PLGA NPs Research Articles

Nanotechnology for Therapy of Zoonotic Diseases: A Comprehensive Overview

AbstractZoonotic infections belong to multiple infectious diseases transferred from animals to humans. Now, the treatment and diagnosis of zoonotic infections are perplexing due to genetic mutations, target site modifications, and multi‐drug resistance. Despite their benefits, most diagnostic molecular techniques have certain limits in terms of repeatability and sensitivity, mainly due to the heterogeneity among the diverse family of zoonotic pathogens. Therefore, developing more efficient and cost‐effective theranostics tools is the need of the hour to address these concerns. For this purpose, nanotechnology has revolutionized medicine with versatile potential capabilities for diagnosing and treating zoonosis via the targeted and controlled delivery of antimicrobial drugs via binding to the overexpressed infectious macrophages. Massive advancements have been made in fabricating novel nano‐based formulations to control zoonosis based on the use of poly(ethylenimine)‐conjugated nanomicelles, mannosylated thiolated chitosan (MTC)‐coated PM‐loaded PLGA NPs, mannose linked thiolated nanocarriers, adjuvanted pDNA hydrogel, arginine‐based nanocarriers, quantum dots to treat and diagnose a wide range of zoonotic diseases, including zoonotic influenza, salmonellosis, leishmaniasis, rabies, brucellosis, Lyme Disease, tuberculosis, and other infections caused by West Nile Virus, emerging coronaviruses (SARS, MERS, COVID‐19), in a preferentially targeted way. Recently developed anti‐pathogen loaded‐nanoformulations with enhanced cellular uptake, biocompatibility, and hemocompatibility have shown the ability to cross biological barriers when orally administrated. Therefore, this article reviewed the latest milestones and future growth areas in the field of efficient theranostics platforms to manage zoonotic infections.

Paclitaxel and Lapatinib dual loaded chitosan-coated PLGA nanoparticles enhance cytotoxicity by circumventing MDR1-mediated trastuzumab resistance in HER2 positive breast cancers: In-vitro and in-vivo studies

Treatment options for multidrug-resistant breast cancer are limited and ineffective. Few combinations of chemotherapeutic agents are clinically successful in treating multiple drug-resistant cancers. However, due to their varied pharmacokinetic characteristics, it is challenging to deliver dual drugs to the tumor simultaneously with the best proportion by simple co-administration. This study aimed to generate chitosan-coated PLGA nanoparticles delivering a synergistic combination of Paclitaxel (PTX) and Lapatinib (LPB) to improve efficacy in patients with multidrug-resistant breast cancer. In comparison to sensitive BT-474 cells, the 3:1 M ratio of PTX/LPB demonstrated significant synergism with a reversal index of approximately 13.4 in trastuzumab-resistant BT-474/TR cells. Particle diameters of the prepared chitosan (CS) PLGA Nps ranged from 157.4 ± 9.2 to 263.5 ± 13.5 nm. CS-coated Nps exhibited good EE and DL values of 80.8 ± 3.4% and 1.5 ± 0.12%, respectively. Moreover, CS-coating allowed successful co-delivery of PTX and LPB, resulting in the maximum in-vitro release within 72 h. Cytotoxicity against BT-474/TR cells was significantly increased when CS-coated dual loaded Nps were compared to other Nps, including free PTX, LPB, and their mixture. Quantification of the intracellular drug accumulation revealed that the encapsulation effectively increased drug uptake in BT-474/TR cells. These CS-coated dual loaded Nps exerted an excellent synergistic effect in BT-474/TR cells, leading to significantly improved cell inhibition via circumventing the MDR1 mediated trastuzumab resistance. Additionally, co-delivery of PTX and LPB demonstrated the most effective tumor growth reduction in the BT-474/TR human breast tumor xenograft compared to the saline control, single loaded PTX, and LPB Nps and a mixture of PTX and LPB combinations. The data suggest that CS-coated PLGA Nps loaded with PTX and LPB concurrently may be one of the most promising formulations for treating MDR1 mediated chemoresistance in HER2-positive breast tumors.

Curcumin-Encapsulated Chitosan-Coated Nanoformulation as an Improved Otoprotective Strategy for Ototoxic Hearing Loss.

Overexpression of apoptotic factors in the inner ear is generally proven to induce ototoxicity. This has aroused research interest in various antiapoptotic drugs, the most representative of which is curcumin (CUR). In this study, two nanoformulations of CUR were developed with sustained-release behavior to improve their protective effects against ototoxic hearing loss (HL), which were the nanoparticles of CUR-loaded poly(lactic acid-glycolic acid) (CUR-PLGA NPs) and CUR-loaded chitosan-coated PLGA NPs (CUR-CS/PLGA NPs). The obtained results revealed that both CUR-NPs provided otoprotection in vitro and in vivo, and their effective doses in guinea pigs were much less than that of dexamethasone, which was clinically used to treat HL. Moreover, relative to CUR and CUR-PLGA NPs, CUR-CS/PLGA NPs exhibited the highest accumulation in HEI-OC1 cells and guinea pigs' cochlea. In pharmacodynamic experiments, the optimal administration timing was investigated, and CUR-CS/PLGA NPs showed sustained efficacy and the best hearing improvement at all tested sound frequencies. Lastly, the protective effect of CUR nanoformulations was further validated via inhibition of Caspase-3 and Bax activation, thereby reducing the concentration of reactive oxygen species and protecting mitochondrial integrity in hair cells. Collectively, CUR-CS/PLGA NPs demonstrated potent and lasting effects against ototoxic HL, making our novel formulation a promising candidate for the alleviation of sensorineural HL.

A novel approach to control Botrytis cinerea fungal infections: uptake and biological activity of antifungals encapsulated in nanoparticle based vectors

Botrytis cinerea, responsible for grey mold diseases, is a pathogen with a broad host range, affecting many important agricultural crops, in pre and post harvesting of fruits and vegetables. Commercial fungicides used to control this pathogen are often subjected to photolysis, volatilization, degradation, leaching, and runoff during application. In this context, the use of a delivery system, based on poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) represents an innovative approach to develop new pesticide formulations to successfully fight B. cinerea infections. In order to study NPs uptake, B. cinerea conidia and mycelium were treated with PLGA NPs loaded with the high fluorescent probe coumarin 6 (Cu6-PLGA NPs) and analyzed under ApoTome fluorescence microscopy. The observations revealed that 50 nm Cu6-PLGA NPs penetrated into B. cinerea conidia and hyphae, as early as 10 min after administration. Pterostilbene, a natural compound, and fluopyram, a synthetic antifungal, were entrapped in PLGA NPs, added to B. cinerea conidia and mycelium, and their antifungal activity was tested. The results revealed that the compounds loaded in NPs exhibited a higher activity against B. cinerea. These results lay the foundations for the use of PLGA NPs as a new strategy in plant pest management.

TLR2 agonistic lipopeptide enriched PLGA nanoparticles as combinatorial drug delivery vehicle

The use of multiple Toll-Like Receptor (TLR) agonists as vaccine adjuvants has been proved to be beneficial against various diseases. Polymeric nanoparticles (Nps) provide wide range of options to incorporate multiple TLR agonists while ensuring optimal delivery and non-toxicity. To synergistically engage the cross-talk of TLR2 and TLR7, we synthesized pathogen mimicking Poly(lactic-co-glycolic acid) (PLGA) Nps encapsulating T7 (TLR7 agonist) and T2 lipopeptide (TLR2 agonist). The single emulsification-solvent evaporation process was employed for the synthesis where both hydrophobic T7 and TLR2 agonists were incorporated in a single step. Fourier Transform Infrared (FTIR) spectroscopy, Thermogravimetric (TGA) and Differential Scanning Calorimetry (DSC) analysis of pure PLGA and both agonists (T2 and T7) were compared with that of synthesized PLGA Nps to better understand the chemical bonding and stability. The physicochemical assessment was performed starting with particle size analysis and was confirmed using Transmission Electron Microscopy (TEM). During in-vitro release studies, about 40% of T7 was released for the first 5 hr followed by a two-day period of sustained release. Kinetics modelling results showed that the release kinetics was unaffected by the addition of T2 lipopeptide into PLGA Nps. These findings confirmed successful co-delivery of both agonists in same cargo that can be utilise to generate a balance immune response against various infectious diseases such as malaria, leishmania, hepatitis, influenza. The higher drug loading and the capability of PLGA suspension to get lyophilised paved the way for long-term storage, effective encapsulation, and co-delivery in vaccination.

DEVELOPMENT OF HERBAL NANOPARTICULATE FORMULATION FOR THE TREATMENT OF SOLID TUMOR IN MICE

The relevance of nanotechnology to drug delivery systems for cancer therapy has progressively received great attention. Castalin has been initiate to be very efficacious against many different types of cancer cells. Our present work investigated the efficiency of encapsulation of castalin in poly (lactic-co- glycolic acid) (PLGA) nanoparticles using solid/oil/water emulsion solvent evaporation method. to conclude, the in vivo anti-tumor activity of Castalin-loaded PLGA NPs was evaluated in tumor-bearing mice. The NPs obtained had smooth surfaces with particle sizes ranged from 161 ± 3.05 to 164 ± 8.7 nm with slightly positive surface charge ranged from 1.09 ± 0.15 to 3.71 ± 0.44 mV. Entrapment of Castalin ranged between 85.5 ± 1.8% and 87 ± 1.3% with yields not less than 102.32%. Total protein adsorbed was less than 25.5 µg total protein/1 mg NP. In vitro drug liberate was less than 89.1% at 12 h. to finish, significant reductions in tumor growth rate and mortality rate were observed for PLGA NP formulations compared to both Castalin solution and naked NPs

Mucoadhesive PLGA Nanospheres and Nanocapsules for Lactoferrin Controlled Ocular Delivery.

Background: the present work describes the preparation, characterization and optimization of eight types of PLGA-based nanosystems (nanospheres and nanocapsules) as innovative mucoadhesive drug delivery systems of lactoferrin, in order to achieve a preclinical consistent base as an alternative pharmacological treatment to different ocular syndromes and diseases. Methods: All different nanoparticles were prepared via two modified nanoprecipitation techniques, using a three-component mixture of drug/polymer/surfactant (Lf/PLGA/Poloxamer), as a way to overcome the inherent limitations of conventional PLGA NPs. These modified polymeric nanocarriers, intended for topical ophthalmic administration, were subjected to in vitro characterization, surface modification and in vitro and in vivo assessments. Results: An appropriate size range, uniform size distribution and negative ζ potential values were obtained for all types of formulations. Lactoferrin could be effectively included into all types of nanoparticles with appropriate encapsulation efficiency and loading capacity values. A greater, extended, and controlled delivery of Lf from the polymeric matrix was observed through the in vitro release studies. No instability or cytotoxicity was proved for all the formulations by means of organotypic models. Additionally, mucoadhesive in vitro and in vivo experiments show a significant increase in the residence time of the nanoparticles in the eye surface. Conclusions: all types of prepared PLGA nanoparticles might be a potential alternative for the topical ophthalmic administration of lactoferrin.

Endothelial cell-targeting, ROS-ultrasensitive drug/siRNA co-delivery nanocomplexes mitigate early-stage neutrophil recruitment for the anti-inflammatory treatment of myocardial ischemia reperfusion injury

Neutrophils serve as a key contributor to the pathophysiology of myocardial ischemia reperfusion injury (MIRI), because the unregulated activation and infiltration of neutrophils lead to overwhelming inflammation in the myocardium to cause tissue damage. Herein, endothelial cell-targeting and reactive oxygen species (ROS)-ultrasensitive nanocomplexes (NCs) were developed to mediate efficient co-delivery of VCAM-1 siRNA (siVCAM-1) and dexamethasone (DXM), which cooperatively inhibited neutrophil recruitment by impeding neutrophil migration and adhesion. RPPT was first synthesized via crosslinking of PEI 600 with ditellurium followed by modification with PEG and the endothelial cell-targeting peptide cRGD. RPPT was allowed to envelope the DXM-loaded PLGA nanoparticles and condense the siVCAM-1. After systemic administration in rats experiencing MIRI, the cRGD-modified NCs efficiently targeted and entered the inflamed endothelial cells, wherein RPPT was sensitively degraded by over-produced ROS to trigger intracellular siVCAM-1 release and potentiate the VCAM-1 silencing efficiency. As a consequence of the complementary function of DXM and siVCAM-1, the NCs notably mitigated neutrophil infiltration into ischemic myocardium, provoking potent anti-inflammatory efficacy to reduce MIRI and recover cardiac function. The present study offers an effective approach for the controlled co-delivery of siRNA and drug cargoes, and it also highlights the importance of multi-dimensional manipulation of neutrophils in anti-inflammatory treatment. Statement of significanceThe unregulated activation and infiltration of neutrophils lead to overwhelming inflammation in the myocardium after myocardial ischemia reperfusion injury (MIRI). Here, endothelial cell-targeting and ROS-ultrasensitive nanocomplexes (NCs), comprised of PLGA NPs decorated with cRGD-poly(ethylene glycol) (PEG)-modified, ditellurium-crosslinked PEI (RPPT), were developed to mediate efficient co-delivery of VCAM-1 siRNA (siVCAM-1) and dexamethasone (DXM). DXM and siVCAM-1 with complementary functions inhibited both the migration and adhesion of neutrophils, efficiently interventing the neutrophil recruitment and interrupting the self-amplified inflammation cascade in the injured myocardium. The molecular design of RPPT renders an effective example for constructing polymeric materials with high ROS sensitivity, and it resolves the critical dilemma related to polycation-mediated siRNA delivery, such as siRNA encapsulation versus release, and transfection efficiency versus toxicity.

Cocktail strategy based on a dual function nanoparticle and immune activator for effective tumor suppressive

BackgroundImmune checkpoint inhibitor-mediated immunotherapy cannot be carried out on a large scale clinically due to its low universality. In recent years, cyclic guanosine monophosphate synthase/interferon gene stimulating factor (cGAS/STING)-mediated innate immune signaling pathway-mediated immunotherapy has attracted more and more attention. In addition, metabolic inhibitors also show good effects on tumor treatment, but their application is often limited because of their large first pass effect or difficult administration.MethodsThe particle size and potential parameters were measured by DLS. In order to determine the optimal ratio of the two drugs, we calculated the CI value of different nanoparticles through MTT experiment, and simulated their synergistic effect through Gaussian software. Then the morphology and crystal form of the best proportion of drugs were studied by TEM and XRD. The anti-tumor mechanism of composite nanoparticles was confirmed by the determination of metabolic related indexes, Q-PCR and WB. The antitumor effect and immune activation effect were comprehensively evaluated by in vivo and in vitro experiments.ResultsHere, we found and synthesized BCP nanoparticles ((BPA + CPI) @ PLGA NPs) which can effectively reduce the metabolism of tumor cells and inhibit cell proliferation. At the same time, the release of mitochondrial DNA (mtDNA) caused by mitochondrial metabolism disorder further activated the cGAS/STING signal pathway in Hepa1–6 cells. We found that the drug-treated Hepa1–6 cells had obvious TBK1 phosphorylation and STING dimerization. Combined with STING agonist, it could effectively promote the activation of CD8 T cells and enhanced the therapeutic effect on liver cancer.ConclusionOur results showed that PLGA nanocarrier can successfully improve the dosage forms of two metabolic inhibitors and show the effect of synergistic therapy. BCP nanoparticles can also activate the innate immunity of tumor cells and significantly enhance tumor inhibition after combined with STING agonists. This study has high reference and transformation value for the combined treatment of immunosuppression and metabolic inhibition.Graphical

Receptor-targeted nanoparticles modulate cannabinoid anticancer activity through delayed cell internalization

Δ9-tetrahydrocannabinol (Δ9-THC) is known for its antitumor activity and palliative effects. However, its unfavorable physicochemical and biopharmaceutical properties, including low bioavailability, psychotropic side effects and resistance mechanisms associated to dosing make mandatory the development of successful drug delivery systems. In this work, transferring (Tf) surface-modified Δ9-THC-loaded poly(lactide-co-glycolic) nanoparticles (Tf-THC-PLGA NPs) were proposed and evaluated as novel THC-based anticancer therapy. Furthermore, in order to assess the interaction of both the nanocarrier and the loaded drug with cancer cells, a double-fluorescent strategy was applied, including the chemical conjugation of a dye to the nanoparticle polymer along with the encapsulation of either a lipophilic or a hydrophilic dye. Tf-THC PLGA NPs exerted a cell viability decreased down to 17% vs. 88% of plain nanoparticles, while their internalization was significantly slower than plain nanoparticles. Uptake studies in the presence of inhibitors indicated that the nanoparticles were internalized through cholesterol-associated and clathrin-mediated mechanisms. Overall, Tf-modification of PLGA NPs showed to be a highly promising approach for Δ9-THC-based antitumor therapies, potentially maximizing the amount of drug released in a sustained manner at the surface of cells bearing cannabinoid receptors.

A study of lovastatin and L-arginine co-loaded PLGA nanomedicine for enhancing nitric oxide production and eNOS expression.

Nitric oxide (NO) is an exceptional endogenous biological gas that mediates and regulates physiological and pathological processes in the human body. However, its synthesis process is impaired during athero-progression and formation. Hence, a strategy to boost NO production and target endothelial nitric oxide synthase (eNOS) is crucial and intriguing in atherosclerosis (AS) management. Herein, we prepare L-arginine (LA) and lovastatin (LV) co-loaded PLGA nanomedicine to achieve sustainable release for enhancing NO production. The utilization of LA reveals that LA has dual contributions, acting as a NO donor and enhancing the solubility of LV by stabilizing PLGA NPs. PLGA-LA/LV demonstrated its potential to boost NO in vitro and in vivo confirmed using DAF-FM DA, augment eNOS and p-eNOS mRNA and protein levels, and suppress the ki67 proliferation marker in VSMCs; in addition, it lowers the total cholesterol level of blood plasma in C57BL/6 mice. Moreover, PLGA can protect the compound delivered and enhance the bioavailability to reach and get released in the blood circulation after oral administration. Collectively, our results endow a safe and efficient nanomedicine outcome, specifically with potential for AS management.

Pre-Clinical Evidence for the Anti-Obesity Potential of Quercetin and Curcumin Loaded Chitosan/PEG Blended PLGA Nanoparticles

This research aimed to formulate quercetin (Qu) and curcumin (CUR)-loaded PLGA NPs coated with chitosan (CS) & PEG and to explore their therapeutic effect against obesity in rats. Qu and CUR nanostructures were prepared and characterized by Zetasizer and TEM. Then, the formulated nanoparticles and their free couterparts were employed for mitigation of obesity in female rats. The size of NPs was in nanometer range with an average size distribution 307.9 nm for Qu NPs and 322.5 nm for CUR NPs. The Qu NPs and CUR NPs were appeared in the TEM image containing core in which the Qu or CUR was localized and surrounded by the coat of PLGA-CS-PEG. The Qu NPs exhibited negative zeta potential at -8.5 mV, while, CUR NPs exhibited positive zeta potential at +0.916 mV. Treatment with orlistat, free Qu, Qu NPs, free CURor CUR NPs elicited significant decline in body weight, BMI and Lee index. Orlistat and CUR NPs significantly diminished liver, heart and visceral adipose tissue weights. Furthermore, the suggested treatments significantly reduced the gonadal and subcutaneous adipose tissue weights. Orlistat significantly lessened kidney and adrenal weights. All treatments significantly minimized serum Chol., TG, LDL, glucose, INS, HOMA-IR, LH, MDA, TLR4 and NF-κB levels and elevated serum HDL, E2 and TAC levels. Orlistat significantly enhanced serum IL-10 level. Conclusively, Qu and CUR nanoformulations offer anti-obesity potency through their hypolipidemic, hypoglycemic,antioxidative and anti-inflammatory effects. Both Qu and CUR NPs manifested superior effect than their free counterparts, may be because of solubility elevation as well as bioavailability of the nanoencapsulation.

Nanoarchitectonics of PLGA based polymeric nanoparticles with oseltamivir phosphate for lung cancer therapy: In vitro-in vivo evaluation

Oseltamivir phosphate (OSE) is an antiviral drug that also can inhibit tumor vascularization, growth and metastasis. The target of the present research was the delivery of OSE into the lung adenocarcinoma cells by means of developing nanosized, biocompatible and stealth nanoarchitectonics of pegylated PLGA NPs. For this goal, OSE encapsulated nanoarchitectonics of pegylated PLGA NPs were formulated and investigated for zeta potential, particle size, encapsulation efficiency, DSC, FT-IR, 1H-NMR and SEM analyses. In vitro release, cytotoxicity, determination of apoptotic pathways and in vivo CAM assay were carried out. NPs exhibited smaller particle size, relatively higher EE%, spherical shape, amorphous matrix formation and biphasic prolonged release pattern (fitted Peppas-Sahlin and Weibull model). All NPs was found as 103 times more effective than OSE on cancerous cells. Flow cytometry was employed to evaluate the apoptotic pathways using the Annexin V-FITC/PI, FITC Active Caspase-3 staining assay and mitochondrial membrane potential determination tests. Activations on caspase-3 pathways made us think that OSE loaded pegylated PLGA NPs triggered to apoptosis using intrinsic pathway. Upon in vivo studies, PLGA-OSE 3 demonstrated moderate antiangiogenic activity. These results indicate that OSE loaded PLGA NPs (especially PLGA-OSE 3) were chosen as a promising candidate and a potent formulation to treat lung cancer.

Bioadhesive poly(methyl vinyl ether-co-maleic anhydride)-TPGS copolymer modified PLGA/lipid hybrid nanoparticles for improving intestinal absorption of cabazitaxel

A bioadhesive nanocarrier, PTNP, was constructed by utilizing a novel poly(methyl vinyl ether-co-maleic anhydride)- D-α-Tocopheryl polyethylene glycol succinate (PVMMA-TPGS) copolymer in the PLGA/lipid hybrid nanoparticles (PLGA NPs) for improving oral delivery of cabazitaxel (CTX). The PVMMA-TPGS was synthesized by the ring-opening polymerization of the anhydride groups with the hydroxyl groups, combining the bioadhesive property of PVMMA with P-glycoprotein (P-gp) inhibitory effect of TPGS. The CTX-loaded PTNPs (CTX-PTNPs) were prepared by an emulsification-solvent evaporation method and performed a spherical appearance with a uniform particle size of 192.2 nm. The CTX-PTNPs were surface negatively charged, and exhibited good drug loading (10.2%) and encapsulation efficiency (92.1%). A sustained drug release and high stability in simulated gastrointestinal environment were confirmed in in vitro studies. The in vitro mucin adhesion and in vivo intestinal retention experiments indicated that the PTNPs had a stronger bioadhesive effect and a notably longer intestinal retention than the control PLGA NPs, due to the interaction of PVMMA on the PTNP surface with the intestinal mucosa. Moreover, an enhanced intestinal permeability of the PTNPs was also verified in in vivo and ex vivo intestinal permeation studies, which was probably attributed to the extended retention of PTNPs in intestinal mucosa and the P-gp inhibitory effect of TPGS. As respected, in in vivo pharmacokinetic study, the Tmax and oral bioavailability of CTX were dramatically improved to 1.08 h and 28.84% by the PTNPs, respectively, obviously superior to the CTX solution and the PLGA NPs, further demonstrating the high-efficiency in oral delivery of CTX. Hence, this bioadhesive carrier is proposed to be a potential and promising strategy for increasing oral absorption of small molecule insoluble drugs.

Polymeric Nanoparticles as a Promising Drug Delivery Platform for the Efficacious Delivery of Toll-Like Receptor 7/8 Agonists and IDO-Inhibitor

The current investigation delineates the poly(lactide-co-glycolic acid) nanoparticles (PLGA NPs) formulation as the drug encapsulating assembly using nanoprecipitation method. Specifically, for the first time, 8-fluorotryptanthrin (Try, an IDO1 inhibitor) and 1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4 amine (BBIQ, a TLR7 agonist) have been encapsulated in the PLGA NPs. BBIQ and Try are the immunomodulating agents which have some shortcomings such as their low solubility and dose-related side effects associated with their systematic administration. To overcome these shortcomings, successful loading of the BBIQ and Try has been done in the polymer-based assembly. To confirm the surfactant coating and drug interaction with the NPs, differential scanning calorimetry and fourier transform infrared spectroscopy have been employed. Physicochemical characterization of the blank and loaded NPs has been done using dynamic light scattering, zeta potential, thermogravimetric analysis a high-resolution transmission electron microscope, atomic force microscopy, and X-ray diffraction analysis. To study the drug release behaviour of the NPs, drug release profiles and kinetic modelling was employed. Thus, co-encapsulation of BBIQ and try within the NPs have proven to be a promising assembly that can be investigated further in cancer vaccines.

Improved oral delivery of insulin by PLGA nanoparticles coated with 5β-cholanic acid conjugated glycol chitosan

Oral insulin has been regarded as the best alternative to insulin injection in therapy of diabetes because of its convenience and painlessness. However, several obstacles in the gastrointestinal tract, such as gastric acid and enzyme, greatly reduce the bioavailability of oral insulin. Herein, we report design and preparation of poly (d, l-lactic-co-glycolic acid) nanoparticles (PLGA NPs) coated with 5β-cholanic acid modified glycol chitosan (GC-CA) (GC-CA@PLGA NPs) to improve the oral delivery of insulin. The GC-CA@PLGA NPs with the size of (302.73 ± 5.13 nm) and zeta potential of (25.03 ± 0.31 mV) were synthesized using the double-emulsion method. The insulin-loading capacity and encapsulation efficiency were determined to be 5.77 ± 0.58% and 51.99 ± 5.27%, respectively. Compared with GC-modified PLGA NPs (GC@PLGA NPs) and bare PLGA NPs, the GC-CA@PLGA NPs showed excellent stability and uptake by Caco-2 cells after simulated gastric acid digestion. Further experiment suggests good biocompatibility of GC-CA@PLGA NPs, including hemolysis and cytotoxicity. In in vivo experiment, the insulin loaded in the GC-CA@PLGA NPs exhibited a long-term and stable release profile for lowering blood glucose and presented 30.43% bioavailability in oral administration. In brief, we have developed an efficient and safe drug delivery system, GC-CA@PLGA NPs, for significantly improved oral administration of insulin, which may find potential application in the treatment of diabetes.

Antifungal and antibiofilm efficacy of cinnamaldehyde-loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles against Candida albicans.

Biofilm-associated Candida infections threaten public health and show high mortality. The drugs used in treatment are very limited due to reasons such as toxicity, low efficacy, and drug resistance, and new alternatives are needed. The use of natural products of plant origin in the biofilm management draws attention. CA (cinnamaldehyde, cinnamic aldehyde, or 3-phenyl-2-propenal) is an essential oil component that can also inhibit mold growth and mycotoxin production. However, there are some limitations in its use due to its poor solubility and volatility in water. Recently, the combination of natural components and nanoparticle-based drug delivery systems shows positive results. In this study, the effects of PLGA (poly(DL-lactide-co-glycolide)) nanoparticles arrested with CA (CA-PLGA NPs) on C. albicans planktonic and biofilm forms (prebiofilm and postbiofilm) were investigated. According to the results, the amount of active ingredient loaded in CA-PLGA NPs is much lower than the free CA and a strong antifungal effect was obtained even at this rate. Also, the postbiofilm application is more effective than prebiofilm application. PLGA NPs can also be a useful carrier for other essential oils, and their potential in various antifungal, antibiofilm, and biomedical applications should be investigated.

Co-Delivery of Curcumin and Bioperine via PLGA Nanoparticles to Prevent Atherosclerotic Foam Cell Formation.

Cholesterol-rich arterial plaques characterize atherosclerosis, a significant cause of heart disease. Nutraceuticals have received attention over the years, demonstrating potential benefits towards treating and preventing cardiovascular diseases (CVD), including atherosclerosis. Curcumin, a potent polyphenol present in Curcuma longa, has shown remarkable anti-atherosclerotic activity via anti-inflammatory and anti-oxidative properties. The bioavailability and low water solubility of curcumin limit its clinical translational purposes. These issues can be circumvented effectively by nano-drug delivery systems that can target atherosclerotic plaque sites. In this work, we chose to use curcumin and a natural bioenhancer called Bioperine (derived from Piper nigrum) inside a polymeric nano-drug delivery system for targeting atherosclerotic plaque sites. We selected two different ratios of curcumin:Bioperine to study its comparative effect on the inhibition of oxidized low-density lipoprotein (Ox-LDL)-induced foam cell formation. Our studies demonstrated that Cur-Bio PLGA NPs (both ratios) maintained the cell viability in THP-1 monocyte-derived macrophages above 80% at all periods. The 1:0.2:10 ratio of Cur-Bio PLGA NPs at a concentration of 250 μg/mL illustrated an enhanced reduction in the relative cholesterol content in the THP-1-derived foam cells compared to the 1:1:10 ratio. Confocal microscopy analysis also revealed a reduction in macrophage-mediated foam cell formation when administered with both the ratios of Cur-Bio PLGA NPs. Relative fold change in the mRNA expression of the genes involved in the inflammatory pathways in the atherosclerotic process downregulated NF-κB, CCL2/MCP-1, CD-36, and STAT-3 activity while upregulating the SCAR-B1 expression when treated with the Cur-Bio PLGA NPs. This study thus highlights the importance of natural-based compounds towards the therapeutic intervention against atherosclerotic activity when administered as preventive medicine.

Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells

BackgroundThe pathogenesis of chronic myeloid leukemia (CML) is the formation of the BCR/ABL protein, which is encoded by the bcr/abl fusion gene, possessing abnormal tyrosine kinase activity. Despite the wide application of tyrosine kinase inhibitors (TKIs) in CML treatment, TKIs drug resistance or intolerance limits their further usage in a subset of patients. Furthermore, TKIs inhibit the tyrosine kinase activity of the BCR/ABL oncoprotein while failing to eliminate the pathologenic oncoprotein. To develop alternative strategies for CML treatment using therapeutic antibodies, and to address the issue that antibodies cannot pass through cell membranes, we have established a novel intracellular delivery of anti-BCR/ABL antibodies, which serves as a prerequisite for CML therapy.MethodsAnti-BCR/ABL antibodies were encapsulated in poly(d, l-lactide-co-glycolide) nanoparticles (PLGA NPs) by a double emulsion method, and transferrin was labeled on the surface of the nanoparticles (Ab@Tf-Cou6-PLGA NPs). The characteristics of nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cellular uptake of nanoparticles was measured by flow cytometry (FCM). The effect of nanoparticles on the apoptosis and proliferation of CML cells was testified by FCM and CCK-8 assay. In addition, the anti-cancer impact of nanoparticles was evaluated in mouse models of CML.ResultsThe results demonstrated that the Ab@Tf-Cou6-PLGA NPs functioned as an intracellular deliverer of antibodies, and exhibited an excellent effect on degrading BCR/ABL oncoprotein in CML cells via the Trim-Away pathway. Treatment with Ab@Tf-Cou6-PLGA NPs inhibited the proliferation and induced the apoptosis of CML cells in vitro as well as impaired the oncogenesis ability of CML cells in vivo.ConclusionsIn conclusion, our study indicated that this approach achieved safe and efficient intracellular delivery of antibodies and degraded BCR/ABL oncoprotein via the Trim-Away pathway, which provides a promising therapeutic strategy for CML patients, particularly those with TKI resistance.

N-trimethyl chitosan coated nano-complexes enhance the oral bioavailability and chemotherapeutic effects of gemcitabine

N-trimethyl chitosan (TMC) is a multifunctional polymer that can be used in various nanoparticle forms in the pharmaceutical, nutraceutical and biomedical fields. In this study, TMC was used as a mucoadhesive adjuvant to enhance the oral bioavailability and hence antitumour effects of gemcitabine formulated into nanocomplexes composed of poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) conjugated with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). A central composite design was applied to achieve the optimal formulation. Cellular uptake and drug transportation studies revealed the nanocomplexes permeate over the intestinal cells via adsorptive-mediated and caveolae-mediated endocytosis. Pharmacokinetic studies demonstrated the oral drug bioavailability of the nanocomplexes was increased 5.1-fold compared with drug solution. In pharmacodynamic studies, the formulation reduced tumour size 3.1-fold compared with the drug solution. The data demonstrates that TMC modified nanocomplexes can enhance gemcitabine oral bioavailability and promote the anticancer efficacy.