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29 pages, 5549 KiB

Open AccessArticle

Effect of Solvents, Stabilizers and the Concentration of Stabilizers on the Physical Properties of Poly(d,l-lactide-co-glycolide) Nanoparticles: Encapsulation, In Vitro Release of Indomethacin and Cytotoxicity against HepG2-Cell

by Musaed Alkholief, Mohd Abul Kalam, Md Khalid Anwer and Aws Alshamsan

Pharmaceutics 2022, 14(4), 870; https://doi.org/10.3390/pharmaceutics14040870 - 15 Apr 2022

Cited by 14 | Viewed by 2642

Abstract

A biocompatible, biodegradable and FDA-approved polymer [Poly lactic-co-glycolic acid (PLGA)] was used to prepare the nanoparticles (NPs) to observe the effect of solvents, stabilizers and their concentrations on the physical properties of the PLGA-NPs, following the encapsulation and in vitro release [...] Read more.

A biocompatible, biodegradable and FDA-approved polymer [Poly lactic-co-glycolic acid (PLGA)] was used to prepare the nanoparticles (NPs) to observe the effect of solvents, stabilizers and their concentrations on the physical properties of the PLGA-NPs, following the encapsulation and in vitro release of Indomethacin (IND). PLGA-NPs were prepared by the single-emulsion solvent evaporation technique using dichloromethane (DCM)/chloroform as the organic phase with Polyvinyl-alcohol (PVA)/Polyvinylpyrrolidone (PVP) as stabilizers to encapsulate IND. The effects of different proportions of PVA/PVP with DCM/chloroform on the physiochemical properties (particle size, the polydispersity index, the zeta potential by Malvern Zetasizer and morphology by SEM) of the NPs were investigated. DSC was used to check the physical state, the possible complexation of PLGA with stabilizer(s) and the crystallinity of the encapsulated drug. Stabilizers at all concentrations produced spherical, regular-shaped, smooth-surfaced discrete NPs. Average size of 273.2–563.9 nm was obtained when PVA (stabilizer) with DCM, whereas it ranged from 317.6 to 588.1 nm with chloroform. The particle size was 273.2–563.9 nm when PVP was the stabilizer with DCM, while it was 381.4–466.6 nm with chloroform. The zeta potentials of PVA-stabilized NPs were low and negative (−0.62 mV) while they were comparatively higher and positive for PVP-stabilized NPs (+17.73 mV). Finally, drug-loaded optimal NPs were composed of PLGA (40 mg) and IND (4 mg) in 1 mL DCM/chloroform with PVA/PVP (1–3%), which resulted in sufficient encapsulation (54.94–74.86%) and drug loading (4.99–6.81%). No endothermic peak of PVA/PVP appeared in the optimized formulation, which indicated the amorphous state of IND in the core of the PLGA-NPs. The in vitro release study indicated a sustained release of IND (32.83–52.16%) from the PLGA-NPs till 72 h and primarily followed the Higuchi matrix release kinetics followed by Korsmeyer–Peppas models. The cell proliferation assay clearly established that the organic solvents used to prepare PLGA-NPs had evaporated. The PLGA-NPs did not show any particular toxicity in the HepG2 cells within the dose range of IND (250–500 µg/mL) and at an equivalent concentration of PLGA-NPs (3571.4–7142.7 µg/mL). The cytotoxicity of the hepatotoxic drug (IND) was reduced by its encapsulation into PLGA-NPs. The outcomes of this investigation could be implemented to prepare PLGA-NPs of acceptable properties for the encapsulation of low/high molecular weight drugs. It would be useful for further in vitro and in vivo applications to use this delivery system. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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21 pages, 7109 KiB

Open AccessArticle

Design, Development, Physicochemical Characterization, and In Vitro Drug Release of Formoterol PEGylated PLGA Polymeric Nanoparticles

by Ernest L. Vallorz, David Encinas-Basurto, Rick G. Schnellmann and Heidi M. Mansour

Pharmaceutics 2022, 14(3), 638; https://doi.org/10.3390/pharmaceutics14030638 - 14 Mar 2022

Cited by 6 | Viewed by 2701

Abstract

Polymeric nanoparticles’ drug delivery systems represent a promising platform for targeted controlled release since they are capable of improving the bioavailability and tissue localization of drugs compared to traditional means of administration. Investigation of key parameters of nanoparticle preparation and their impact on [...] Read more.

Polymeric nanoparticles’ drug delivery systems represent a promising platform for targeted controlled release since they are capable of improving the bioavailability and tissue localization of drugs compared to traditional means of administration. Investigation of key parameters of nanoparticle preparation and their impact on performance, such as size, drug loading, and sustained release, is critical to understanding the synthesis parameters surrounding a given nanoparticle formulation. This comprehensive and systematic study reports for the first time and focuses on the development and characterization of formoterol polymeric nanoparticles that have potential application in a variety of acute and chronic diseases. Nanoparticles were prepared by a variety of solvent emulsion methods with varying modifications to the polymer and emulsion system with the aim of increasing drug loading and tuning particle size for renal localization and drug delivery. Maximal drug loading was achieved by amine modification of polyethylene glycol (PEG) conjugated to the poly(lactic-co-glycolic acid) (PLGA) backbone. The resulting formoterol PEGylated PLGA polymeric nanoparticles were successfully lyophilized without compromising size distribution by using either sucrose or trehalose as cryoprotectants. The physicochemical characteristics of the nanoparticles were examined comprehensively, including surface morphology, solid-state transitions, crystallinity, and residual water content. In vitro formoterol drug release characteristics from the PEGylated PLGA polymeric nanoparticles were also investigated as a function of both polymer and emulsion parameter selection, and release kinetics modeling was successfully applied. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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13 pages, 2393 KiB

Open AccessEditor’s ChoiceArticle

Glycosylated Ang-(1-7) MasR Agonist Peptide Poly Lactic-co-Glycolic Acid (PLGA) Nanoparticles and Microparticles in Cognitive Impairment: Design, Particle Preparation, Physicochemical Characterization, and In Vitro Release

by David Encinas-Basurto, John P. Konhilas, Robin Polt, Meredith Hay and Heidi M. Mansour

Pharmaceutics 2022, 14(3), 587; https://doi.org/10.3390/pharmaceutics14030587 - 08 Mar 2022

Cited by 2 | Viewed by 2853

Abstract

Heart failure (HF) causes decreased brain perfusion in older adults, and increased brain and systemic inflammation increases the risk of cognitive impairment and Alzheimer’s disease (AD). Glycosylated Ang-(1-7) MasR agonists (PNA5) has shown improved bioavailability, stability, and brain penetration compared to Ang-(1-7) native [...] Read more.

Heart failure (HF) causes decreased brain perfusion in older adults, and increased brain and systemic inflammation increases the risk of cognitive impairment and Alzheimer’s disease (AD). Glycosylated Ang-(1-7) MasR agonists (PNA5) has shown improved bioavailability, stability, and brain penetration compared to Ang-(1-7) native peptide. Despite promising results and numerous potential applications, clinical applications of PNA5 glycopeptide are limited by its short half-life, and frequent injections are required to ensure adequate treatment for cognitive impairment. Therefore, sustained-release injectable formulations of PNA5 glycopeptide are needed to improve its bioavailability, protect the peptide from degradation, and provide sustained drug release over a prolonged time to reduce injection administration frequency. Two types of poly(D,L-lactic-co-glycolic acid) (PLGA) were used in the synthesis to produce nanoparticles (≈0.769–0.35 µm) and microparticles (≈3.7–2.4 µm) loaded with PNA5 (ester and acid-end capped). Comprehensive physicochemical characterization including scanning electron microscopy, thermal analysis, molecular fingerprinting spectroscopy, particle sizing, drug loading, encapsulation efficiency, and in vitro drug release were conducted. The data shows that despite the differences in the size of the particles, sustained release of PNA5 was successfully achieved using PLGA R503H polymer with high drug loading (% DL) and high encapsulation efficiency (% EE) of >8% and >40%, respectively. While using the ester-end PLGA, NPs showed poor sustained release as after 72 h, nearly 100% of the peptide was released. Also, lower % EE and % DL values were observed (10.8 and 3.4, respectively). This is the first systematic and comprehensive study to report on the successful design, particle synthesis, physicochemical characterization, and in vitro glycopeptide drug release of PNA5 in PLGA nanoparticles and microparticles. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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17 pages, 9418 KiB

Open AccessArticle

Sustained and Long-Term Release of Doxorubicin from PLGA Nanoparticles for Eliciting Anti-Tumor Immune Responses

by Jeongrae Kim, Yongwhan Choi, Suah Yang, Jaewan Lee, Jiwoong Choi, Yujeong Moon, Jinseong Kim, Nayeon Shim, Hanhee Cho, Man Kyu Shim, Sangmin Jeon, Dong-Kwon Lim, Hong Yeol Yoon and Kwangmeyung Kim

Pharmaceutics 2022, 14(3), 474; https://doi.org/10.3390/pharmaceutics14030474 - 22 Feb 2022

Cited by 17 | Viewed by 3326

Abstract

Immunogenic cell death (ICD) is a powerful trigger eliciting strong immune responses against tumors. However, traditional chemoimmunotherapy (CIT) does not last long enough to induce sufficient ICD, and also does not guarantee the safety of chemotherapeutics. To overcome the disadvantages of the conventional [...] Read more.

Immunogenic cell death (ICD) is a powerful trigger eliciting strong immune responses against tumors. However, traditional chemoimmunotherapy (CIT) does not last long enough to induce sufficient ICD, and also does not guarantee the safety of chemotherapeutics. To overcome the disadvantages of the conventional approach, we used doxorubicin (DOX) as an ICD inducer, and poly(lactic-co-glycolic acid) (PLGA)-based nanomedicine platform for controlled release of DOX. The diameter of 138.7 nm of DOX-loaded PLGA nanoparticles (DP-NPs) were stable for 14 days in phosphate-buffered saline (PBS, pH 7.4) at 37 °C. Furthermore, DOX was continuously released for 14 days, successfully inducing ICD and reducing cell viability in vitro. Directly injected DP-NPs enabled the remaining of DOX in the tumor site for 14 days. In addition, repeated local treatment of DP-NPs actually lasted long enough to maintain the enhanced antitumor immunity, leading to increased tumor growth inhibition with minimal toxicities. Notably, DP-NPs treated tumor tissues showed significantly increased maturated dendritic cells (DCs) and cytotoxic T lymphocytes (CTLs) population, showing enhanced antitumor immune responses. Finally, the therapeutic efficacy of DP-NPs was maximized in combination with an anti-programmed death-ligand 1 (PD-L1) antibody (Ab). Therefore, we expect therapeutic efficacies of cancer CIT can be maximized by the combination of DP-NPs with immune checkpoint blockade (ICB) by achieving proper therapeutic window and continuously inducing ICD, with minimal toxicities. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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18 pages, 2862 KiB

Open AccessArticle

Improving Antibacterial Activity of a HtrA Protease Inhibitor JO146 against Helicobacter pylori: A Novel Approach Using Microfluidics-Engineered PLGA Nanoparticles

by Jimin Hwang, Sonya Mros, Allan B. Gamble, Joel D. A. Tyndall and Arlene McDowell

Pharmaceutics 2022, 14(2), 348; https://doi.org/10.3390/pharmaceutics14020348 - 01 Feb 2022

Cited by 3 | Viewed by 2177

Abstract

Nanoparticle drug delivery systems have emerged as a promising strategy for overcoming limitations of antimicrobial drugs such as stability, bioavailability, and insufficient exposure to the hard-to-reach bacterial drug targets. Although size is a vital colloidal feature of nanoparticles that governs biological interactions, the [...] Read more.

Nanoparticle drug delivery systems have emerged as a promising strategy for overcoming limitations of antimicrobial drugs such as stability, bioavailability, and insufficient exposure to the hard-to-reach bacterial drug targets. Although size is a vital colloidal feature of nanoparticles that governs biological interactions, the absence of well-defined size control technology has hampered the investigation of optimal nanoparticle size for targeting bacterial cells. Previously, we identified a lead antichlamydial compound JO146 against the high temperature requirement A (HtrA) protease, a promising antibacterial target involved in protein quality control and virulence. Here, we reveal that JO146 was active against Helicobacter pylori with a minimum bactericidal concentration of 18.8–75.2 µg/mL. Microfluidic technology using a design of experiments approach was utilized to formulate JO146-loaded poly(lactic-co-glycolic) acid nanoparticles and explore the effect of the nanoparticle size on drug delivery. JO146-loaded nanoparticles of three different sizes (90, 150, and 220 nm) were formulated with uniform particle size distribution and drug encapsulation efficiency of up to 25%. In in vitro microdilution inhibition assays, 90 nm nanoparticles improved the minimum bactericidal concentration of JO146 two-fold against H. pylori compared to the free drug alone, highlighting that controlled engineering of nanoparticle size is important in drug delivery optimization. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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18 pages, 1478 KiB

Open AccessEditor’s ChoiceArticle

Industrial Scale Manufacturing and Downstream Processing of PLGA-Based Nanomedicines Suitable for Fully Continuous Operation

by Maria Camilla Operti, Alexander Bernhardt, Vladimir Sincari, Eliezer Jager, Silko Grimm, Andrea Engel, Martin Hruby, Carl Gustav Figdor and Oya Tagit

Pharmaceutics 2022, 14(2), 276; https://doi.org/10.3390/pharmaceutics14020276 - 25 Jan 2022

Cited by 9 | Viewed by 4095

Abstract

Despite the efficacy and potential therapeutic benefits that poly(lactic-co-glycolic acid) (PLGA) nanomedicine formulations can offer, challenges related to large-scale processing hamper their clinical and commercial development. Major hurdles for the launch of a polymeric nanocarrier product on the market are batch-to-batch variations and [...] Read more.

Despite the efficacy and potential therapeutic benefits that poly(lactic-co-glycolic acid) (PLGA) nanomedicine formulations can offer, challenges related to large-scale processing hamper their clinical and commercial development. Major hurdles for the launch of a polymeric nanocarrier product on the market are batch-to-batch variations and lack of product consistency in scale-up manufacturing. Therefore, a scalable and robust manufacturing technique that allows for the transfer of nanomedicine production from the benchtop to an industrial scale is highly desirable. Downstream processes for purification, concentration, and storage of the nanomedicine formulations are equally indispensable. Here, we develop an inline sonication process for the production of polymeric PLGA nanomedicines at the industrial scale. The process and formulation parameters are optimized to obtain PLGA nanoparticles with a mean diameter of 150 ± 50 nm and a small polydispersity index (PDI < 0.2). Downstream processes based on tangential flow filtration (TFF) technology and lyophilization for the washing, concentration, and storage of formulations are also established and discussed. Using the developed manufacturing and downstream processing technologies, production of two PLGA nanoformulations encasing ritonavir and celecoxib was achieved at 84 g/h rate. As a measure of actual drug content, encapsulation efficiencies of 49.5 ± 3.2% and 80.3 ± 0.9% were achieved for ritonavir and celecoxib, respectively. When operated in-series, inline sonication and TFF can be adapted for fully continuous, industrial-scale processing of PLGA-based nanomedicines. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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16 pages, 3087 KiB

Open AccessArticle

Targeting Cancer Cell Tight Junctions Enhances PLGA-Based Photothermal Sensitizers’ Performance In Vitro and In Vivo

by Victoria O. Shipunova, Vera L. Kovalenko, Polina A. Kotelnikova, Anna S. Sogomonyan, Olga N. Shilova, Elena N. Komedchikova, Andrei V. Zvyagin, Maxim P. Nikitin and Sergey M. Deyev

Pharmaceutics 2022, 14(1), 43; https://doi.org/10.3390/pharmaceutics14010043 - 26 Dec 2021

Cited by 18 | Viewed by 3794

Abstract

The development of non-invasive photothermal therapy (PTT) methods utilizing nanoparticles as sensitizers is one of the most promising directions in modern oncology. Nanoparticles loaded with photothermal dyes are capable of delivering a sufficient amount of a therapeutic substance and releasing it with the [...] Read more.

The development of non-invasive photothermal therapy (PTT) methods utilizing nanoparticles as sensitizers is one of the most promising directions in modern oncology. Nanoparticles loaded with photothermal dyes are capable of delivering a sufficient amount of a therapeutic substance and releasing it with the desired kinetics in vivo. However, the effectiveness of oncotherapy methods, including PTT, is often limited due to poor penetration of sensitizers into the tumor, especially into solid tumors of epithelial origin characterized by tight cellular junctions. In this work, we synthesized 200 nm nanoparticles from the biocompatible copolymer of lactic and glycolic acid, PLGA, loaded with magnesium phthalocyanine, PLGA/Pht-Mg. The PLGA/Pht-Mg particles under the irradiation with NIR light (808 nm), heat the surrounding solution by 40 °C. The effectiveness of using such particles for cancer cells elimination was demonstrated in 2D culture in vitro and in our original 3D model with multicellular spheroids possessing tight cell contacts. It was shown that the mean inhibitory concentration of such nanoparticles upon light irradiation for 15 min worsens by more than an order of magnitude: IC50 increases from 3 µg/mL for 2D culture vs. 117 µg/mL for 3D culture. However, when using the JO-4 intercellular junction opener protein, which causes a short epithelial–mesenchymal transition and transiently opens intercellular junctions in epithelial cells, the efficiency of nanoparticles in 3D culture was comparable or even outperforming that for 2D (IC50 = 1.9 µg/mL with JO-4). Synergy in the co-administration of PTT nanosensitizers and JO-4 protein was found to retain in vivo using orthotopic tumors of BALB/c mice: we demonstrated that the efficiency in the delivery of such nanoparticles to the tumor is 2.5 times increased when PLGA/Pht-Mg nanoparticles are administered together with JO-4. Thus the targeting the tumor cell junctions can significantly increase the performance of PTT nanosensitizers. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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13 pages, 2379 KiB

Open AccessArticle

Synthesis and Biodistribution of ^99mTc-Labeled PLGA Nanoparticles by Microfluidic Technique

by Michela Varani, Giuseppe Campagna, Valeria Bentivoglio, Matteo Serafinelli, Maria Luisa Martini, Filippo Galli and Alberto Signore

Pharmaceutics 2021, 13(11), 1769; https://doi.org/10.3390/pharmaceutics13111769 - 22 Oct 2021

Cited by 12 | Viewed by 2161

Abstract

The aim of present study was to develop radiolabeled NPs to overcome the limitations of fluorescence with theranostic potential. Synthesis of PLGA-NPs loaded with technetium-99m was based on a Dean-Vortex-Bifurcation Mixer (DVBM) using an innovative microfluidic technique with high batch-to-batch reproducibility and tailored-made [...] Read more.

The aim of present study was to develop radiolabeled NPs to overcome the limitations of fluorescence with theranostic potential. Synthesis of PLGA-NPs loaded with technetium-99m was based on a Dean-Vortex-Bifurcation Mixer (DVBM) using an innovative microfluidic technique with high batch-to-batch reproducibility and tailored-made size of NPs. Eighteen different formulations were tested and characterized for particle size, zeta potential, polydispersity index, labeling efficiency, and in vitro stability. Overall, physical characterization by dynamic light scattering (DLS) showed an increase in particle size after radiolabeling probably due to the incorporation of the isotope into the PLGA-NPs shell. NPs of 60 nm (obtained by 5:1 PVA:PLGA ratio and 15 mL/min TFR with ^99mTc included in PVA) had high labeling efficiency (94.20 ± 5.83%) and >80% stability after 24 h and showed optimal biodistribution in BALB/c mice. In conclusion, we confirmed the possibility of radiolabeling NPs with ^99mTc using the microfluidics and provide best formulation for tumor targeting studies. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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21 pages, 7393 KiB

Open AccessArticle

A Novel Sustained Anti-Inflammatory Effect of Atorvastatin—Calcium PLGA Nanoparticles: In Vitro Optimization and In Vivo Evaluation

by Dalia H. Abdelkader, Ahmed Kh. Abosalha, Mohamed A. Khattab, Basmah N. Aldosari and Alanood S. Almurshedi

Pharmaceutics 2021, 13(10), 1658; https://doi.org/10.3390/pharmaceutics13101658 - 11 Oct 2021

Cited by 25 | Viewed by 2380

Abstract

Atorvastatin Calcium (At-Ca) has pleiotropic effect as anti-inflammatory drug beside its main antihyperlipidemic action. Our study was conducted to modulate the anti-inflammatory effect of At-Ca to be efficiently sustained for longer time. Single oil-water emulsion solvent evaporation technique was used to fabricate At-Ca [...] Read more.

Atorvastatin Calcium (At-Ca) has pleiotropic effect as anti-inflammatory drug beside its main antihyperlipidemic action. Our study was conducted to modulate the anti-inflammatory effect of At-Ca to be efficiently sustained for longer time. Single oil-water emulsion solvent evaporation technique was used to fabricate At-Ca into polymeric nanoparticles (NPs). In vitro optimization survey was performed on Poly(lactide-co-glycolide) (PLGA) loaded with At-Ca regrading to particle size, polydispersity index (PDI), zeta potential, percent entrapment efficiency (% EE), surface morphology and in vitro release pattern. In vitro drug-polymers interactions were fully scanned using Fourier-Transform Infrared Spectroscopy (FTIR) and Differential Scanning calorimetry (DSC) proving that the method of fabrication is an optimal strategy maintaining the drug structure with no interaction with polymeric matrix. The optimized formula with particle size (248.2 ± 15.13 nm), PDI (0.126 ± 0.048), zeta potential (−12.41 ± 4.80 mV), % EE (87.63 ± 3.21%), initial burst (39.78 ± 6.74%) and percent cumulative release (83.63 ± 3.71%) was orally administered in Male Sprague–Dawley rats to study the sustained anti-inflammatory effect of At-Ca PLGA NPs after carrageenan induced inflammation. In vivo results demonstrate that AT-Ca NPs has a sustained effect extending for approximately three days. Additionally, the histological examination revealed that the epidermal/dermal layers restore their typical normal cellular alignment with healthy architecture. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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15 pages, 1648 KiB

Open AccessArticle

Optimisation of a Microfluidic Method for the Delivery of a Small Peptide

by Felicity Y. Han, Weizhi Xu, Vinod Kumar, Cedric S. Cui, Xaria Li, Xingyu Jiang, Trent M. Woodruff, Andrew K. Whittaker and Maree T. Smith

Pharmaceutics 2021, 13(9), 1505; https://doi.org/10.3390/pharmaceutics13091505 - 18 Sep 2021

Cited by 3 | Viewed by 3527

Abstract

Peptides hold promise as therapeutics, as they have high bioactivity and specificity, good aqueous solubility, and low toxicity. However, they typically suffer from short circulation half-lives in the body. To address this issue, here, we have developed a method for encapsulation of an [...] Read more.

Peptides hold promise as therapeutics, as they have high bioactivity and specificity, good aqueous solubility, and low toxicity. However, they typically suffer from short circulation half-lives in the body. To address this issue, here, we have developed a method for encapsulation of an innate-immune targeted hexapeptide into nanoparticles using safe non-toxic FDA-approved materials. Peptide-loaded nanoparticles were formulated using a two-stage microfluidic chip. Microfluidic-related factors (i.e., flow rate, organic solvent, theoretical drug loading, PLGA type, and concentration) that may potentially influence the nanoparticle properties were systematically investigated using dynamic light scattering and transmission electron microscopy. The pharmacokinetic (PK) profile and biodistribution of the optimised nanoparticles were assessed in mice. Peptide-loaded lipid shell-PLGA core nanoparticles with designated size (~400 nm) and a sustained in vitro release profile were further characterized in vivo. In the form of nanoparticles, the elimination half-life of the encapsulated peptide was extended significantly compared with the peptide alone and resulted in a much higher distribution into the lung. These novel nanoparticles with lipid shells have considerable potential for increasing the circulation half-life and improving the biodistribution of therapeutic peptides to improve their clinical utility, including peptides aimed at treating lung-related diseases. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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12 pages, 1778 KiB

Open AccessArticle

Pharmacokinetics and Toxicity Evaluation of a PLGA and Chitosan-Based Micro-Implant for Sustained Release of Methotrexate in Rabbit Vitreous

by Soumyarwit Manna, Anna M. Donnell, Rafaela Q. Caixeta Faraj, Blanca I. Riemann, Christopher D. Riemann, James J. Augsburger, Zelia M. Correa and Rupak K. Banerjee

Pharmaceutics 2021, 13(8), 1227; https://doi.org/10.3390/pharmaceutics13081227 - 09 Aug 2021

Cited by 6 | Viewed by 2114

Abstract

The present research investigates the pharmacokinetics and toxicity of a chitosan (CS) and poly(lactic-co-glycolic) acid (PLGA)-based methotrexate (MTX) intravitreal micro-implant in normal rabbit eyes. PLGA and CS-based micro-implants containing 400 µg of MTX were surgically inserted in the vitreous of twenty-four New Zealand [...] Read more.

The present research investigates the pharmacokinetics and toxicity of a chitosan (CS) and poly(lactic-co-glycolic) acid (PLGA)-based methotrexate (MTX) intravitreal micro-implant in normal rabbit eyes. PLGA and CS-based micro-implants containing 400 µg of MTX were surgically inserted in the vitreous of twenty-four New Zealand rabbits using minimally invasive procedures. The PLGA-coated CS-MTX micro-implant and the placebo micro-implant were inserted in the right eye and in the left eye, respectively, of each rabbit. The intravitreal MTX concentration was evaluated on Days 1, 3, 7, 14, 28 and 56. A therapeutic concentration of MTX (0.1–1.0 µM) in the rabbit vitreous was observed for 56 days. The release of MTX in the therapeutic release phase followed first-order kinetics. Histopathologic evaluation on Days 14, 28 and 56 of the enucleated eyes demonstrated no signs of toxicity or any anatomical irregularity in the vitreoretinal domain. Additionally, the micro-implants were stationary at the position of their implantation throughout the duration of the study. The PLGA-coated CS-MTX micro-implant can serve as a potential alternative to the current treatment modality of intravitreal MTX injections based on its performance, thereby avoiding associated complications and the treatment burden of multiple injections. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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13 pages, 2828 KiB

Open AccessArticle

Preparation of Poly-Lactic-Co-Glycolic Acid Nanoparticles in a Dry Powder Formulation for Pulmonary Antigen Delivery

by Regina Scherließ and Julia Janke

Pharmaceutics 2021, 13(8), 1196; https://doi.org/10.3390/pharmaceutics13081196 - 03 Aug 2021

Cited by 14 | Viewed by 2552

Abstract

One of the key requirements for successful vaccination via the mucosa is particulate antigen uptake. Poly-lactic-co-glycolic acid (PLGA) particles were chosen as well-known model carriers and ovalbumin (OVA) as the model antigen. Aiming at application to the respiratory tract, which allows direct interaction [...] Read more.

One of the key requirements for successful vaccination via the mucosa is particulate antigen uptake. Poly-lactic-co-glycolic acid (PLGA) particles were chosen as well-known model carriers and ovalbumin (OVA) as the model antigen. Aiming at application to the respiratory tract, which allows direct interaction of the formulation with the mucosal immune system, this work focuses on the feasibility of delivering the antigen in a nanoparticulate carrier within a powder capable of pulmonary delivery. Further requirements were adequate antigen encapsulation in order to use the characteristics of the particulate carrier for (tunable) antigen release, and capability of the production process for industrialisation (realisation in industry). For an effective particulate antigen uptake, nanoparticles with a size of around 300 nm were prepared. For this, two production methods for nanoparticles, solvent change precipitation and the double emulsion method, were evaluated with respect to antigen incorporation, transfer to a dry powder formulation, redispersion and antigen release characteristics. A spray drying step was included in the production procedure in order to obtain a respirable powder with an aerodynamic particle size of between 0.5 and 5 μm. The dried products were characterised for particle size, dispersibility and aerodynamic behaviour, as well as for immune response and cytotoxicity in cell culture models. It could be shown that the double emulsion method is suitable to prepare nanoparticles (270 nm) and to incorporate the antigen. By modifying the production method to prepare porous particles, it was possible to obtain an acceptable antigen release while maintaining an antigen load of about 10%. By the choice of polyvinyl alcohol as a stabiliser, nanoparticles could be dried and redispersed without further excipients and the production steps were capable of realisation in industry. Aerodynamic characteristics were good with a mass median aerodynamic diameter of 3.3 µm upon dispersion from a capsule-based inhaler. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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28 pages, 4395 KiB

Open AccessArticle

Fluorescently Labeled PLGA Nanoparticles for Visualization In Vitro and In Vivo: The Importance of Dye Properties

by Vasilisa Zhukova, Nadezhda Osipova, Aleksey Semyonkin, Julia Malinovskaya, Pavel Melnikov, Marat Valikhov, Yuri Porozov, Yaroslav Solovev, Pavel Kuliaev, Enqi Zhang, Bernhard A. Sabel, Vladimir Chekhonin, Maxim Abakumov, Alexander Majouga, Jörg Kreuter, Petra Henrich-Noack, Svetlana Gelperina and Olga Maksimenko

Pharmaceutics 2021, 13(8), 1145; https://doi.org/10.3390/pharmaceutics13081145 - 27 Jul 2021

Cited by 11 | Viewed by 5180

Abstract

Fluorescently labeled nanoparticles are widely used for evaluating their distribution in the biological environment. However, dye leakage can lead to misinterpretations of the nanoparticles’ biodistribution. To better understand the interactions of dyes and nanoparticles and their biological environment, we explored PLGA nanoparticles labeled [...] Read more.

Fluorescently labeled nanoparticles are widely used for evaluating their distribution in the biological environment. However, dye leakage can lead to misinterpretations of the nanoparticles’ biodistribution. To better understand the interactions of dyes and nanoparticles and their biological environment, we explored PLGA nanoparticles labeled with four widely used dyes encapsulated (coumarin 6, rhodamine 123, DiI) or bound covalently to the polymer (Cy5.5.). The DiI label was stable in both aqueous and lipophilic environments, whereas the quick release of coumarin 6 was observed in model media containing albumin (42%) or liposomes (62%), which could be explained by the different affinity of these dyes to the polymer and lipophilic structures and which we also confirmed by computational modeling (log PDPPC/PLGA: DiI—2.3, Cou6—0.7). The importance of these factors was demonstrated by in vivo neuroimaging (ICON) of the rat retina using double-labeled Cy5.5/Cou6-nanoparticles: encapsulated Cou6 quickly leaked into the tissue, whereas the stably bound Cy.5.5 label remained associated with the vessels. This observation is a good example of the possible misinterpretation of imaging results because the coumarin 6 distribution creates the impression that nanoparticles effectively crossed the blood–retina barrier, whereas in fact no signal from the core material was found beyond the blood vessels. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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Review

Jump to: Research

24 pages, 2008 KiB

Open AccessReview

PLGA-Based Nanoparticles for Neuroprotective Drug Delivery in Neurodegenerative Diseases

by Anthony Cunha, Alexandra Gaubert, Laurent Latxague and Benjamin Dehay

Pharmaceutics 2021, 13(7), 1042; https://doi.org/10.3390/pharmaceutics13071042 - 08 Jul 2021

Cited by 41 | Viewed by 6762

Abstract

Treatment of neurodegenerative diseases has become one of the most challenging topics of the last decades due to their prevalence and increasing societal cost. The crucial point of the non-invasive therapeutic strategy for neurological disorder treatment relies on the drugs’ passage through the [...] Read more.

Treatment of neurodegenerative diseases has become one of the most challenging topics of the last decades due to their prevalence and increasing societal cost. The crucial point of the non-invasive therapeutic strategy for neurological disorder treatment relies on the drugs’ passage through the blood-brain barrier (BBB). Indeed, this biological barrier is involved in cerebral vascular homeostasis by its tight junctions, for example. One way to overcome this limit and deliver neuroprotective substances in the brain relies on nanotechnology-based approaches. Poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) are biocompatible, non-toxic, and provide many benefits, including improved drug solubility, protection against enzymatic digestion, increased targeting efficiency, and enhanced cellular internalization. This review will present an overview of the latest findings and advances in the PLGA NP-based approach for neuroprotective drug delivery in the case of neurodegenerative disease treatment (i.e., Alzheimer’s, Parkinson’s, Huntington’s diseases, Amyotrophic Lateral, and Multiple Sclerosis). Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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Open AccessReview

PLGA Nanoparticle-Based Formulations to Cross the Blood–Brain Barrier for Drug Delivery: From R&D to cGMP

by Kaining Zhi, Babatunde Raji, Anantha R. Nookala, Mohammad Moshahid Khan, Xuyen H. Nguyen, Swarna Sakshi, Tayebeh Pourmotabbed, Murali M. Yallapu, Harry Kochat, Erene Tadrous, Shelby Pernell and Santosh Kumar

Pharmaceutics 2021, 13(4), 500; https://doi.org/10.3390/pharmaceutics13040500 - 06 Apr 2021

Cited by 67 | Viewed by 5903

Abstract

The blood–brain barrier (BBB) is a natural obstacle for drug delivery into the human brain, hindering treatment of central nervous system (CNS) disorders such as acute ischemic stroke, brain tumors, and human immunodeficiency virus (HIV)-1-associated neurocognitive disorders. Poly(lactic-co-glycolic acid) (PLGA) is [...] Read more.

The blood–brain barrier (BBB) is a natural obstacle for drug delivery into the human brain, hindering treatment of central nervous system (CNS) disorders such as acute ischemic stroke, brain tumors, and human immunodeficiency virus (HIV)-1-associated neurocognitive disorders. Poly(lactic-co-glycolic acid) (PLGA) is a biocompatible polymer that is used in Food and Drug Administration (FDA)-approved pharmaceutical products and medical devices. PLGA nanoparticles (NPs) have been reported to improve drug penetration across the BBB both in vitro and in vivo. Poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), and poloxamer (Pluronic) are widely used as excipients to further improve the stability and effectiveness of PLGA formulations. Peptides and other linkers can be attached on the surface of PLGA to provide targeting delivery. With the newly published guidance from the FDA and the progress of current Good Manufacturing Practice (cGMP) technologies, manufacturing PLGA NP-based drug products can be achieved with higher efficiency, larger quantity, and better quality. The translation from bench to bed is feasible with proper research, concurrent development, quality control, and regulatory assurance. Full article

(This article belongs to the Special Issue Nanomedicine Formulations Based on PLGA Nanoparticles for Diagnosis, Monitoring and Treatment of Disease: From Bench to Bedside)

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