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1.
Eur J Pharm Biopharm ; 198: 114249, 2024 May.
Article in English | MEDLINE | ID: mdl-38467334

ABSTRACT

In recent years, microneedles (MNs) have gained considerable interest in drug formulation due to their non-invasive and patient-friendly nature. Dissolving MNs have emerged as a promising approach to enhance drug delivery across the skin in a painless manner without generating sharp waste and providing the possibility for self-administration. Cyclodextrins, a group of cyclic oligosaccharides, are well-established in pharmaceutical products due to their safety and unique ability to form inclusion complexes with various drug molecules. In this manuscript, we report the development and characterization of dissolving MNs composed of cyclodextrins for intradermal delivery of a cyclodextrin-based nanoparticulate vaccine. Different cyclodextrins were tested and the most promising candidates were fabricated into MNs by micromolding. The MNs' piercing effectiveness and drug permeation across the skin were tested ex vivo. Furthermore, in vivo studies were carried out to assess the skin's tolerance to cyclodextrin-based MNs, and to evaluate the immune response using a model peptide antigen in a mouse model. The data revealed that the MNs were well-tolerated and effective, even leading to dose-sparing effects. This study highlights the potential of cyclodextrin-based dissolving MNs as a versatile platform for intradermal vaccine delivery, providing a compatible matrix for nanoparticulate formulations to enhance immune responses.


Subject(s)
Cyclodextrins , Nanoparticles , Vaccines , Mice , Animals , Humans , Nanovaccines , Skin , Drug Delivery Systems , Antigens , Peptides , Needles , Administration, Cutaneous
2.
J Control Release ; 365: 688-702, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38040343

ABSTRACT

Microbiome-based therapies hold great promise for treating various diseases, but the efficient delivery of live bacteria to the colon remains a challenge. Furthermore, current oral formulations, such as lyophilized bacterial capsules or tablets, are produced using processes that can decrease bacterial viability. Consequently, high dosages are required to achieve efficacy. Herein, we report the design of pressure-sensitive colonic capsules for the encapsulation and delivery of aqueous suspensions of live bacteria. The capsules consisted of 2 functional thin-films (hydrophobic and enteric) of ethyl cellulose and Eudragit S100 dip-coated onto hydroxypropyl methylcellulose molds. The capsules could be loaded with aqueous media and provide protection against acidic fluids and, to some extent, oxygen diffusion, suggesting their potential suitability for delivering anaerobic bacterial strains. Disintegration and mechanical studies indicated that the capsules could withstand transit through the stomach and upper/proximal small intestinal segments and rupture in the ileum/colon. In vitro studies showed that bacterial cells (anaerobic and aerobic commensals) remained highly viable (74-98%) after encapsulation and exposure to the simulated GI tract conditions. In vivo studies with a beagle dog model revealed that 67% of the capsules opened after 3.5 h, indicating content release in the distal gastrointestinal tract. These data demonstrate that live aqueous bacterial suspensions comprised of both aerobic and anaerobic commensals can be encapsulated and in the future might be efficiently delivered to the distal gastrointestinal tract, suggesting the practical applications of these capsules in microbiome-based therapies.


Subject(s)
Ileum , Intestine, Small , Animals , Dogs , Gastrointestinal Tract , Capsules/chemistry , Hydrogen-Ion Concentration , Drug Delivery Systems , Colon
3.
Int J Pharm ; 631: 122528, 2023 Jan 25.
Article in English | MEDLINE | ID: mdl-36563799

ABSTRACT

Dental caries is one of the most widespread chronic infectious diseases in the world. It is mainly caused by the production of acid in the biofilm from the bacterial metabolism of carbohydrates. Nowadays, the prevention of caries is mainly based on the use of topical formulations containing fluoride. However, effective fluoride supplementation may not be sufficient in high-risk individuals, leading to the exploration of alternative strategies such as the neutralization of acid in the oral cavity. Urea is hydrolyzed into ammonia by oral bacteria, leading to a local alkalization that may counteract tooth decay. Herein, we report the fabrication of 3D printed personalized dental trays with a local and prolonged release of urea. Composite filaments with tunable urea release kinetics were produced by hot melt extrusion of poly(ε-caprolactone) and poly(vinyl alcohol) or poly(ethylene glycol) blends mixed with urea. The filaments were further used to 3D print by fused deposition modeling objects capable of releasing urea in a sustained and spatially controlled manner. In vitro studies performed in the presence of Streptococcus salivarius demonstrated the ability of urea released from a 3D printed model toothguards to reduce the pH drop induced by carbohydrates. This study showed the potential of urea-loaded devices to reduce cariogenic acidification of the environment surrounding the enamel by delivering urea directly to the tooth surface.


Subject(s)
Dental Caries , Urea , Humans , Drug Liberation , Fluorides , Dental Caries/prevention & control , Printing, Three-Dimensional , Carbohydrates , Technology, Pharmaceutical , Tablets
4.
Theranostics ; 12(14): 6339-6362, 2022.
Article in English | MEDLINE | ID: mdl-36168618

ABSTRACT

Rationale: Cutaneous melanoma is the most aggressive and deadliest of all skin malignancies. Complete primary tumor removal augmented by advanced imaging tools and effective post-operative treatment is critical in the prevention of tumor recurrence and future metastases formation. Methods: To meet this challenge, we designed novel polymeric imaging and therapeutic systems, implemented in a two-step theranostic approach. Both are composed of the biocompatible and biodegradable poly(α,L-glutamic acid) (PGA) nanocarrier that facilitates extravasation-dependent tumor targeting delivery. The first system is a novel, fluorescent, Turn-ON diagnostic probe evaluated for the precise excision of the primary tumor during image-guided surgery (IGS). The fluorescence activation of the probe occurs via PGA degradation by tumor-overexpressed cathepsins that leads to the separation of closely-packed, quenched FRET pair. This results in the emission of a strong fluorescence signal enabling the delineation of the tumor boundaries. Second, therapeutic step is aimed to prevent metastases formation with minimal side effects and maximal efficacy. To that end, a targeted treatment containing a BRAF (Dabrafenib - mDBF)/MEK (Selumetinib - SLM) inhibitors combined on one polymeric platform (PGA-SLM-mDBF) was evaluated for its anti-metastatic, preventive activity in combination with immune checkpoint inhibitors (ICPi) αPD1 and αCTLA4. Results: IGS in melanoma-bearing mice led to a high tumor-to-background ratio and reduced tumor recurrence in comparison with mice that underwent surgery under white light (23% versus 33%, respectively). Adjuvant therapy with PGA-SLM-mDBF combined with ICPi, was well-tolerated and resulted in prolonged survival and prevention of peritoneal and brain metastases formation in BRAF-mutated melanoma-bearing mice. Conclusions: The results reveal the great clinical potential of our PGA-based nanosystems as a tool for holistic melanoma treatment management.


Subject(s)
Melanoma , Skin Neoplasms , Surgery, Computer-Assisted , Animals , Mice , Cathepsins , Glutamic Acid , Immune Checkpoint Inhibitors , Melanoma/drug therapy , Mitogen-Activated Protein Kinase Kinases , Nanoconjugates , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/prevention & control , Polyglutamic Acid/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf , Skin Neoplasms/pathology
5.
ACS Appl Bio Mater ; 4(1): 669-681, 2021 01 18.
Article in English | MEDLINE | ID: mdl-33490884

ABSTRACT

The performance of supramolecular nanocarriers as drug delivery systems depends on their stability in the complex and dynamic biological media. After administration, nanocarriers are challenged by physiological barriers such as shear stress and proteins present in blood, endothelial wall, extracellular matrix, and eventually cancer cell membrane. While early disassembly will result in a premature drug release, extreme stability of the nanocarriers can lead to poor drug release and low efficiency. Therefore, comprehensive understanding of the stability and assembly state of supramolecular carriers in each stage of delivery is the key factor for the rational design of these systems. One of the main challenges is that current 2D in vitro models do not provide exhaustive information, as they fail to recapitulate the 3D tumor microenvironment. This deficiency in the 2D model complexity is the main reason for the differences observed in vivo when testing the performance of supramolecular nanocarriers. Herein, we present a real-time monitoring study of self-assembled micelles stability and extravasation, combining spectral confocal microscopy and a microfluidic cancer-on-a-chip. The combination of advanced imaging and a reliable 3D model allows tracking of micelle disassembly by following the spectral properties of the amphiphiles in space and time during the crucial steps of drug delivery. The spectrally active micelles were introduced under flow and their position and conformation continuously followed by spectral imaging during the crossing of barriers, revealing the interplay between carrier structure, micellar stability, and extravasation. Integrating the ability of the micelles to change their fluorescent properties when disassembled, spectral confocal imaging and 3D microfluidic tumor blood vessel-on-a-chip resulted in the establishment of a robust testing platform suitable for real-time imaging and evaluation of supramolecular drug delivery carrier's stability.


Subject(s)
Micelles , Microfluidics/methods , Anthracenes/chemistry , Cell Culture Techniques, Three Dimensional , Drug Carriers/chemistry , Extracellular Matrix/chemistry , Extracellular Matrix/metabolism , HeLa Cells , Human Umbilical Vein Endothelial Cells , Humans , Lab-On-A-Chip Devices , Microfluidics/instrumentation , Microscopy, Confocal , Models, Biological , Nanoparticles/chemistry , Neoplasms/blood supply , Neoplasms/pathology , Polyethylene Glycols/chemistry , Polymers/chemistry , Spheroids, Cellular/cytology , Spheroids, Cellular/metabolism
6.
Polymers (Basel) ; 12(7)2020 Jul 08.
Article in English | MEDLINE | ID: mdl-32650512

ABSTRACT

The development of efficient synthetic strategies for incorporating antibacterial coatings into textiles for pharma and medical applications is of great interest. This paper describes the preparation of functional nonwoven fabrics coated with polyaniline (PANI) via in situ polymerization of aniline in aqueous solution. The effect of three different monomer concentrations on the level of polyaniline coating on the fibers comprising the fabrics, and its electrical resistivities and antibacterial attributes, were studied. Experimental results indicated that weight gains of 0.7 and 3.0 mg/cm2 of PANI were achieved. These levels of coatings led to the reduction of both volume and surface resistivities by several orders of magnitude for PANI-coated polyester-viscose fabrics, i.e., from 108 to 105 (Ω/cm) and from 109 to 105 Ω/square, respectively. Fourier Transform Infrared (FTIR) Spectroscopy and Scanning Electron Microscopy (SEM) confirmed the incorporation of PANI coating with an average thickness of 0.4-1.5 µm, while Thermogravimetric Analysis (TGA) demonstrated the preservation of the thermal stability of the pristine fabrics. The unique molecular structure of PANI, consisting of quaternary ammonium ions under acidic conditions, yielded an antibacterial effect in the modified fabrics. The results revealed that all types of PANI-coated fabrics totally killed S. aureus bacteria, while PANI-coated viscose fabrics also demonstrated 100% elimination of S. epidermidis bacteria. In addition, PANI-coated, PET-viscose and PET fabrics showed 2.5 log and 5.5 log reductions against S. epidermidis, respectively.

7.
J Am Chem Soc ; 139(46): 16677-16687, 2017 11 22.
Article in English | MEDLINE | ID: mdl-29076736

ABSTRACT

The dynamic nature of polymeric assemblies makes their stability in biological media a crucial parameter for their potential use as drug delivery systems in vivo. Therefore, it is essential to study and understand the behavior of self-assembled nanocarriers under conditions that will be encountered in vivo such as extreme dilutions and interactions with blood proteins and cells. Herein, using a combination of fluorescence spectroscopy and microscopy, we studied four amphiphilic PEG-dendron hybrids and their self-assembled micelles in order to determine their structure-stability relations. The high molecular precision of the dendritic block enabled us to systematically tune the hydrophobicity and stability of the assembled micelles. Using micelles that change their fluorescent properties upon disassembly, we observed that serum proteins bind to and interact with the polymeric amphiphiles in both their assembled and monomeric states. These interactions strongly affected the stability and enzymatic degradation of the micelles. Finally, using spectrally resolved confocal imaging, we determined the relations between the stability of the polymeric assemblies in biological media and their cell entry. Our results highlight the important interplay between molecular structure, micellar stability, and cell internalization pathways, pinpointing the high sensitivity of stability-activity relations to minor structural changes and the crucial role that these relations play in designing effective polymeric nanostructures for biomedical applications.


Subject(s)
Anthracenes/chemistry , Polyethylene Glycols/chemistry , Anthracenes/metabolism , HeLa Cells , Humans , Micelles , Polyethylene Glycols/metabolism , Serum Albumin/chemistry , Serum Albumin/metabolism
8.
Biomacromolecules ; 18(4): 1218-1228, 2017 04 10.
Article in English | MEDLINE | ID: mdl-28267318

ABSTRACT

Self-assembled nanostructures and their stimuli-responsive degradation have been recently explored to meet the increasing need for advanced biocompatible and biodegradable materials for various biomedical applications. Incorporation of enzymes as triggers that can stimulate the degradation and disassembly of polymeric assemblies may be highly advantageous owing to their high selectivity and natural abundance in all living organisms. One of the key factors to consider when designing enzyme-responsive polymers is the ability to fine-tune the sensitivity of the platform toward its target enzyme in order to control the disassembly rate. In this work, a series of enzyme-responsive amphiphilic PEG-dendron hybrids with increasing number of hydrophobic cleavable end-groups was synthesized, characterized, and compared. These hybrids were shown to self-assemble in aqueous media into nanosized polymeric micelles, which could encapsulate small hydrophobic guests in their cores and release them upon enzymatic stimulus. Utilization of dendritic scaffolds as the responsive blocks granted ultimate control over the number of enzymatically cleavable end-groups. Remarkably, as we increased the number of end-groups, the micellar stability increased significantly and the range of enzymatic sensitivity spanned from highly responsive micelles to practically nondegradable ones. The reported results highlight the remarkable role of hydrophobicity in determining the micellar stability toward enzymatic degradation and its great sensitivity to small structural changes of the hydrophobic block, which govern the accessibility of the cleavable hydrophobic groups to the activating enzyme.


Subject(s)
Enzymes/chemistry , Micelles , Polymers/chemistry , Hydrophobic and Hydrophilic Interactions , Magnetic Resonance Spectroscopy , Nanostructures , Polyethylene Glycols/chemistry , Polymers/chemical synthesis
9.
J Am Chem Soc ; 139(2): 803-810, 2017 01 18.
Article in English | MEDLINE | ID: mdl-27990807

ABSTRACT

Studying the enzymatic degradation of synthetic polymers is crucial for the design of suitable materials for biomedical applications ranging from advanced drug delivery systems to tissue engineering. One of the key parameters that governs enzymatic activity is the limited accessibility of the enzyme to its substrates that may be collapsed inside hydrophobic domains. PEG-dendron amphiphiles can serve as powerful tools for the study of enzymatic hydrolysis of polymeric amphiphiles due to the monodispersity and symmetry of the hydrophobic dendritic block, which significantly simplifies kinetic analyses. Using these hybrids, we demonstrate how precise, minor changes in the hydrophobic block are manifested into tremendous changes in the stability of the assembled micelles toward enzymatic degradation. The obtained results emphasize the extreme sensitivity of self-assembly and its great importance in regulating the accessibility of enzymes to their substrates. Furthermore, the demonstration that the structural differences between readily degradable and undegradable micelles are rather minor, points to the critical roles that self-assembly and polydispersity play in designing biodegradable materials.


Subject(s)
Enzymes , Micelles , Models, Biological , Polymers/chemistry , Drug Delivery Systems , Enzymes/chemistry , Enzymes/metabolism , Hydrophobic and Hydrophilic Interactions
10.
J Mater Chem B ; 4(18): 3037-3042, 2016 May 14.
Article in English | MEDLINE | ID: mdl-32263042

ABSTRACT

Labeling of smart PEG-dendron hybrids with fluorinated groups transformed their assemblies into enzyme-responsive micellar probes for 19F-magnetic resonance (MR). Two distinct labeling approaches were used to study the ability of these smart hybrids to be turned OFF at the assembled micellar state and to turn ON their 19F-MR signal upon enzymatic activation.

11.
Chemistry ; 21(44): 15633-8, 2015 Oct 26.
Article in English | MEDLINE | ID: mdl-26366522

ABSTRACT

The need for advanced fluorescent imaging and delivery platforms has motivated the development of smart probes that change their fluorescence in response to external stimuli. Here a new molecular design of fluorescently labeled PEG-dendron hybrids that self-assemble into enzyme-responsive micelles with tunable fluorescent responses is reported. In the assembled state, the fluorescence of the dyes is quenched or shifted due to intermolecular interactions. Upon enzymatic cleavage of the hydrophobic end-groups, the labeled polymeric hybrids become hydrophilic, and the micelles disassemble. This supramolecular change is translated into a spectral response as the dye-dye interactions are eliminated and the intrinsic fluorescence is regained. We demonstrate the utilization of this molecular design to generate both Turn-On and spectral shift responses by adjusting the type of the labeling dye. This approach enables transformation of non-responsive labeling dyes into smart fluorescent probes.


Subject(s)
Dendrimers/chemistry , Drug Carriers/chemistry , Esterases/chemistry , Esterases/metabolism , Fluorescent Dyes/chemistry , Nanoparticles/chemistry , Polyethylene Glycols/chemistry , Hydrophobic and Hydrophilic Interactions , Micelles , Polymers/chemistry
12.
J Am Chem Soc ; 137(6): 2276-84, 2015 Feb 18.
Article in English | MEDLINE | ID: mdl-25607219

ABSTRACT

The high selectivity and often-observed overexpression of specific disease-associated enzymes make them extremely attractive for triggering the release of hydrophobic drug or probe molecules from stimuli-responsive micellar nanocarriers. Here we utilized highly modular amphiphilic polymeric hybrids, composed of a linear hydrophilic polyethylene glycol (PEG) and an esterase-responsive hydrophobic dendron, to prepare and study two diverse strategies for loading of enzyme-responsive micelles. In the first type of micelles, hydrophobic coumarin-derived dyes were encapsulated noncovalently inside the hydrophobic core of the micelle, which was composed of lipophilic enzyme-responsive dendrons. In the second type of micellar nanocarrier the hydrophobic molecular cargo was covalently linked to the end-groups of the dendron through enzyme-cleavable bonds. These amphiphilic hybrids self-assembled into micellar nanocarriers with their cargo covalently encapsulated within the hydrophobic core. Both types of micelles were highly responsive toward the activating enzyme and released their molecular cargo upon enzymatic stimulus. Importantly, while faster release was observed with noncovalent encapsulation, higher loading capacity and slower release rate were achieved with covalent encapsulation. Our results clearly indicate the great potential of enzyme-responsive micellar delivery platforms due to the ability to tune their payload capacities and release rates by adjusting the loading strategy.


Subject(s)
Chemistry, Pharmaceutical , Drug Carriers , Enzymes/metabolism , Micelles , Microscopy, Electron, Transmission , Spectrometry, Fluorescence
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