Advanced Micro and Nano Drug Delivery Systems Designed for Cancer Therapy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (20 January 2023) | Viewed by 32490

Special Issue Editors


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Guest Editor
Biomedical Engineering Department, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
Interests: drug delivery; cancer therapy; crystallization; encapsulation; nanoparticles; triggered release; biopolymers

E-Mail Website
Guest Editor
Biomedical Engineering Department, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
Interests: biomaterials; microcontainers; nanoparticles; encapsulation; drug delivery

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Guest Editor
Skolkovo Innovation Center, Skolkovo Institute of Science and Technology, 3 Nobel Str., 143005 Moscow, Russia
Interests: biomedical materials; physiology; drug encapsulation; drug release; drug delivery; coatings; lamination; ultrasound; thin films; tissue engineering; cell proliferation

Special Issue Information

Dear Colleagues,

The latest advances in nanomedicine are aimed at targeted delivery of drugs to tumor foci after intravenous administration with the possibility of avoiding excessive accumulation of toxic drugs in normal tissue. The recent successful application of nanostructured particles as delivery vehicles has demonstrated the superior potential of nanostructure-based technology for drug delivery in biomedicine.

This Special Issue addresses the multidisciplinary field and aims to discuss innovative advances in the design and applications of nanostructured systems for cancer diagnosis, imaging, and therapy. We invite authors to report their recently developed inorganic, organic, and composite nano/microparticles for the delivery of anticancer drugs, photosensitizers, siRNA, etc.

Dr. Daria Trushina
Dr. Alexey Ermakov
Dr. Olga Sindeeva
Guest Editors

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Keywords

  • nano-/microparticles
  • polymer carriers
  • drug delivery
  • imaging
  • biomedicine
  • tumor targeting
  • photodynamic therapy

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Published Papers (11 papers)

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Research

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24 pages, 2970 KiB  
Article
Design of A3B-Porphyrin Conjugates with Terpyridine as Potential Theranostic Agents: Synthesis, Complexation with Fe(III), Gd(III), and Photodynamic Activity
by Kseniya A. Zhdanova, Anastasia V. Ivantsova, Fedor Yu. Vyalba, Maxim N. Usachev, Margarita A. Gradova, Oleg V. Gradov, Natalia Yu. Karpechenko and Natal’ya A. Bragina
Pharmaceutics 2023, 15(1), 269; https://doi.org/10.3390/pharmaceutics15010269 - 12 Jan 2023
Cited by 10 | Viewed by 2278
Abstract
This paper reports on the design and synthesis of new multifunctional porphyrin-based therapeutic agents for potential therapeutic and diagnostic applications. Zinc complexes of A3B-type meso-arylporphyrins containing OH- and COOH- groups were modified with chelating ligands based on 4′-(4-methylphenyl)-2,2′:6′,2″-terpyridine derivatives in high yields. [...] Read more.
This paper reports on the design and synthesis of new multifunctional porphyrin-based therapeutic agents for potential therapeutic and diagnostic applications. Zinc complexes of A3B-type meso-arylporphyrins containing OH- and COOH- groups were modified with chelating ligands based on 4′-(4-methylphenyl)-2,2′:6′,2″-terpyridine derivatives in high yields. Novel complexes with Gd(III), Fe(III) were obtained for these conjugates. Aggregation behaviour in solutions of different solubilisers was studied to inform the selection of the optimal solubilising platform for the porphyrins obtained; their photophysical and photochemical properties were also characterised. Micellar Pluronic F127 formulation was found to be the most effective solubiliser for stabilising the fluorescence-active monomolecular form of the photosensitisers (PS). In vitro cytotoxicity of the compounds was studied on the HEP-2 cell line with and without irradiation for 1.5 and 24 h. As a result, the IC50 of compounds 12 and 14 at an irradiation dose of 8.073 J/cm2 was shown to be 1.87 ± 0.333 and 1.4 ± 0.152 μM, respectively; without irradiation, the compound had no toxic effect within the studied concentration range (1.5 h). A test for the inhibition of metabolic cooperation or promoter activity was also performed for the abovementioned compounds, showing the efficacy and safety of the conjugates obtained. Preliminary data have indicated the high potential of the new type of PS to be promising molecular theranostic agents. Full article
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16 pages, 19858 KiB  
Article
Magnetic Platelets as a Platform for Drug Delivery and Cell Trapping
by Oksana A. Mayorova, Olga I. Gusliakova, Ekaterina S. Prikhozhdenko, Roman A. Verkhovskii and Daniil N. Bratashov
Pharmaceutics 2023, 15(1), 214; https://doi.org/10.3390/pharmaceutics15010214 - 7 Jan 2023
Cited by 3 | Viewed by 2635
Abstract
The possibility of using magnetically labeled blood cells as carriers is a novel approach in targeted drug-delivery systems, potentially allowing for improved bloodstream delivery strategies. Blood cells already meet the requirements of biocompatibility, safety from clotting and blockage of small vessels. It would [...] Read more.
The possibility of using magnetically labeled blood cells as carriers is a novel approach in targeted drug-delivery systems, potentially allowing for improved bloodstream delivery strategies. Blood cells already meet the requirements of biocompatibility, safety from clotting and blockage of small vessels. It would solve the important problem of the patient’s immune response to embedded foreign carriers. The high efficiency of platelet loading makes them promising research objects for the development of personalized drug-delivery systems. We are developing a new approach to use platelets decorated with magnetic nanoparticles as a targeted drug-delivery system, with a focus on bloodstream delivery. Platelets are non-nuclear blood cells and are of great importance in the pathogenesis of blood-clotting disorders. In addition, platelets are able to attach to circulating tumor cells. In this article, we studied the effect of platelets labeled with BSA-modified magnetic nanoparticles on healthy and cancer cells. This opens up broad prospects for future research based on the delivery of specific active substances by this method. Full article
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15 pages, 1995 KiB  
Article
Albumin-Functionalized Iron Oxide Nanoparticles for Theranostics: Engineering and Long-Term In Situ Imaging
by Anna V. Bychkova, Marina N. Yakunina, Mariia V. Lopukhova, Yevgeniy N. Degtyarev, Mikhail V. Motyakin, Vadim S. Pokrovsky, Alexander L. Kovarski, Maria G. Gorobets, Vasily M. Retivov and Derenik S. Khachatryan
Pharmaceutics 2022, 14(12), 2771; https://doi.org/10.3390/pharmaceutics14122771 - 11 Dec 2022
Cited by 6 | Viewed by 2211
Abstract
Magnetic nanosystems (MNSs) consisting of magnetic iron oxide nanoparticles (IONPs) coated by human serum albumin (HSA), commonly used as a component of hybrid nanosystems for theranostics, were engineered and characterized. The HSA coating was obtained by means of adsorption and free radical modification [...] Read more.
Magnetic nanosystems (MNSs) consisting of magnetic iron oxide nanoparticles (IONPs) coated by human serum albumin (HSA), commonly used as a component of hybrid nanosystems for theranostics, were engineered and characterized. The HSA coating was obtained by means of adsorption and free radical modification of the protein molecules on the surface of IONPs exhibiting peroxidase-like activity. The generation of hydroxyl radicals in the reaction of IONPs with hydrogen peroxide was proven by the spin trap technique. The methods of dynamic light scattering (DLS) and electron magnetic resonance (EMR) were applied to confirm the stability of the coatings formed on the surface of the IONPs. The synthesized MNSs (d ~35 nm by DLS) were intraarterially administered in tumors implanted to rats in the dose range from 20 to 60 μg per animal and studied in vivo as a contrasting agent for computed tomography. The long-term (within 14 days of the experiment) presence of the MNSs in the tumor vascular bed was detected without immediate or delayed adverse reactions and significant systemic toxic effects during the observation period. The peroxidase-like activity of MNSs was proven by the colorimetric test with o-phenylenediamine (OPD) as a substrate. The potential of the synthesized MNSs to be used for theranostics, particularly, in oncology, was discussed. Full article
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16 pages, 2869 KiB  
Article
Comparative Analysis of Tetra(2-naphthyl)tetracyano-porphyrazine and Its Iron Complex as Photosensitizers for Anticancer Photodynamic Therapy
by Lydia N. Shestakova, Tatyana S. Lyubova, Svetlana A. Lermontova, Artem O. Belotelov, Nina N. Peskova, Larisa G. Klapshina, Irina V. Balalaeva and Natalia Y. Shilyagina
Pharmaceutics 2022, 14(12), 2655; https://doi.org/10.3390/pharmaceutics14122655 - 30 Nov 2022
Cited by 4 | Viewed by 1857
Abstract
Photodynamic therapy (PDT) is a rapidly developing modality of primary and adjuvant anticancer treatment. The main trends today are the search for new effective photodynamic agents and the creation of targeted delivery systems with the function of controlling the release of the agent [...] Read more.
Photodynamic therapy (PDT) is a rapidly developing modality of primary and adjuvant anticancer treatment. The main trends today are the search for new effective photodynamic agents and the creation of targeted delivery systems with the function of controlling the release of the agent in the tumor. Recently, the new group of cyanoarylporphyrazine dyes was reported, which combine the properties of photosensitizers and sensors of the local microenvironment. Such unique characteristics allow the release of the photosensitizer from the transport carrier to be assessed in real time in vivo. The aim of the present work was to compare the photophysical and photobiological properties of tetra(2-naphthyl)tetracyanoporphyrazine and its newly synthesized Fe(II) complex. We have shown that the chelation of the Fe(II) cation with the porphyrazine macrocycle leads to a decrease in molar extinction and an increase in the quantum yield of fluorescence and photostability. We demonstrate that the iron cation significantly affects the rate of dye accumulation in cells, the dark toxicity and photodynamic activity, and the direction of the changes depends on the particular cell line. However, in all the cases, the photodynamic index of a metal complex was higher than that of a metal-free base. In general, both of the compounds were found to be very promising for PDT, including for the use with transport delivery systems, and can be recommended for further in vivo studies. Full article
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23 pages, 7119 KiB  
Article
Structural Optimization of Platinum Drugs to Improve the Drug-Loading and Antitumor Efficacy of PLGA Nanoparticles
by Maria B. Sokol, Margarita V. Chirkina, Nikita G. Yabbarov, Mariia R. Mollaeva, Tatyana A. Podrugina, Anna S. Pavlova, Viktor V. Temnov, Rania M. Hathout, Abdelkader A. Metwally and Elena D. Nikolskaya
Pharmaceutics 2022, 14(11), 2333; https://doi.org/10.3390/pharmaceutics14112333 - 29 Oct 2022
Cited by 7 | Viewed by 2378
Abstract
Currently, molecular dynamics simulation is being widely applied to predict drug–polymer interaction, and to optimize drug delivery systems. Our study describes a combination of in silico and in vitro approaches aimed at improvement in polymer-based nanoparticle design for cancer treatment. We applied the [...] Read more.
Currently, molecular dynamics simulation is being widely applied to predict drug–polymer interaction, and to optimize drug delivery systems. Our study describes a combination of in silico and in vitro approaches aimed at improvement in polymer-based nanoparticle design for cancer treatment. We applied the PASS service to predict the biological activity of novel carboplatin derivatives. Subsequent molecular dynamics simulations revealed the dependence between the drug–polymer binding energy along with encapsulation efficacy, drug release profile, and the derivatives’ chemical structure. We applied ICP-MS analysis, the MTT test, and hemolytic activity assay to evaluate drug loading, antitumor activity, and hemocompatibility of the formulated nanoparticles. The drug encapsulation efficacy varied from 0.2% to 1% and correlated with in silico modelling results. The PLGA nanoparticles revealed higher antitumor activity against A549 human non-small-cell lung carcinoma cells compared to non-encapsulated carboplatin derivatives with IC50 values of 1.40–23.20 µM and 7.32–79.30 µM, respectively; the similar cytotoxicity profiles were observed against H69 and MCF-7 cells. The nanoparticles efficiently induced apoptosis in A549 cells. Thus, nanoparticles loaded with novel carboplatin derivatives demonstrated high application potential for anticancer therapy due to their efficacy and high hemocompatibility. Our results demonstrated the combination of in silico and in vitro methods applicability for the optimization of encapsulation and antitumor efficacy in novel drug delivery systems design. Full article
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11 pages, 2031 KiB  
Article
Ultrasound-Triggerable Coatings for Foley Catheter Balloons for Local Release of Anti-Inflammatory Drugs during Bladder Neck Dilation
by Olga A. Sindeeva, Arkady S. Abdurashitov, Pavel I. Proshin, Alexey V. Kadrev, Oleg A. Kulikov, Boris M. Shaparov, Nikolay I. Sorokin, Valentin P. Ageev, Nikolay A. Pyataev, Aleksandr Kritskiy, Alexander Tishin, Armais A. Kamalov and Gleb B. Sukhorukov
Pharmaceutics 2022, 14(10), 2186; https://doi.org/10.3390/pharmaceutics14102186 - 13 Oct 2022
Cited by 3 | Viewed by 3256
Abstract
Bladder neck contracture (BNC) is a complication of the surgical treatment of benign and malignant prostate conditions and is associated with the partial or complete blockage of urination. Correction of this condition usually requires repeated surgical intervention, which does not guarantee recovery. Balloon [...] Read more.
Bladder neck contracture (BNC) is a complication of the surgical treatment of benign and malignant prostate conditions and is associated with the partial or complete blockage of urination. Correction of this condition usually requires repeated surgical intervention, which does not guarantee recovery. Balloon dilation is a minimally invasive alternative to the surgical dissection of tissues; however, it significantly reduces the patient’s quality of life. Additional local anti-inflammatory treatment may reduce the number of procedures requested and increase the attractiveness of this therapeutic strategy. Here, we report about an ultrathin biocompatible coating based on polylactic acid for Foley catheter balloons that can provide localized release of Prednol-L in the range of 56–99 µg in the BNC zone under conventional diagnostic ultrasound exposure. Note that the exposure of a transrectal probe with a conventional gray-scale ultrasound regimen with and without shear wave elastography (SWE) was comparably effective for Prednol-L release from the coating surface of a Foley catheter balloon. This strategy does not require additional manipulations by clinicians. The trigger for the drug release is the ultrasound exposure, which is applied for visualization of the balloon’s location during the dilation process. In vivo experiments demonstrated the absence of negative effects of the usage of a coated Foley catheter for balloon dilation of the bladder neck and urethra. Full article
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10 pages, 2840 KiB  
Article
Laser Microperforation Assisted Drug-Elution from Biodegradable Films
by Arkady S. Abdurashitov, Pavel I. Proshin, Olga A. Sindeeva and Gleb B. Sukhorukov
Pharmaceutics 2022, 14(10), 2144; https://doi.org/10.3390/pharmaceutics14102144 - 9 Oct 2022
Cited by 1 | Viewed by 1587
Abstract
In a modern high-tech medicine, drug-eluting polymer coatings are actively used to solve a wide range of problems, including the prevention of post-surgery infection, inflammatory, restenosis, thrombosis and many other implant-associated complications. For major assumptions, the drug elution mechanism is considered mainly to [...] Read more.
In a modern high-tech medicine, drug-eluting polymer coatings are actively used to solve a wide range of problems, including the prevention of post-surgery infection, inflammatory, restenosis, thrombosis and many other implant-associated complications. For major assumptions, the drug elution mechanism is considered mainly to be driven by the degradation of the polymer matrix. This process is very environmentally dependent, unpredictable and often leads to a non-linear drug release kinetic. In the present work, we demonstrate how the laser microperforation of cargo-loaded biodegradable films could be used as a tool to achieve zero-order release kinetics with different elution rates. The effects of the laser-induced hole’s diameter (10, 18, 22, 24 µm) and their density (0, 1, 2, 4 per sample) on release kinetic are studied. The linear dynamics of elution was measured for all perforation densities. Release rates were estimated to be 0.018 ± 0.01 µg/day, 0.211 ± 0.08 µg/day, 0.681 ± 0.1 µg/day and 1.19 ± 0.12 µg/day for groups with 0, 1, 2, 4 microperforations, respectively. The role of biodegradation of the polymer matrix is reduced only to the decomposition of the film over time with no major influence on elution rates. Full article
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18 pages, 3828 KiB  
Article
Doxorubicin-Loaded Core–Shell UiO-66@SiO2 Metal–Organic Frameworks for Targeted Cellular Uptake and Cancer Treatment
by Daria B. Trushina, Anastasiia Yu. Sapach, Olga A. Burachevskaia, Pavel V. Medvedev, Dmitry N. Khmelenin, Tatiana N. Borodina, Mikhail A. Soldatov and Vera V. Butova
Pharmaceutics 2022, 14(7), 1325; https://doi.org/10.3390/pharmaceutics14071325 - 23 Jun 2022
Cited by 37 | Viewed by 4442
Abstract
Beneficial features of biocompatible high-capacity UiO-66 nanoparticles, mesoporous SiO2, and folate-conjugated pluronic F127 were combined to prepare the core–shell UiO-66@SiO2/F127-FA drug delivery carrier for targeted cellular uptake in cancer treatment. UiO-66 and UiO-66-NH2 nanoparticles with a narrow size [...] Read more.
Beneficial features of biocompatible high-capacity UiO-66 nanoparticles, mesoporous SiO2, and folate-conjugated pluronic F127 were combined to prepare the core–shell UiO-66@SiO2/F127-FA drug delivery carrier for targeted cellular uptake in cancer treatment. UiO-66 and UiO-66-NH2 nanoparticles with a narrow size and shape distribution were used to form a series of core–shell MOF@SiO2 structures. The duration of silanization was varied to change the thickness of the SiO2 shell, revealing a nonlinear dependence that was attributed to silicon penetration into the porous MOF structure. Doxorubicin encapsulation showed a similar final loading of 5.6 wt % for both uncoated and silica-coated particles, demonstrating the potential of the nanocomposite’s application in small molecule delivery. Silica coating improved the colloidal stability of the composites in a number of model physiological media, enabled grafting of target molecules to the surface, and prevented an uncontrolled release of their cargo, with the drawback of decreased overall porosity. Further modification of the particles with the conjugate of pluronic and folic acid was performed to improve the biocompatibility, prolong the blood circulation time, and target the encapsulated drug to the folate-expressing cancer cells. The final DOX-loaded UiO-66@SiO2/F127-FA nanoparticles were subjected to properties characterization and in vitro evaluation, including studies of internalization into cells and antitumor activity. Two cell lines were used: MCF-7 breast cancer cells, which have overexpressed folate receptors on the cell membranes, and RAW 264.7 macrophages without folate overexpression. These findings will provide a potential delivery system for DOX and increase the practical value of MOFs. Full article
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23 pages, 43181 KiB  
Article
Renal Artery Catheterization for Microcapsules’ Targeted Delivery to the Mouse Kidney
by Olga I. Gusliakova, Ekaterina S. Prikhozhdenko, Valentina O. Plastun, Oksana A. Mayorova, Natalia A. Shushunova, Arkady S. Abdurashitov, Oleg A. Kulikov, Maxim A. Abakumov, Dmitry A. Gorin, Gleb B. Sukhorukov and Olga A. Sindeeva
Pharmaceutics 2022, 14(5), 1056; https://doi.org/10.3390/pharmaceutics14051056 - 14 May 2022
Cited by 8 | Viewed by 3759
Abstract
The problem of reducing the side effects associated with drug distribution throughout the body in the treatment of various kidney diseases can be solved by effective targeted drug delivery. The method described herein involves injection of a drug encapsulated in polyelectrolyte capsules to [...] Read more.
The problem of reducing the side effects associated with drug distribution throughout the body in the treatment of various kidney diseases can be solved by effective targeted drug delivery. The method described herein involves injection of a drug encapsulated in polyelectrolyte capsules to achieve prolonged local release and long-term capillary retention of several hours while these capsules are administered via the renal artery. The proposed method does not imply disruption (puncture) of the renal artery or aorta and is suitable for long-term chronic experiments on mice. In this study, we compared how capsule size and dosage affect the target kidney blood flow. It has been established that an increase in the diameter of microcapsules by 29% (from 3.1 to 4.0 μm) requires a decrease in their concentration by at least 50% with the same suspension volume. The photoacoustic method, along with laser speckle contrast imaging, was shown to be useful for monitoring blood flow and selecting a safe dose. Capsules contribute to a longer retention of a macromolecular substance in the target kidney compared to its free form due to mechanical retention in capillaries and slow impregnation into surrounding tissues during the first 1–3 h, which was shown by fluorescence tomography and microscopy. At the same time, the ability of capillaries to perform almost complete “self-cleaning” from capsular shells during the first 12 h leads to the preservation of organ tissues in a normal state. The proposed strategy, which combines endovascular surgery and the injection of polymer microcapsules containing the active substance, can be successfully used to treat a wide range of nephropathies. Full article
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Review

Jump to: Research

37 pages, 2985 KiB  
Review
Recent Advances in the Development of Nanodelivery Systems Targeting the TRAIL Death Receptor Pathway
by Anne V. Yagolovich, Marine E. Gasparian and Dmitry A. Dolgikh
Pharmaceutics 2023, 15(2), 515; https://doi.org/10.3390/pharmaceutics15020515 - 3 Feb 2023
Cited by 6 | Viewed by 2602
Abstract
The TRAIL (TNF-related apoptosis-inducing ligand) apoptotic pathway is extensively exploited in the development of targeted antitumor therapy due to TRAIL specificity towards its cognate receptors, namely death receptors DR4 and DR5. Although therapies targeting the TRAIL pathway have encountered many obstacles in attempts [...] Read more.
The TRAIL (TNF-related apoptosis-inducing ligand) apoptotic pathway is extensively exploited in the development of targeted antitumor therapy due to TRAIL specificity towards its cognate receptors, namely death receptors DR4 and DR5. Although therapies targeting the TRAIL pathway have encountered many obstacles in attempts at clinical implementation for cancer treatment, the unique features of the TRAIL signaling pathway continue to attract the attention of researchers. Special attention is paid to the design of novel nanoscaled delivery systems, primarily aimed at increasing the valency of the ligand for improved death receptor clustering that enhances apoptotic signaling. Optionally, complex nanoformulations can allow the encapsulation of several therapeutic molecules for a combined synergistic effect, for example, chemotherapeutic agents or photosensitizers. Scaffolds for the developed nanodelivery systems are fabricated by a wide range of conventional clinically approved materials and innovative ones, including metals, carbon, lipids, polymers, nanogels, protein nanocages, virus-based nanoparticles, dendrimers, DNA origami nanostructures, and their complex combinations. Most nanotherapeutics targeting the TRAIL pathway are aimed at tumor therapy and theranostics. However, given the wide spectrum of action of TRAIL due to its natural role in immune system homeostasis, other therapeutic areas are also involved, such as liver fibrosis, rheumatoid arthritis, Alzheimer’s disease, and inflammatory diseases caused by bacterial infections. This review summarizes the recent innovative developments in the design of nanodelivery systems modified with TRAIL pathway-targeting ligands. Full article
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23 pages, 3385 KiB  
Review
Microbubbles Stabilized by Protein Shell: From Pioneering Ultrasound Contrast Agents to Advanced Theranostic Systems
by Polina G. Rudakovskaya, Roman A. Barmin, Pavel S. Kuzmin, Elena P. Fedotkina, Alexander N. Sencha and Dmitry A. Gorin
Pharmaceutics 2022, 14(6), 1236; https://doi.org/10.3390/pharmaceutics14061236 - 10 Jun 2022
Cited by 23 | Viewed by 4016
Abstract
Ultrasound is a widely-used imaging modality in clinics as a low-cost, non-invasive, non-radiative procedure allowing therapists faster decision-making. Microbubbles have been used as ultrasound contrast agents for decades, while recent attention has been attracted to consider them as stimuli-responsive drug delivery systems. Pioneering [...] Read more.
Ultrasound is a widely-used imaging modality in clinics as a low-cost, non-invasive, non-radiative procedure allowing therapists faster decision-making. Microbubbles have been used as ultrasound contrast agents for decades, while recent attention has been attracted to consider them as stimuli-responsive drug delivery systems. Pioneering microbubbles were Albunex with a protein shell composed of human serum albumin, which entered clinical practice in 1993. However, current research expanded the set of proteins for a microbubble shell beyond albumin and applications of protein microbubbles beyond ultrasound imaging. Hence, this review summarizes all-known protein microbubbles over decades with a critical evaluation of formulations and applications to optimize the safety (low toxicity and high biocompatibility) as well as imaging efficiency. We provide a comprehensive overview of (1) proteins involved in microbubble formulation, (2) peculiarities of preparation of protein stabilized microbubbles with consideration of large-scale production, (3) key chemical factors of stabilization and functionalization of protein-shelled microbubbles, and (4) biomedical applications beyond ultrasound imaging (multimodal imaging, drug/gene delivery with attention to anticancer treatment, antibacterial activity, biosensing). Presented critical evaluation of the current state-of-the-art for protein microbubbles should focus the field on relevant strategies in microbubble formulation and application for short-term clinical translation. Thus, a protein bubble-based platform is very perspective for theranostic application in clinics. Full article
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