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22 pages, 4276 KiB

Open AccessArticle

mPEG-PLGA Nanoparticles Labelled with Loaded or Conjugated Rhodamine-B for Potential Nose-to-Brain Delivery

by Emanuela Fabiola Craparo, Teresa Musumeci, Angela Bonaccorso, Rosalia Pellitteri, Alessia Romeo, Irina Naletova, Lorena Maria Cucci, Gennara Cavallaro and Cristina Satriano

Pharmaceutics 2021, 13(9), 1508; https://doi.org/10.3390/pharmaceutics13091508 - 18 Sep 2021

Cited by 19 | Viewed by 4317

Abstract

Nowdays, neurodegenerative diseases represent a great challenge from both the therapeutic and diagnostic points of view. Indeed, several physiological barriers of the body, including the blood brain barrier (BBB), nasal, dermal, and intestinal barriers, interpose between the development of new drugs and their [...] Read more.

Nowdays, neurodegenerative diseases represent a great challenge from both the therapeutic and diagnostic points of view. Indeed, several physiological barriers of the body, including the blood brain barrier (BBB), nasal, dermal, and intestinal barriers, interpose between the development of new drugs and their effective administration to reach the target organ or target cells at therapeutic concentrations. Currently, the nose-to-brain delivery with nanoformulations specifically designed for intranasal administration is a strategy widely investigated with the goal to reach the brain while bypassing the BBB. To produce nanosystems suitable to study both in vitro and/or in vivo cells trafficking for potential nose-to-brain delivery route, we prepared and characterized two types of fluorescent poly(ethylene glycol)-methyl-ether-block-poly(lactide-co-glycolide) (PLGA–PEG) nanoparticles (PNPs), i.e., Rhodamine B (RhB) dye loaded- and grafted- PNPs, respectively. The latter were produced by blending into the PLGA–PEG matrix a RhB-labeled polyaspartamide/polylactide graft copolymer to ensure a stable fluorescence during the time of analysis. Photon correlation spectroscopy (PCS), UV-visible (UV-vis) spectroscopies, differential scanning calorimetry (DSC), atomic force microscopy (AFM) were used to characterize the RhB-loaded and RhB-grafted PNPs. To assess their potential use for brain targeting, cytotoxicity tests were carried out on olfactory ensheathing cells (OECs) and neuron-like differentiated PC12 cells. Both PNP types showed mean sizes suitable for nose-to-brain delivery (<200 nm, PDI < 0.3) and were not cytotoxic toward OECs in the concentration range tested, while a reduction in the viability on PC12 cells was found when higher concentrations of nanomedicines were used. Both the RhB-labelled NPs are suitable drug carrier models for exploring cellular trafficking in nose-to-brain delivery for short-time or long-term studies. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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24 pages, 3845 KiB

Open AccessArticle

Study the Antifungal and Ocular Permeation of Ketoconazole from Ophthalmic Formulations Containing Trans-Ethosomes Nanoparticles

by Tarek A. Ahmed, Maram M. Alzahrani, Alaa Sirwi and Nabil A. Alhakamy

Pharmaceutics 2021, 13(2), 151; https://doi.org/10.3390/pharmaceutics13020151 - 24 Jan 2021

Cited by 43 | Viewed by 4247

Abstract

Ketoconazole (KET), a synthetic imidazole broad-spectrum antifungal agent, is characterized by its poor aqueous solubility and high molecular weight, which might hamper its corneal permeation. The aim was to develop an ophthalmic formulation loaded with optimized trans-ethosomal vesicles to enhance KET ocular permeation, [...] Read more.

Ketoconazole (KET), a synthetic imidazole broad-spectrum antifungal agent, is characterized by its poor aqueous solubility and high molecular weight, which might hamper its corneal permeation. The aim was to develop an ophthalmic formulation loaded with optimized trans-ethosomal vesicles to enhance KET ocular permeation, antifungal activity, rapid drug drainage, and short elimination half-life. Four formulation factors affecting the vesicles’ size, zeta potential, entrapment efficiency, and flexibility of the trans-ethosomes formulations were optimized. The optimum formulation was characterized, and their morphological and antifungal activity were studied. Different ophthalmic formulations loaded with the optimized vesicles were prepared and characterized. The ocular irritation and in vivo corneal permeation were investigated. Results revealed that the drug-to-phospholipid-molar ratio, the percentage of edge activator, the percentage of ethanol, and the percentage of stearyl amine significantly affect the characteristics of the vesicles. The optimized vesicles were spherical and showed an average size of 151.34 ± 8.73 nm, a zeta potential value of +34.82 ± 2.64 mV, an entrapment efficiency of 94.97 ± 5.41%, and flexibility of 95.44 ± 4.33%. The antifungal activity of KET was significantly improved following treatment with the optimized vesicles. The developed in situ gel formulations were found to be nonirritating to the cornea. The trans-ethosomes vesicles were able to penetrate deeper into the posterior eye segment without any toxic effects. Accordingly, the in situ developed gel formulation loaded with KET trans-ethosomes vesicles represents a promising ocular delivery system for the treatment of deep fungal eye infections. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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21 pages, 3718 KiB

Open AccessArticle

Lipophilic Peptide Dendrimers for Delivery of Splice-Switching Oligonucleotides

by Haneen Daralnakhla, Osama Saher, Susanna Zamolo, Safa Bazaz, Jeremy P. Bost, Marc Heitz, Karin E. Lundin, Samir EL Andaloussi, Tamis Darbre, Jean-Louis Reymond, Rula Zain and C. I. Edvard Smith

Pharmaceutics 2021, 13(1), 116; https://doi.org/10.3390/pharmaceutics13010116 - 18 Jan 2021

Cited by 9 | Viewed by 4404

Abstract

Non-viral transfection reagents are continuously being developed in attempt to replace viral vectors. Among those non-viral vectors, dendrimers have gained increasing interest due to their unique molecular structure and multivalency. However, more improvements are still needed to achieve higher efficacy and lower toxicity. [...] Read more.

Non-viral transfection reagents are continuously being developed in attempt to replace viral vectors. Among those non-viral vectors, dendrimers have gained increasing interest due to their unique molecular structure and multivalency. However, more improvements are still needed to achieve higher efficacy and lower toxicity. In this study, we have examined 18 peptide dendrimers conjugated to lipophilic moieties, such as fatty acids or hydrophobic amino acids, that were previously explored for siRNA. Reporter cells were employed to investigate the transfection of single strand splice-switching oligonucleotides (ONs) using these peptide dendrimers. Luciferase level changes reflecting efficiency varied with amino acid composition, stereochemistry, and complexation media used. 3rd generation peptide dendrimers with D-amino acid configuration were superior to L-form. Lead formulations with 3rd generation, D-amino acid peptide dendrimers increased the correction level of the delivered ON up to 93-fold over untreated HeLa Luc/705 cells with minimal toxicity. To stabilize the formed complexes, Polyvinyl alcohol 18 (PVA18) polymer was added. Although PVA18 addition increased activity, toxicity when using our best candidates G 2,3KL-(Leu)₄ (D) and G 2,3KL-diPalmitamide (D) was observed. Our findings demonstrate the potential of lipid-conjugated, D-amino acid-containing peptide dendrimers to be utilized as an effective and safe delivery vector for splice-switching ONs. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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17 pages, 1888 KiB

Open AccessArticle

Pulmonary Targeting of Inhalable Moxifloxacin Microspheres for Effective Management of Tuberculosis

by Bhavya Vishwa, Afrasim Moin, D. V. Gowda, Syed M. D. Rizvi, Wael A. H. Hegazy, Amr S. Abu Lila, El-Sayed Khafagy and Ahmed N. Allam

Pharmaceutics 2021, 13(1), 79; https://doi.org/10.3390/pharmaceutics13010079 - 8 Jan 2021

Cited by 45 | Viewed by 3838

Abstract

In the present study, the objective was to attain a localized lung delivery of an anti-tubercular fluoroquinolone, moxifloxacin (MXF), targeting the alveolar macrophages through a non-invasive pulmonary route using inhalable microspheres as a dry powder inhaler approach. MXF-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres [...] Read more.

In the present study, the objective was to attain a localized lung delivery of an anti-tubercular fluoroquinolone, moxifloxacin (MXF), targeting the alveolar macrophages through a non-invasive pulmonary route using inhalable microspheres as a dry powder inhaler approach. MXF-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres (MXF-PLGA-MSs) were fabricated by solvent evaporation technique and optimized by using a central composite statistical design. The morphology and particle size, as well as the flowability of the optimized microspheres, were characterized. In addition, the aerosolization performance of the optimized formula was inspected using an Andersen cascade impactor. Furthermore, in vivo fate following intrapulmonary administration of the optimized formula was evaluated. The optimized MXF-PLGA-MSs were spherical in shape with a particle size of 3.16 µm, drug loading of 21.98% and entrapment efficiency of 78.0%. The optimized formula showed a mass median aerodynamic diameter (MMAD) of 2.85 ± 1.04 µm with a favorable fine particle fraction of 72.77 ± 1.73%, suggesting that the powders were suitable for inhalation. Most importantly, in vivo studies revealed that optimized MXF-PLGA-MSs preferentially accumulated in lung tissue as manifested by a two-fold increase in the area under the curve AUC_0–24h, compared to plain drug. In addition, optimized MXF-PLGA-MS sustained drug residence in the lung for up to 24 h following inhalation, compared to plain drug. In conclusion, inhalable microspheres of MXF could be a promising therapeutic approach that might aid in the effective eradiation of tuberculosis along with improving patient adherence to the treatment. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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14 pages, 1919 KiB

Open AccessArticle

Nasal Gel Loaded with Amphotericin Nanotransferosomes as Antifungal Treatment for Fungal Sinusitis

by Khaled M. Hosny and Nabil A. Alhakamy

Pharmaceutics 2021, 13(1), 35; https://doi.org/10.3390/pharmaceutics13010035 - 28 Dec 2020

Cited by 3 | Viewed by 2513

Abstract

On the basis of fungal involvement, rhinosinusitis is categorized into allergic, mycetoma, chronic, and acute invasive types. The aim of the current study was to evaluate the efficacy of an amphotericin gel in situ loaded with nanotransferosomes against Aspergillus flavus, which causes [...] Read more.

On the basis of fungal involvement, rhinosinusitis is categorized into allergic, mycetoma, chronic, and acute invasive types. The aim of the current study was to evaluate the efficacy of an amphotericin gel in situ loaded with nanotransferosomes against Aspergillus flavus, which causes allergic rhinosinusitis. A Box–Behnken design was utilized to study the interaction among the nanotransferosomes and optimize independent variables in formulating them, in order to match the prerequisites of selected responses. The optimal formulation was determined to be 300 mg/mL soybean lecithin, 200 mg/mL amphotericin B (AMP), and 150 mg/mL clove oil, resulting in a particle size of 155.09 nm, 84.30% entrapment efficacy (EE), inhibition zone of 16.0 mm, and 0.1197 mmol serum creatinine. The optimized batch was further prepared into an in situ gel and evaluated for various parameters. The optimized formulation released 79.25% AMP and enhanced permeation through the nasal membrane, while the other formulations did not achieve complete absorption. According to in vivo tests using rabbits as animal models, the optimized AMP-nanotransferosomal formulations (NT) in in situ gel result in a non-significant difference among the various kidney function parameters. In conclusion, nasal in situ gel loaded with AMP-clove oil nanotreansfersomes can act as a promising novel carrier that enhances antifungal activity and decreases AMP nephrotoxicity. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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19 pages, 3191 KiB

Open AccessArticle

Development, Characterization Optimization, and Assessment of Curcumin-Loaded Bioactive Self-Nanoemulsifying Formulations and Their Inhibitory Effects on Human Breast Cancer MCF-7 Cells

by Mohsin Kazi, Fahd A. Nasr, Omar Noman, Abdulrahman Alharbi, Mohammed S. Alqahtani and Fars K. Alanazi

Pharmaceutics 2020, 12(11), 1107; https://doi.org/10.3390/pharmaceutics12111107 - 18 Nov 2020

Cited by 25 | Viewed by 3163

Abstract

Curcumin (CUR) is an attractive polyphenol for its anti-inflammatory, antibacterial, antioxidant, and anticancer properties. Poor solubility in water and sensitivity against sunlight are the most challenging characteristics in the development of CUR for clinical use. The aim is to develop oral lipid-based bioactive [...] Read more.

Curcumin (CUR) is an attractive polyphenol for its anti-inflammatory, antibacterial, antioxidant, and anticancer properties. Poor solubility in water and sensitivity against sunlight are the most challenging characteristics in the development of CUR for clinical use. The aim is to develop oral lipid-based bioactive self-nanoemulsifying drug delivery systems (Bio-SNEDDSs) for curcumin as a candidate for cancer therapy. Bio-SNEDDSs containing black seed oil, medium-chain mono- and diglycerides, and surfactants were prepared as CUR delivery vehicles. The morphology, droplet size, physical stability, encapsulation efficiency, risk of precipitation, lipid digestion, antioxidant activity, and antimicrobial activity were evaluated for the representative formulations. Finally, an MTT assay was performed on MCF-7 cells to determine the cytotoxic effect of the different formulations. The results showed lower droplet size (28.53 nm) and higher drug-loading (CUR 20 mg, thymoquinone 1.2 mg) for the representative Bio-SNEDDS (black seed oil/Imwitor 988/KolliphorEL (35/15/50) % w/w), along with a transparent appearance upon aqueous dilution. The dynamic dispersion and in-vitro lipolysis data proved that the Bio-SNEDDS was able to keep the CUR in a solubilized form in the gastrointestinal tract. From the antioxidant and antimicrobial studies, it was suggested that the Bio-SNEDDS had the highest activity for disease control. The MTT assay showed that the representative Bio-SNEDDS treatment led to a reduction of cell viability of MCF-7 cells compared to pure CUR and conventional SNEDDSs. A Bio-SNEDDS with elevated entrapment efficiency, antioxidant/antimicrobial activities, and an antiproliferative effect could be the best anticancer drug candidate for potential oral delivery. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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16 pages, 2959 KiB

Open AccessArticle

The Importance of Poly(ethylene glycol) and Lipid Structure in Targeted Gene Delivery to Lymph Nodes by Lipid Nanoparticles

by Danijela Zukancic, Estelle J. A. Suys, Emily H. Pilkington, Azizah Algarni, Hareth Al-Wassiti and Nghia P. Truong

Pharmaceutics 2020, 12(11), 1068; https://doi.org/10.3390/pharmaceutics12111068 - 9 Nov 2020

Cited by 62 | Viewed by 8335

Abstract

Targeted delivery of nucleic acids to lymph nodes is critical for the development of effective vaccines and immunotherapies. However, it remains challenging to achieve selective lymph node delivery. Current gene delivery systems target mainly to the liver and typically exhibit off-target transfection at [...] Read more.

Targeted delivery of nucleic acids to lymph nodes is critical for the development of effective vaccines and immunotherapies. However, it remains challenging to achieve selective lymph node delivery. Current gene delivery systems target mainly to the liver and typically exhibit off-target transfection at various tissues. Here we report novel lipid nanoparticles (LNPs) that can deliver plasmid DNA (pDNA) to a draining lymph node, thereby significantly enhancing transfection at this target organ, and substantially reducing gene expression at the intramuscular injection site (muscle). In particular, we discovered that LNPs stabilized by 3% Tween 20, a surfactant with a branched poly(ethylene glycol) (PEG) chain linking to a short lipid tail, achieved highly specific transfection at the lymph node. This was in contrast to conventional LNPs stabilized with a linear PEG chain and two saturated lipid tails (PEG-DSPE) that predominately transfected at the injection site (muscle). Interestingly, replacing Tween 20 with Tween 80, which has a longer unsaturated lipid tail, led to a much lower transfection efficiency. Our work demonstrates the importance of PEGylation in selective organ targeting of nanoparticles, provides new insights into the structure–property relationship of LNPs, and offers a novel, simple, and practical PEGylation technology to prepare the next generation of safe and effective vaccines against viruses or tumours. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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11 pages, 3184 KiB

Open AccessArticle

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

by Francisco J. Cimas, Enrique Niza, Alberto Juan, María del Mar Noblejas-López, Iván Bravo, Agustín Lara-Sanchez, Carlos Alonso-Moreno and Alberto Ocaña

Pharmaceutics 2020, 12(10), 986; https://doi.org/10.3390/pharmaceutics12100986 - 19 Oct 2020

Cited by 47 | Viewed by 5513

Abstract

Bromo and extraterminal domain (BET) inhibitors-PROteolysis TArgeting Chimera (BETi-PROTAC) is a new family of compounds that induce proteasomal degradation through the ubiquitination of the tagged to BET inhibitors Bromodomain proteins, BRD2 and BRD. The encapsulation and controlled release of BET-PROTACs through their vectorization [...] Read more.

Bromo and extraterminal domain (BET) inhibitors-PROteolysis TArgeting Chimera (BETi-PROTAC) is a new family of compounds that induce proteasomal degradation through the ubiquitination of the tagged to BET inhibitors Bromodomain proteins, BRD2 and BRD. The encapsulation and controlled release of BET-PROTACs through their vectorization with antibodies, like trastuzumab, could facilitate their pharmacokinetic and efficacy profile. Antibody conjugated nanoparticles (ACNPs) using PROTACs have not been designed and evaluated. In this pioneer approach, the commercial MZ1 PROTAC was encapsulated into the FDA-approved polymeric nanoparticles. The nanoparticles were conjugated with trastuzumab to guide the delivery of MZ1 to breast tumoral cells that overexpress HER2. These ACNPs were characterized by means of size, polydispersity index, and Z-potential. Morphology of the nanoparticles, along with stability and release studies, completed the characterization. MZ1-loaded ACNPs showed a significant cytotoxic effect maintaining its mechanism of action and improving its therapeutic properties. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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22 pages, 4708 KiB

Open AccessArticle

Optimization and Evaluation of Poly(lactide-co-glycolide) Nanoparticles for Enhanced Cellular Uptake and Efficacy of Paclitaxel in the Treatment of Head and Neck Cancer

by Mohamed Haider, Amr Elsherbeny, Jayalakshmi Jagal, Anna Hubatová-Vacková and Iman Saad Ahmed

Pharmaceutics 2020, 12(9), 828; https://doi.org/10.3390/pharmaceutics12090828 - 30 Aug 2020

Cited by 32 | Viewed by 3475

Abstract

The particle size (PS) and encapsulation efficiency (EE%) of drug-loaded nanoparticles (NPs) may inhibit their cellular uptake and lead to possible leakage of the drug into the systemic circulation at the tumor site. In this work, ultra-high paclitaxel-loaded poly(lactide-co-glycolide) NPs (PTX-PLGA-NPs) [...] Read more.

The particle size (PS) and encapsulation efficiency (EE%) of drug-loaded nanoparticles (NPs) may inhibit their cellular uptake and lead to possible leakage of the drug into the systemic circulation at the tumor site. In this work, ultra-high paclitaxel-loaded poly(lactide-co-glycolide) NPs (PTX-PLGA-NPs) with ultra-small sizes were prepared and optimized by adopting the principles of quality by design (QbD) approach. The optimized PTX-PLGA-NPs showed ultra-small spherical particles of about 53 nm with EE% exceeding 90%, a relatively low polydispersity index (PDI) of 0.221, an effective surface charge of −10.1 mV, and a 10-fold increase in the in vitro drug release over 72 h relative to free drug. The cellular viability of pharynx carcinoma cells decreased by almost 50% in 24 h following treatment with optimized PTX-PLGA-NPs, compared to only 20% from the free drug. The intracellular uptake of PTX-PLGA-NPs was highly favored, and the antitumor activity of PTX was remarkably improved with a reduction in its half maximal inhibitory concentration (IC₅₀), by almost 50% relative to free drug solution. These results suggest that the optimal critical formulation parameters, guided by QbD principles, could produce PLGA-NPs with remarkably high EE% and ultra-small PS, resulting in enhanced cellular uptake and efficacy of PTX. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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23 pages, 4194 KiB

Open AccessArticle

Catechol Containing Polyelectrolyte Complex Nanoparticles as Local Drug Delivery System for Bortezomib at Bone Substitute Materials

by David Vehlow, Jeremy P. H. Wong, Birgit Urban, Janek Weißpflog, Annett Gebert, Matthias Schumacher, Michael Gelinsky, Manfred Stamm and Martin Müller

Pharmaceutics 2020, 12(9), 799; https://doi.org/10.3390/pharmaceutics12090799 - 24 Aug 2020

Cited by 4 | Viewed by 3441

Abstract

The proteasome inhibitor bortezomib (BZM) is one of the most potent anti-cancer drugs in the therapy of multiple myeloma. In this study, an adhesive drug delivery system (DDS) for BZM was developed. Therefore, we extended the present DDS concept of polyelectrolyte complex (PEC) [...] Read more.

The proteasome inhibitor bortezomib (BZM) is one of the most potent anti-cancer drugs in the therapy of multiple myeloma. In this study, an adhesive drug delivery system (DDS) for BZM was developed. Therefore, we extended the present DDS concept of polyelectrolyte complex (PEC) nanoparticle (NP) based on electrostatic interactions between charged drug and polyelectrolyte (PEL) to a DDS concept involving covalent bonding between PEL and uncharged drugs. For this purpose, 3,4-dihydroxyphenyl acetic acid (DOPAC) was polymerized via an oxidatively induced coupling reaction. This novel chemo-reactive polyanion PDOPAC is able to temporarily bind boronic acid groups of BZM via its catechol groups, through esterification. PDOPAC was admixed to poly(l-glutamic acid) (PLG) and poly(l-lysine) (PLL) forming a redispersible PEC NP system after centrifugation, which is advantageous for further colloid and BZM loading processing. It was found that the loading capacity (LC) strongly depends on the PDOPAC and catechol content in the PEC NP. Furthermore, the type of loading and the net charge of the PEC NP affect LC and the residual content (RC) after release. Release experiments of PDOPAC/PEC coatings were performed at medically relevant bone substitute materials (calcium phosphate cement and titanium niobium alloy) whereby the DDS worked independently of the surface properties. Additionally, in contrast to electrostatically based drug loading the release behavior of covalently bound, uncharged BZM is independent of the ionic strength (salt content) in the release medium. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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20 pages, 3500 KiB

Open AccessArticle

Assessment of Intracellular Delivery Potential of Novel Sustainable Poly(δ-decalactone)-Based Micelles

by Kuldeep Kumar Bansal, Ezgi Özliseli, Gaurav Kumar Saraogi and Jessica M. Rosenholm

Pharmaceutics 2020, 12(8), 726; https://doi.org/10.3390/pharmaceutics12080726 - 2 Aug 2020

Cited by 12 | Viewed by 3518

Abstract

Biodegradable polymers from renewable resources have attracted much attention in recent years within the biomedical field. Lately, poly(δ-decalactone) based copolymer micelles have emerged as a potential drug delivery carrier material as a sustainable alternative to fossil-based polymers. However, their intracellular drug delivery potential [...] Read more.

Biodegradable polymers from renewable resources have attracted much attention in recent years within the biomedical field. Lately, poly(δ-decalactone) based copolymer micelles have emerged as a potential drug delivery carrier material as a sustainable alternative to fossil-based polymers. However, their intracellular drug delivery potential is not yet investigated and therefore, in this work, we report on the synthesis and cellular uptake efficiency of poly(δ-decalactone) based micelles with or without a targeting ligand. Folic acid was chosen as a model targeting ligand and Rhodamine B as a fluorescent tracer to demonstrate the straightforward functionalisation aspect of copolymers. The synthesis of block copolymers was accomplished by a combination of facile ring-opening polymerisation and click chemistry to retain the structure uniformity. The presence of folic acid on the surface of micelles with diameter ~150 nm upsurge the uptake efficiency by 1.6 fold on folate receptor overexpressing MDA-MB-231 cells indicating the attainment of targeting using ligand functionality. The drug delivery capability of these carriers was ascertained by using docetaxel as a model drug, whereby the in vitro cytotoxicity of the drug was significantly increased after incorporation in micelles 48 h post incubation. We have also investigated the possible endocytosis route of non-targeted micelles and found that caveolae-mediated endocytosis was the preferred route of uptake. This work strengthens the prospect of using novel bio-based poly(δ-decalactone) micelles as efficient multifunctional drug delivery nanocarriers towards medical applications. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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16 pages, 2685 KiB

Open AccessArticle

Targeting Activated Hepatic Stellate Cells Using Collagen-Binding Chitosan Nanoparticles for siRNA Delivery to Fibrotic Livers

by Menna Azzam, Sara El Safy, Sarah A. Abdelgelil, Ralf Weiskirchen, Anastasia Asimakopoulou, Federica de Lorenzi, Twan Lammers, Samar Mansour and Salma Tammam

Pharmaceutics 2020, 12(6), 590; https://doi.org/10.3390/pharmaceutics12060590 - 25 Jun 2020

Cited by 29 | Viewed by 4267

Abstract

Activated hepatic stellate cells (aHSCs) are the main orchestrators of the fibrotic cascade in inflamed livers, with transforming growth factor-beta (TGF-β) being the most potent pro-fibrotic cytokine. Hence, aHSCs serve as interesting therapeutic targets. However, drug delivery to aHSCs is hindered by excessive [...] Read more.

Activated hepatic stellate cells (aHSCs) are the main orchestrators of the fibrotic cascade in inflamed livers, with transforming growth factor-beta (TGF-β) being the most potent pro-fibrotic cytokine. Hence, aHSCs serve as interesting therapeutic targets. However, drug delivery to aHSCs is hindered by excessive collagen deposition in the extracellular matrix (ECM) and capillarization of liver sinusoids. Chitosan-nanoparticles (CS-NPs) show intrinsic affinity for collagen, holding potential for drug delivery to fibrotic livers. Here, we employed CS-NPs for anti-TGF-β siRNA delivery, promoting delivery into aHSCs via modification with platelet-derived growth factor receptor-beta binding peptides. In-vitro experiments using aHSCs demonstrated the association of unmodified CS-NPs to the collagen-rich ECM, with reduced intracellular accumulation. Peptide-modified CS-NPs showed a higher propensity to localize intracellularly; however, this was only the case upon ECM-collagen reduction via collagenase treatment. Peptide-modified CS-NPs were more potent than unmodified CS-NPs in reducing TGF-β expression, implying that while collagen binding promotes liver accumulation, it hinders cell-specific siRNA delivery. In-vivo, CS-NPs successfully accumulated in fibrotic livers via collagen binding. Similar to in-vitro findings, when mice were pretreated with collagenase-loaded CS-NPs, the accumulation of peptide-modified NPs increased. Our findings demonstrate the usefulness of NPs modification with targeting ligands and collagenase treatment for aHSCs targeting and highlight the importance of chitosan–collagen binding in drug delivery to fibrotic diseases. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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15 pages, 3582 KiB

Open AccessArticle

Cytoprotection, Genoprotection, and Dermal Exposure Assessment of Chitosan-Based Agronanofungicides

by Farhatun Najat Maluin, Mohd Zobir Hussein, Nor Azah Yusof, Abu Seman Idris, Leona Daniela Jeffery Daim, Murni Nazira Sarian, Nor Fadilah Rajab, Siew Ee Ling, Noramiwati Rashid and Sharida Fakurazi

Pharmaceutics 2020, 12(6), 497; https://doi.org/10.3390/pharmaceutics12060497 - 29 May 2020

Cited by 5 | Viewed by 2879

Abstract

Health risks which result from exposure to pesticides have sparked awareness among researchers, triggering the idea of developing nanoencapsulation pesticides with the aim to enhance cytoprotection as well as genoprotection of the pesticides. In addition, nanocapsules of pesticides have slow release capability, high [...] Read more.

Health risks which result from exposure to pesticides have sparked awareness among researchers, triggering the idea of developing nanoencapsulation pesticides with the aim to enhance cytoprotection as well as genoprotection of the pesticides. In addition, nanocapsules of pesticides have slow release capability, high bioavailability, and site-specific delivery, which has attracted great interest from researchers. Hence, the objective of this work is to synthesize a nanoformulation of a fungicide of different sizes, namely, chitosan-hexaconazole nanoparticles (18 nm), chitosan-dazomet nanoparticles (7 nm), and chitosan-hexaconazole-dazomet nanoparticles (5 nm), which were then subjected to toxicological evaluations, including cytotoxicity, genotoxicity, cell death assay, and dermal irritation assays. Incubation of chitosan-based nanofungicides with V79-4 hamster lung cell did not reveal cytotoxicity or genotoxicity, potentially suggesting that encapsulation with chitosan reduces direct toxicity of the toxic fungicides. Meanwhile, pure fungicide revealed its high cytotoxic effect on V79-4 hamster lung cells. In addition, dermal exposure assessment on rabbits revealed that chitosan-hexaconazole nanoparticles are classified under corrosive subcategory 1C, while chitosan-dazomet nanoparticles are classified under corrosive subcategory 1B. Moreover, both chitosan-hexaconazole nanoparticles and chitosan-dazomet nanoparticles are classified as causing mild irritation. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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Review

Jump to: Research

15 pages, 5316 KiB

Open AccessReview

Polymer–Lipid Pharmaceutical Nanocarriers: Innovations by New Formulations and Production Technologies

by Sabrina Bochicchio, Gaetano Lamberti and Anna Angela Barba

Pharmaceutics 2021, 13(2), 198; https://doi.org/10.3390/pharmaceutics13020198 - 2 Feb 2021

Cited by 40 | Viewed by 5340

Abstract

Some issues in pharmaceutical therapies such as instability, poor membrane permeability, and bioavailability of drugs can be solved by the design of suitable delivery systems based on the combination of two pillar classes of ingredients: polymers and lipids. At the same time, modern [...] Read more.

Some issues in pharmaceutical therapies such as instability, poor membrane permeability, and bioavailability of drugs can be solved by the design of suitable delivery systems based on the combination of two pillar classes of ingredients: polymers and lipids. At the same time, modern technologies are required to overcome production limitations (low productivity, high energy consumption, expensive setup, long process times) to pass at the industrial level. In this paper, a summary of applications of polymeric and lipid materials combined as nanostructures (hybrid nanocarriers) is reported. Then, recent techniques adopted in the production of hybrid nanoparticles are discussed, highlighting limitations still present that hold back the industrial implementation. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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25 pages, 5455 KiB

Open AccessReview

Nanostructured Polymeric, Liposomal and Other Materials to Control the Drug Delivery for Cardiovascular Diseases

by Dimitrios Skourtis, Dimitra Stavroulaki, Varvara Athanasiou, Panagiota G. Fragouli and Hermis Iatrou

Pharmaceutics 2020, 12(12), 1160; https://doi.org/10.3390/pharmaceutics12121160 - 28 Nov 2020

Cited by 30 | Viewed by 3998

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death globally, taking an estimated 17.9 million lives each year, representing one third of global mortality. As existing therapies still have limited success, due to the inability to control the biodistribution of the currently approved [...] Read more.

Cardiovascular diseases (CVDs) are the leading cause of death globally, taking an estimated 17.9 million lives each year, representing one third of global mortality. As existing therapies still have limited success, due to the inability to control the biodistribution of the currently approved drugs, the quality of life of these patients is modest. The advent of nanomedicine has brought new insights in innovative treatment strategies. For this reason, several novel nanotechnologies have been developed for both targeted and prolonged delivery of therapeutics to the cardiovascular system tο minimize side effects. In this regard, nanoparticles made of natural and/or synthetic nanomaterials, like liposomes, polymers or inorganic materials, are emerging alternatives for the encapsulation of already approved drugs to control their delivery in a targeted way. Therefore, nanomedicine has attracted the attention of the scientific community as a potential platform to deliver therapeutics to the injured heart. In this review, we discuss the current types of biomaterials that have been investigated as potential therapeutic interventions for CVDs as they open up a host of possibilities for more targeted and effective therapies, as well as minimally invasive treatments. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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20 pages, 964 KiB

Open AccessReview

An Overview of Antibody Conjugated Polymeric Nanoparticles for Breast Cancer Therapy

by Alberto Juan, Francisco J. Cimas, Iván Bravo, Atanasio Pandiella, Alberto Ocaña and Carlos Alonso-Moreno

Pharmaceutics 2020, 12(9), 802; https://doi.org/10.3390/pharmaceutics12090802 - 25 Aug 2020

Cited by 77 | Viewed by 8459

Abstract

Nanoparticles (NPs) are promising drug delivery systems (DDS) for identifying and treating cancer. Active targeting NPs can be generated by conjugation with ligands that bind overexpressed or mutant cell surface receptors on target cells that are poorly or not even expressed on normal [...] Read more.

Nanoparticles (NPs) are promising drug delivery systems (DDS) for identifying and treating cancer. Active targeting NPs can be generated by conjugation with ligands that bind overexpressed or mutant cell surface receptors on target cells that are poorly or not even expressed on normal cells. Receptor-mediated endocytosis of the NPs occurs and the drug is released inside the cell or in the surrounding tissue due to the bystander effect. Antibodies are the most frequently used ligands to actively target tumor cells. In this context, antibody-based therapies have been extensively used in HER2+ breast cancer. However, some patients inherently display resistance and in advanced stages, almost all eventually progress. Functionalized NPs through conjugation with antibodies appear to be a promising strategy to optimize targeted therapies due to properties related to biocompatibility, suitable delivery control and efficiency of functionalization. This review is focused on the different strategies to conjugate antibodies into polymeric NPs. Recent antibody conjugation approaches applied to the improvement of breast cancer therapy are highlighted in this review. Full article

(This article belongs to the Special Issue Lipid- and/or Polymer-Based Drug Delivery Systems)

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