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15 pages, 6963 KiB

Open AccessEditor’s ChoiceArticle

Chitosan-Functionalized Poly(β-Amino Ester) Hybrid System for Gene Delivery in Vaginal Mucosal Epithelial Cells

by Xueqin Gao, Dirong Dong, Chong Zhang, Yuxing Deng, Jiahui Ding, Shiqi Niu, Songwei Tan and Lili Sun

Pharmaceutics 2024, 16(1), 154; https://doi.org/10.3390/pharmaceutics16010154 - 22 Jan 2024

Cited by 1 | Viewed by 1419

Abstract

Gene therapy displays great promise in the treatment of cervical cancer. The occurrence of cervical cancer is highly related to persistent human papilloma virus (HPV) infection. The HPV oncogene can be cleaved via gene editing technology to eliminate carcinogenic elements. However, the successful application of the gene therapy method depends on effective gene delivery into the vagina. To improve mucosal penetration and adhesion ability, quaternized chitosan was introduced into the poly(β-amino ester) (PBAE) gene-delivery system in the form of quaternized chitosan-g-PBAE (QCP). At a mass ratio of PBAE:QCP of 2:1, the polymers exhibited the highest green fluorescent protein (GFP) transfection efficiency in HEK293T and ME180 cells, which was 1.1 and 5.4 times higher than that of PEI 25 kD. At this mass ratio, PBAE–QCP effectively compressed the GFP into spherical polyplex nanoparticles (PQ–GFP NPs) with a diameter of 255.5 nm. In vivo results indicated that owing to the mucopenetration and adhesion capability of quaternized CS, the GFP transfection efficiency of the PBAE–QCP hybrid system was considerably higher than those of PBAE and PEI 25 kD in the vaginal epithelial cells of Sprague–Dawley rats. Furthermore, the new system demonstrated low toxicity and good safety, laying an effective foundation for its further application in gene therapy. Full article

(This article belongs to the Special Issue Delivery System for Biomacromolecule Drugs: Design and Application)

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20 pages, 1049 KiB

Open AccessEditor’s ChoiceReview

Recent Advancements in the Development of Nanocarriers for Mucosal Drug Delivery Systems to Control Oral Absorption

by Hideyuki Sato, Kohei Yamada, Masateru Miyake and Satomi Onoue

Pharmaceutics 2023, 15(12), 2708; https://doi.org/10.3390/pharmaceutics15122708 - 30 Nov 2023

Cited by 3 | Viewed by 1344

Abstract

Oral administration of active pharmaceutical ingredients is desirable because it is easy, safe, painless, and can be performed by patients, resulting in good medication adherence. The mucus layer in the gastrointestinal (GI) tract generally acts as a barrier to protect the epithelial membrane from foreign substances; however, in the absorption process after oral administration, it can also disturb effective drug absorption by trapping it in the biological sieve structured by mucin, a major component of mucus, and eliminating it by mucus turnover. Recently, functional nanocarriers (NCs) have attracted much attention due to their immense potential and effectiveness in the field of oral drug delivery. Among them, NCs with mucopenetrating and mucoadhesive properties are promising dosage options for controlling drug absorption from the GI tracts. Mucopenetrating and mucoadhesive NCs can rapidly deliver encapsulated drugs to the absorption site and/or prolong the residence time of NCs close to the absorption membrane, providing better medications than conventional approaches. The surface characteristics of NCs are important factors that determine their functionality, owing to the formation of various kinds of interactions between the particle surface and mucosal components. Thus, a deeper understanding of surface modifications on the biopharmaceutical characteristics of NCs is necessary to develop the appropriate mucosal drug delivery systems (mDDS) for the treatment of target diseases. This review summarizes the basic information and functions of the mucosal layer, highlights the recent progress in designing functional NCs for mDDS, and discusses their performance in the GI tract. Full article

(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)

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26 pages, 2635 KiB

Open AccessReview

The Role of Mucoadhesion and Mucopenetration in the Immune Response Induced by Polymer-Based Mucosal Adjuvants

by Nathaly Vasquez-Martínez, Daniel Guillen, Silvia Andrea Moreno-Mendieta, Sergio Sanchez and Romina Rodríguez-Sanoja

Polymers 2023, 15(7), 1615; https://doi.org/10.3390/polym15071615 - 24 Mar 2023

Cited by 11 | Viewed by 3648

Abstract

Mucus is a viscoelastic gel that acts as a protective barrier for epithelial surfaces. The mucosal vehicles and adjuvants need to pass through the mucus layer to make drugs and vaccine delivery by mucosal routes possible. The mucoadhesion of polymer particle adjuvants significantly increases the contact time between vaccine formulations and the mucosa; then, the particles can penetrate the mucus layer and epithelium to reach mucosa-associated lymphoid tissues. This review presents the key findings that have aided in understanding mucoadhesion and mucopenetration while exploring the influence of physicochemical characteristics on mucus–polymer interactions. We describe polymer-based particles designed with mucoadhesive or mucopenetrating properties and discuss the impact of mucoadhesive polymers on local and systemic immune responses after mucosal immunization. In future research, more attention paid to the design and development of mucosal adjuvants could lead to more effective vaccines. Full article

(This article belongs to the Special Issue Development of Bio-Based Materials: Synthesis, Characterization, and Applications II)

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22 pages, 3888 KiB

Open AccessArticle

Amidated Pluronic Decorated Muco-Penetrating Self-Nano Emulsifying Drug Delivery System (SNEDDS) for Improved Anti-Salmonella typhi Potential

by Rabia Arshad, Muhammad Salman Arshad, Tanveer A. Tabish, Syed Nisar Hussain Shah, Saira Afzal and Gul Shahnaz

Pharmaceutics 2022, 14(11), 2433; https://doi.org/10.3390/pharmaceutics14112433 - 10 Nov 2022

Cited by 5 | Viewed by 2289

Abstract

The enteric system residing notorious Salmonella typhimurium (S. typhi) is an intracellular, food-borne, and zoonotic pathogen causing typhoid fever. Typhoid fever is one of the leading causes of mortality and morbidity in developing and underdeveloped countries. It also increased the prevalence of multidrug resistance globally. Currently, available anti-bacterial modalities are unable to penetrate into the intracellular compartments effectively for eradicating S. typhi infection. Therefore, in this study, we developed nanostructured lipid-based carriers in the form of a self-nanoemulsifying drug delivery system (SNEDDS) for targeted delivery of ciprofloxacin (CIP) into the S. typhi intracellular reservoirs. Capryol 90, Tween 80, and Span 20 were finalized as suitable oil, surfactant, and co-surfactant, respectively, according to the pseudoternary phase diagram emulsifying region. Targeting capability and mucopenetration of the SNEDDS was attributed to the inclusion of amidated pluronic (NH₂-F₁₂₇). Developed NH₂-F₁₂₇ SNEDDS were characterized via physicochemical, in vitro, ex vivo, and in vivo evaluation parameters. The size of the SNEDDS was found to be 250 nm, having positively charged zeta potential. In vitro dissolution of SNEDDS showed 80% sustained release of CIP in 72 h with maximum entrapment efficiency up to 90% as well as good hemocompatibility by showing less than 0.2% hemolysis and 90% biocompatibility. The survival rate of S. typhi in macrophages (RAW 264.7) was minimal, i.e., only 2% in the case of NH₂-F₁₂₇ SNEDDS. Macrophage uptake assay via nanostructures confirmed the maximum cellular uptake as evidenced by the highest fluorescence. Biofilm dispersion assay showed rapid eradication of developed resistant biofilms on the gall bladder. In vivo pharmacokinetics showed improved bioavailability by showing an increased area under the curve (AUC) value. Taken together, NH₂-F₁₂₇-SNEDDS can be utilized as an alternative and efficient delivery system for the sustained release of therapeutic amounts of CIP for the treatment of S. typhi. Full article

(This article belongs to the Special Issue Nanostructured Lipid Carriers: Design, Properties and Applications in Drug Delivery)

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18 pages, 3366 KiB

Open AccessArticle

Papain-Decorated Mucopenetrating SEDDS: A Tentative Approach to Combat Absorption Issues of Acyclovir via the Oral Route

by Arshad Mahmood, Rabbia Haneef, Ahmad Z. Al Meslamani, Mohammad F. Bostanudin, Muhammad Sohail, Muhammad Sarfraz and Mosab Arafat

Pharmaceutics 2022, 14(8), 1584; https://doi.org/10.3390/pharmaceutics14081584 - 29 Jul 2022

Cited by 3 | Viewed by 2086

Abstract

The aim of the current study was to enhance the oral bioavailability of Acyclovir (ACV) based on the papain-functionalized self-emulsifying drug delivery systems (SEDDS). The optimum control SEDDS formulation comprised of kolliphore (40%), transcutol (30%), propylene glycol (20%) and oleoyl chloride (10%). However, in the targeted SEDDS formulation, oleoyl chloride was replaced with oleoyl chloride-papain (OC-PAP) conjugate that was synthesized via an amide bond formation between the acyl halide groups of oleoyl chloride and the amino group of papain. Prior to adding in the SEDDS formulation, the newly synthesized conjugate was evaluated quantitatively by a Bradford assay that demonstrated 45 µg of papain contents per mg of the conjugate. Moreover, the conjugate formation was qualitatively confirmed through FTIR analysis and thin layer chromatography. ACV (a BCS class III drug) was incorporated into the SEDDS formulations after being hydrophobically ion paired with sodium deoxycholate, thereby making it lipophilic. The drug-loaded formulations were emulsified in the 0.1 M phosphate buffer (pH 6.8) and evaluated in vitro with respect to drug release and rabbit mucosal permeation studies. Both the formulations illustrated a very comparable drug release over a period of 4 h, afterwards, the OC-PAP-based formulation demonstrated a more sustaining effect. The extent of mucus diffusion evaluated via the silicon tube method demonstrated a 4.92-fold and a 1.46-fold higher penetration of the drug, a 3.21-fold and a 1.56-fold higher permeation through the rabbit intestinal mucus layer, and a 22.94-fold and a 2.27-fold higher retention of the drug over the intact mucosa of rabbit intestine, illustrated by OC-PAP-based nanoemulsions compared to the drug-free solution and controlled nanoemulsion, respectively. According to these in vitro results, papain-functionalized SEDDS is a promising approach for the oral delivery of ACV and many other drugs with oral bioavailability issues, however, in vivo studies in this respect have to be employed before making a comprehensive conclusion. Full article

(This article belongs to the Special Issue Mucoadhesive Drug Delivery Systems)

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15 pages, 1937 KiB

Open AccessArticle

Synthesis and Validation of a Bioinspired Catechol-Functionalized Pt(IV) Prodrug for Preclinical Intranasal Glioblastoma Treatment

by Xiaoman Mao, Shuang Wu, Pilar Calero-Pérez, Ana P. Candiota, Paula Alfonso, Jordi Bruna, Victor J. Yuste, Julia Lorenzo, Fernando Novio and Daniel Ruiz-Molina

Cancers 2022, 14(2), 410; https://doi.org/10.3390/cancers14020410 - 14 Jan 2022

Cited by 9 | Viewed by 2736

Abstract

Glioblastoma is the most malignant and frequently occurring type of brain tumors in adults. Its treatment has been greatly hampered by the difficulty to achieve effective therapeutic concentration in the tumor sites due to its location and the blood–brain barrier. Intranasal administration has emerged as an alternative for drug delivery into the brain though mucopenetration, and rapid mucociliary clearance still remains an issue to be solved before its implementation. To address these issues, based on the intriguing properties of proteins secreted by mussels, polyphenol and catechol functionalization has already been used to promote mucopenetration, intranasal delivery and transport across the blood–brain barrier. Thus, herein we report the synthesis and study of complex 1, a Pt(IV) prodrug functionalized with catecholic moieties. This complex considerably augmented solubility in contrast to cisplatin and showed a comparable cytotoxic effect on cisplatin in HeLa, 1Br3G and GL261 cells. Furthermore, preclinical in vivo therapy using the intranasal administration route suggested that it can reach the brain and inhibit the growth of orthotopic GL261 glioblastoma. These results open new opportunities for catechol-bearing anticancer prodrugs in the treatment for brain tumors via intranasal administration. Full article

(This article belongs to the Section Cancer Therapy)

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15 pages, 2789 KiB

Open AccessArticle

Mucoadhesion and Mucopenetration of Cannabidiol (CBD)-Loaded Mesoporous Carrier Systems for Buccal Drug Delivery

by Ulrike Söpper, Anja Hoffmann and Rolf Daniels

Sci. Pharm. 2021, 89(3), 35; https://doi.org/10.3390/scipharm89030035 - 2 Aug 2021

Cited by 5 | Viewed by 5433

Abstract

Transmucosal drug delivery represents a promising noninvasive option when drugs are employed which have a low oral bioavailability like CBD. However, this concept can only be successful as long as the formulation provides sufficient buccal retention and mucosal penetration. In this study, mucoadhesive carrier systems were evaluated consisting of CBD-loaded silica (Aeroperl 300) carriers, mucoadhesive polymers (Hypromellose (HPMC), chitosan and carbomer) and propylene glycol as a penetration enhancer. Mucoadhesive effect, drug release and penetration ability were evaluated for each carrier system. The results show that the addition of HPMC and carbomer substantially improve mucoadhesion compared to pure CBD, with an increase of 16-fold and 20-fold, respectively. However, due to their strong swelling, HPMC and carbomer hinder the penetration of CBD and rely on co-administration of propylene glycol as an enhancer to achieve sufficient mucosal absorption. Chitosan, on the other hand, achieves an 8-fold increase in mucoadhesion and enhances the amount of CBD absorbed by three times compared to pure CBD. Thus, chitosan represents a promising polymer to combine both effects. Considering the results, the development of silica-based buccal drug delivery systems is a promising approach for the effective delivery of CBD. Full article

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24 pages, 4476 KiB

Open AccessReview

Recent Advancements in Polymer/Liposome Assembly for Drug Delivery: From Surface Modifications to Hybrid Vesicles

by Vincenzo De Leo, Francesco Milano, Angela Agostiano and Lucia Catucci

Polymers 2021, 13(7), 1027; https://doi.org/10.3390/polym13071027 - 26 Mar 2021

Cited by 100 | Viewed by 8345

Abstract

Liposomes are consolidated and attractive biomimetic nanocarriers widely used in the field of drug delivery. The structural versatility of liposomes has been exploited for the development of various carriers for the topical or systemic delivery of drugs and bioactive molecules, with the possibility of increasing their bioavailability and stability, and modulating and directing their release, while limiting the side effects at the same time. Nevertheless, first-generation vesicles suffer from some limitations including physical instability, short in vivo circulation lifetime, reduced payload, uncontrolled release properties, and low targeting abilities. Therefore, liposome preparation technology soon took advantage of the possibility of improving vesicle performance using both natural and synthetic polymers. Polymers can easily be synthesized in a controlled manner over a wide range of molecular weights and in a low dispersity range. Their properties are widely tunable and therefore allow the low chemical versatility typical of lipids to be overcome. Moreover, depending on their structure, polymers can be used to create a simple covering on the liposome surface or to intercalate in the phospholipid bilayer to give rise to real hybrid structures. This review illustrates the main strategies implemented in the field of polymer/liposome assembly for drug delivery, with a look at the most recent publications without neglecting basic concepts for a simple and complete understanding by the reader. Full article

(This article belongs to the Special Issue Progress in Polymer Research: From Sustainable Materials to Biomedical Application)

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18 pages, 4154 KiB

Open AccessArticle

Permeability of Novel Chitosan-g-Poly(Methyl Methacrylate) Amphiphilic Nanoparticles in a Model of Small Intestine In Vitro

by Imrit Noi, Inbar Schlachet, Murali Kumarasamy and Alejandro Sosnik

Polymers 2018, 10(5), 478; https://doi.org/10.3390/polym10050478 - 27 Apr 2018

Cited by 24 | Viewed by 5492

Abstract

Engineering of drug nanocarriers combining fine-tuned mucoadhesive/mucopenetrating properties is currently being investigated to ensure more efficient mucosal drug delivery. Aiming to improve the transmucosal delivery of hydrophobic drugs, we designed a novel nanogel produced by the self-assembly of amphiphilic chitosan graft copolymers ionotropically crosslinked with sodium tripolyphosphate. In this work, we synthesized, for the first time, chitosan-g-poly(methyl methacrylate) nanoparticles thiolated by the conjugation of N-acetyl cysteine. First, we confirmed that both non-crosslinked and crosslinked nanoparticles in the 0.05–0.1% w/v concentration range display very good cell compatibility in two cell lines that are relevant to oral delivery, Caco-2 cells that mimic the intestinal epithelium and HT29-MTX cells that are a model of mucin-producing goblet cells. Then, we evaluated the effect of crosslinking, nanoparticle concentration, and thiolation on the permeability in vitro utilizing monolayers of (i) Caco-2 and (ii) Caco-2:HT29-MTX cells (9:1 cell number ratio). Results confirmed that the ability of the nanoparticles to cross Caco-2 monolayer was affected by the crosslinking. In addition, thiolated nanoparticles interact more strongly with mucin, resulting in a decrease of the apparent permeability coefficient (P_app) compared to the pristine nanoparticles. Moreover, for all the nanoparticles, higher concentration resulted in lower P_app, suggesting that the transport pathways can undergo saturation. Full article

(This article belongs to the Collection Polysaccharides)

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1292 KiB

Open AccessReview

Inhalable PEGylated Phospholipid Nanocarriers and PEGylated Therapeutics for Respiratory Delivery as Aerosolized Colloidal Dispersions and Dry Powder Inhalers

by Priya Muralidharan, Evan Mallory, Monica Malapit, Don Hayes and Heidi M. Mansour

Pharmaceutics 2014, 6(2), 333-353; https://doi.org/10.3390/pharmaceutics6020333 - 20 Jun 2014

Cited by 57 | Viewed by 11778

Abstract

Nanomedicine is making groundbreaking achievements in drug delivery. The versatility of nanoparticles has given rise to its use in respiratory delivery that includes inhalation aerosol delivery by the nasal route and the pulmonary route. Due to the unique features of the respiratory route, research in exploring the respiratory route for delivery of poorly absorbed and systemically unstable drugs has been increasing. The respiratory route has been successfully used for the delivery of macromolecules like proteins, peptides, and vaccines, and continues to be examined for use with small molecules, DNA, siRNA, and gene therapy. Phospholipid nanocarriers are an attractive drug delivery system for inhalation aerosol delivery in particular. Protecting these phospholipid nanocarriers from pulmonary immune system attack by surface modification by polyethylene glycol (PEG)ylation, enhancing mucopenetration by PEGylation, and sustaining drug release for controlled drug delivery are some of the advantages of PEGylated liposomal and proliposomal inhalation aerosol delivery. This review discusses the advantages of using PEGylated phospholipid nanocarriers and PEGylated therapeutics for respiratory delivery through the nasal and pulmonary routes as inhalation aerosols. Full article

(This article belongs to the Special Issue Liposome Technologies)

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928 KiB

Open AccessArticle

Amoxicillin Loaded Chitosan–Alginate Polyelectrolyte Complex Nanoparticles as Mucopenetrating Delivery System for H. Pylori

by Saahil ARORA, Sankalp GUPTA, Raj K. NARANG and Ramji D. BUDHIRAJA

Sci. Pharm. 2011, 79(3), 673-694; https://doi.org/10.3797/scipharm.1011-05 - 19 May 2011

Cited by 105 | Viewed by 2939

Abstract

The present study has been undertaken to apply the concept of nanoparticulate mucopenetrating drug delivery system for complete eradication of Helicobacter pylori (H. pylori), colonised deep into the gastric mucosal lining. Most of the existing drug delivery systems have failed on account of either improper mucoadhesion or mucopenetration and no dosage form with dual activity of adhesion and penetration has been designed till date for treating H. pylori induced disorders. In the present study, novel chitosan-alginate polyelectrolyte complex (CS-ALG PEC) nanoparticles of amoxicillin have been designed and optimized for various variables such as pH and mixing ratio of polymers, concentrations of polymers, drug and surfactant, using 3³ Box-Behnken design. Various studies like particle size, surface charge, percent drug entrapment, in-vitro mucoadhesion and in-vivo mucopenetration of nanoparticles on rat models were conducted. The optimised FITC labelled CS-ALG PEC nanoparticles have shown comparative low in-vitro mucoadhesion with respect to plain chitosan nanoparticles, but excellent mucopenetration and localization as observed with increased fluorescence in gastric mucosa continuously over 6 hours, which clinically can help in eradication of H. pylori. Full article

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