg/ml for chitosan NPs. As determined by fluorescence microscopy chitosan NPs did not enter the cells during 1-hour incubation whereas the same amount of PLGA NPs were in the cells already after 5 min of incubation. Cystatin delivered into MCF-10A neoT cells by PLGA NPs effectively inhibited intracellular proteolytic activity of cathepsin B, as detected by specific fluorogenic substrate Z-Arg2 cresyl violet. On the contrary, free cystatin in solution did not internalise into the cells and inhibit cathepsin B. To conclude, PLGA NPs with cystatin but not chitosan NPs were targeted through endocytosis to the lysosomal compartments that are rich of proteases enzymes. Our results suggest new strategy to inactivate intracellular tumour-associated proteases, and consequently the invasion behaviour of tumour cells, which could contribute to cancer therapy.     

Preparation and in vitro evaluation of meloxicam-loaded PLGA nanoparticles on HT-29 human colon adenocarcinoma cells

Context: The inhibitors of cyclooxygenase (COX)-2 play an important role in cancer chemoprevention. Certain COX-2 inhibitors exert antiproliferative and pro-apoptotic effects on cancer cells.

Objective: In this study, meloxicam, which is an enolic acid-type preferential COX-2 inhibitor, was encapsulated in poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) to maintain local high concentration, and its efficacy was determined.

Methods: NPs were prepared by using salting-out and emulsion-evaporation steps. Meloxicam-loaded NP formulations were evaluated with respect to the drug loading, particle size, polydispersity index, zeta potential, drug release rate, and residual poly(vinyl alcohol) (PVA) percentage. The effects of PLGA and PVA molecular weight variations on the physicochemical properties of NPs were investigated. Stability of meloxicam in NPs was assessed over 3 months. COX-2 expressing human colon adenocarcinoma cell line HT-29 was used in cellular uptake and viability assays.

Results: NPs had a spherical shape and a negative zeta potential, and their size ranged between 170–231?nm with a lower polydispersity index. NPs prepared with high molecular weight PLGA were shown to be physically stable over three months at 4°C. The increase in molecular weight of the polymer and emulsifier reduced the in vitro release rate of meloxicam from NPs. Meloxicam-loaded NPs showed cytotoxic effects on HT-29 cells markedly at 800 µM. Cancer cells had high uptake of coumarin-6-loaded NPs.

Conclusion: The PLGA NPs developed in this study can be a potentially effective drug delivery system of meloxicam for the treatment of colon cancer.     

Fabrication and characterization of porous poly(lactic-<Emphasis Type="Italic">co</Emphasis>-glycolic acid) (PLGA) microspheres for use as a drug delivery system

In this work, Simvastatin (SIM) loaded porous poly(lactic-co-glycolic acid) (PLGA) microspheres were fabricated using the W/O/W1/W2 double emulsion and solvent evaporation method. The optimal conditions for fabricating porous PLGA microspheres were determined to be 20% distilled water (v/v), 10% PLGA (m/v), and a 4:1 ratio of internal polyvinyl alcohol (PVA) to dichloromethane (DCM). The pores size distribution of porous PLGA microspheres was varied from 0.01 to 40 μm, while their particle displayed a bimodal size distribution that had two diameter peaks at around 100 μm and 500 μm. The SIM encapsulation efficacy was found to be very high with a yield near 80% and the porous PLGA microspheres showed the excellent biocompatibility. In addition, the drug release profile was found to be significantly different from a temporal basis. Base on the combined results of this study, SIM loaded PLGA microspheres holds great promise for use in biomedical applications, especially in drug delivery system or tissue regeneration.     

In vitro and in vivo evaluation of cubosomal in situ nasal gel containing resveratrol for brain targeting

The aim of this study was to enhance the delivery of resveratrol to the brain through the transnasal route by cubosomes. Cubosomes were prepared using glycerol monooleate and Lutrol F127 by probe sonication method. A 3² full factorial design was used for optimization of cubosomes and batch containing 4% w/v glycerol monooleate and 1.5% w/v of Lutrol F 127 was optimized. The selected cubosomal batch was cubical in shape, having mean particle size 161.5?±?0.12?nm. Entrapment efficiency was found to be 83.08% with zeta potential of –20.9?mV. In vitro release of cubosomal batch showed controlled release of drug profile (67%) up to 24?h. The optimized cubosomal dispersion was dispersed into gelling polymer (poloxamer 407) to form in situ gel for nasal use. The optimal cubosomal gel (containing 12% w/v poloxamer 407) had been subjected to ex-vivo permeation and in vivo biodistribution studies. It showed significantly higher transnasal permeation and better distribution to brain, when compared to the drug solution (i.n.) and drug solution (oral). Finally the cubosomal gel could be considered as a promising carrier for brain targeting of Resveratrol (Res) through transnasal route.     

Microfluidic Synthesis of Ultrasmall Chitosan/Graphene Quantum Dots Particles for Intranasal Delivery in Alzheimer's Disease Treatment

Nanoparticles (NPs) based therapies for Alzheimer's disease (AD) attract interest due to their ability to pass across or bypass the blood-brain barrier. Chitosan (CS) NPs or graphene quantum dots (GQDs) are promising drug carriers with excellent physicochemical and electrical properties. The current study proposes the combination of CS and GQDs in ultrasmall NP form not as drug carriers but as theranostic agents for AD. The microfluidic-based synthesis of the CS/GQD NPs with optimized characteristics makes them ideal for transcellular transfer and brain targeting after intranasal (IN) delivery. The NPs have the ability to enter the cytoplasm of C6 glioma cells in vitro and show dose and time-dependent effects on the viability of the cells. IN administration of the NPs to streptozotocin (STZ) induced AD-like models lead to a significant number of entrances of the treated rats to the target arm in the radial arm water maze (RAWM) test. It shows the positive effect of the NPs on the memory recovery of the treated rats. The NPs are detectable in the brain via in vivo bioimaging due to GQDs as diagnostic markers. The noncytotoxic NPs localize in the myelinated axons of hippocampal neurons. They do not affect the clearance of amyloid β (Aβ) plaques at intercellular space. Moreover, they showed no positive impact on the enhancement of MAP2 and NeuN expression as markers of neural regeneration. The memory improvement in treated AD rats may be due to neuroprotection via the anti-inflammation effect and regulation of the brain tissue microenvironment that needs to be studied.     

Phospholipid–polymer hybrid nanoparticle-mediated transfollicular delivery of quercetin: prospective implement for the treatment of androgenic alopecia

Abstract

Objectives: The aim of the study was to deliver effective doses of quercetin (Que) to the lower region of hair follicles (HFs) using the transfollicular route through dipalmotylphosphatidylcholine (DPPC)-reinforced poly lactide-co- glycolide nanoparticles (DPPC-PLGA hybrid NPs) for the treatment of alopecia.

Method: PLGA and DPPC-PLGA hybrid NPs were prepared by double-emulsification solvent evaporation method. NPs were characterized for size, shape, zeta potential entrapment and drug release. Drug-polymer interactions were determined by infrared spectroscopy (Fourier transform infrared spectroscopy, FTIR) and differential scanning calorimetry (DSC). Follicular uptake of fluorescent marker tagged NPs was assessed on isolated rat skin by fluorescent microscopy. Potential of hybrid NPs to induce hair regrowth was tested on testosterone-induced alopecia in rat models by visual inspection, hair follicular density measurement (no./mm), and histological skin tissue section studies.

Key findings: Hybrid NPs had mean vesicles size 339?±?1.6, zeta potential –32.6?±?0.51, and entrapment efficiency 78?±?5.5. Cumulative drug release after 12?h was found to be 47.27?±?0.79%. FTIR and DSC confirmed that drug was independently dispersed in the amorphous form in the polymer. Data from fluorescence microscopy suggested that NPs were actively taken up by HFs. In-vivo studies on alopecia-induced rat models showed that hybrid NPs improved hair regrowth potential of Que and accumulation of NPs at HFs end region inhibit HFs cells apoptosis.

Conclusion: This study concludes that phospholipid–polymer hybrid NPs could be the promising transfollicular delivery system for Que in the treatment of androgenic alopecia management.     

Targeted nanoparticles for the non-invasive detection of traumatic brain injury by optical imaging and fluorine magnetic resonance imaging

Necrosis is a form of cell death that occurs only under pathological conditions such as ischemic diseases and traumatic brain injury (TBI). Non-invasive imaging of the affected tissue is a key component of novel therapeutic interventions and measurement of treatment responses in patients. Here, we report a bimodal approach for the detection and monitoring of TBI. PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), encapsulating both near infrared (NIR) fluorophores and perfluorocarbons (PFCs), were targeted to necrotic cells. We used cyanine dyes such as IRDye 800CW, for which we have previously demonstrated specific targeting to intracellular proteins of cells that have lost membrane integrity. Here, we show specific in vivo detection of necrosis by optical imaging and fluorine magnetic resonance imaging (¹⁹F MRI) using newly designed PLGA NP(NIR700 + PFC)-PEG-800CW. Quantitative ex vivo optical imaging and ¹⁹F MR spectroscopy of NIR-PFC content in injured brain regions and in major organs were well correlated. Both modalities allowed the in vivo identification of necrotic brain lesions in a mouse model of TBI, with optical imaging being more sensitive than ¹⁹F MRI. Our results confirm increased blood pool residence time of PLGA NPs coated with a PEG layer and the successful targeting of TBI-damaged tissue. A single PLGA NP containing NIR-PFC enables both rapid qualitative optical monitoring of the TBI state and quantitative 3D information from deeper tissues on the extent of the lesion by MRI. These necrosis-targeting PLGA NPs can potentially be used for clinical diagnosis of brain injuries.

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Size-tunable nanoparticles composed of dextran-b-poly(D,L-lactide) for drug delivery applications

Nanoparticles (NPs) formulated using self-assembly of block copolymers have attracted significant attention as nano-scaled drug delivery vehicles. Here we report the development of a biodegradable NP using self-assembly of a linear amphiphilic block copolymer, Dex-b-PLA, composed of poly(D,L-lactide), and dextran. The size of the NPs can be precisely tuned between 15 and 70 nm by altering the molecular weight (M _W) of the two polymer chains. Using doxorubicin as a model drug, we demonstrated that the NPs can carry up to 21% (w/w) of the drug payload. The release profile of doxorubicin from NPs showed sustained release for over 6 days. Using a rat model, we explored the pharmacokinetics profiles of Dex-b-PLA NPs, and showed proof-of-concept that long circulation lifetime of the NPs can be achieved by tuning the M _W of Dex-b-PLA block copolymer. While the terminal half-life of Dex-b-PLA NPs (29.8 h) was similar to that observed in poly(ethylene glycol)-coated (PEG-coated) NPs (27.0 h), 90% of the injected Dex-b-PLA NPs were retained in the blood circulation for 38.3 h after injection, almost eight times longer than the PEG-coated NPs. The area under curve (AUC) of Dex-b-PLA NPs was almost four times higher than PEG-based NPs. The biodistribution study showed lower accumulation of Dex-b-PLA NPs in the spleen with 19.5% initial dose per gram tissue (IDGT) after 24 h compared to PEG-coated poly(lactide-co-glycolide) (PLGA) NPs (29.8% IDGT). These studies show that Dex-b-PLA block copolymer is a promising new biomaterial for making controlled nanoparticles as drug delivery vehicles.      

Sialic acid‐conjugated PLGA nanoparticles enhance the protective effect of lycopene in chemotherapeutic drug‐induced kidney injury

Lycopene (LYC) is known to protect cells from oxidative damage caused by free radicals in human tissues. In the present study, the authors designed a LYC‐loaded sialic acid (SA)‐conjugated poly(D,L‐lactide‐co‐glycolide) (PLGA) nanoparticle (LYC‐NP) to enhance the therapeutic efficacy of LYC in acute kidney injury. The characteristics of the LYC‐NPs were defined according to particle size, morphology, and in vitro drug release. The LYC‐NPs exhibited a controlled release of LYC over 48 h. Confocal laser scanning microscopy clearly highlighted the targeting potential of SA. Enhanced green fluorescence was observed for the LYC‐NPs in H₂ O₂ ‐treated human umbilical vein endothelial cells, indicating enhanced internalisation of NPs. The LYC‐NPs showed significantly greater cell viability than H₂ O₂ ‐treated cells. In addition, the LYC‐NPs remarkably reduced proinflammatory cytokine levels, attributable mainly to the increased cellular internalisation of the SA‐based carrier delivery system. Furthermore, protein levels of caspase‐3 and ‐9 were significantly down‐regulated after treatment with the LYC‐NPs. Overall, they have demonstrated that SA‐conjugated PLGA‐NPs containing LYC could be used to treat kidney injury.Inspec keywords: fluorescence, biomedical materials, biological tissues, cellular biophysics, drugs, proteins, molecular biophysics, injuries, drug delivery systems, kidney, nanomedicine, biochemistry, optical microscopy, nanoparticles, nanofabrication, cancer, toxicology, blood vessels, particle sizeOther keywords: sialic acid‐conjugated PLGA nanoparticles, chemotherapeutic drug‐induced kidney injury, LYC‐NP, LYC‐loaded sialic acid‐conjugated poly(D,L‐lactide‐co‐glycolide) nanoparticle, SA‐conjugated PLGA‐NP, protective effect, lycopene, human tissues, particle size, in vitro drug release, confocal laser scanning microscopy, green fluorescence, human umbilical vein endothelial cells, cell viability, proinflammatory cytokine levels, cellular internalisation, SA‐based carrier delivery system, time 48.0 hour     

Superior Intratumoral Penetration of Paclitaxel Nanodots Strengthens Tumor Restriction and Metastasis Prevention

Recently discovered intratumoral diffusion resistance, together with poor solubility and nontargeted distribution of chemotherapeutic drugs, has significantly impaired the performance of cancer treatments. By developing a well‐designed droplet‐confined/cryodesiccation‐driven crystallization approach, we herein report the successful preparation of nanocrystallites of insoluble chemotherapeutic drug paclitaxel (PTX) in forms of nanodots (NDs, ≈10 nm) and nanoparticles (NPs, ≈70 nm) with considerably high drug loading capacity. Superficially coated Pluronic F127 is demonstrated to endow the both PTX nanocrystallites with excellent water solubility and prevent undesired phagocyte uptake. Further decoration with tumor‐penetrating peptide iRGD, as expected, indiscriminatively facilitates tumor cell uptake in traditional monolayer cell culture model. On the contrary, distinctly enhanced performances in inward penetration and ensuing elimination of 3D multicellular tumor spheroids are achieved by iRGD‐NDs rather than iRGD‐NPs, revealing the significant influence of particle size variation in nanoscale. In vivo experiments verify that, although efficient tumor enrichment is achieved by all nanocrystallites, only the iRGD‐grafted nanocrystallites of ultranano size realize thorough intratumoral delivery and reach cancer stem cells, which are concealed inside the tumor core. Consequently, much strengthened restriction on progress and metastasis of orthotopic 4T1 mammary adenocarcinoma is achieved in murine model, in sharp contrast to commercial PTX formulation Taxol.     

新型生物素接枝聚乳酸纳米球的制备及性能研究

利用自组装方式制备生物素接枝聚乳酸材料(BPLA)的纳米球,对其性能进行表征;体外探讨BPLA纳米球与链霉亲和素和生物素的结合能力,据此判断BPLA纳米球的潜在靶向性。结果表明BPLA纳米球呈球形,平均粒径<200nm,分散系数<0.15,平均电位<-25mV;静置1月稳定;浓度为0.01～1.0mg/mL的BPLA纳米球的溶血率均低于5%;在37℃体外模拟体液静止和流动情况下能够与链霉亲和素进行结合;同时,在以链霉亲和素为臂时,BPLA纳米球仍然具备与生物素特异性结合能力。显示出BPLA纳米球在药物靶向领域具有潜在应用前景。