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Clinical approval of nanotechnology-based SARS-CoV-2 mRNA vaccines: impact on translational nanomedicine
Lara Milane & Mansoor Amiji
doi : 10.1007/s13346-021-00911-y
Drug Delivery and Translational Research volume 11, pages1309–1315 (2021)
One year after the first human case of SARS-CoV-2, two nanomedicine-based mRNA vaccines have been fast-tracked, developed, and have received emergency use authorization throughout the globe with more vaccine approvals on the heels of these first two. Several SARS-CoV-2 vaccine compositions use nanotechnology-enabled formulations. A silver lining of the COVID-19 pandemic is that the fast-tracked vaccine development for SARS-CoV-2 has advanced the clinical translation pathway for nanomedicine drug delivery systems. The laboratory science of lipid-based nanoparticles was ready and rose to the clinical challenge of rapid vaccine development. The successful development and fast tracking of SARS-CoV-2 nanomedicine vaccines has exciting implications for the future of nanotechnology-enabled drug and gene delivery; it demonstrates that nanomedicine is necessary and critical to the successful delivery of advanced molecular therapeutics such as nucleic acids, it is establishing the precedent of safety and the population effect of phase four clinical trials, and it is laying the foundation for the clinical translation of more complex, non-lipid nanomedicines. The development, fast-tracking, and approval of SARS-CoV-2 nanotechnology-based vaccines has transformed the seemingly daunting challenges for clinically translating nanomedicines into measurable hurdles that can be overcome. Due to the tremendous scientific achievements that have occurred in response to the COVID-19 pandemic, years, perhaps even decades, have been streamlined for certain translational nanomedicines.
Drug delivery for fighting infectious diseases: a global perspective
Brigitta Loretz, Yu-Kyoung Oh, Sarah Hudson, Zhen Gu & Claus-Michael Lehr
doi : 10.1007/s13346-021-01009-1
Drug Delivery and Translational Research volume 11, pages1316–1322 (2021)
Ultrasound-responsive polymer-based drug delivery systems
Ping Wei, Erik Jan Cornel & Jianzhong Du
doi : 10.1007/s13346-021-00963-0
Drug Delivery and Translational Research volume 11, pages1323–1339 (2021)
Ultrasound-responsive polymeric materials have received a tremendous amount of attention from scientists for several decades. Compared to other stimuli-responsive materials (such as UV-, thermal-, and pH-responsive materials), these smart materials are more applicable since they allow more efficient drug delivery and targeted treatment by fairly non-invasive means. This review describes the recent advances of such ultrasound-responsive polymer-based drug delivery systems and illustrates various applications. More specifically, the mechanism of ultrasound-induced drug delivery, typical formulations, and biomedical applications (tumor therapy, disruption of blood–brain barrier, fighting infectious diseases, transdermal drug delivery, and enhanced thrombolysis) are summarized. Finally, a perspective on the future research directions for the development of ultrasound-responsive polymeric materials to facilitate a clinical translation is given.
An overview of chitosan and its application in infectious diseases
Qingye Meng, Ying Sun, Hailin Cong, Hao Hu & Fu-Jian Xu
doi : 10.1007/s13346-021-00913-w
Drug Delivery and Translational Research volume 11, pages1340–1351 (2021)
Infectious diseases, such as the coronavirus disease-19, SARS virus, Ebola virus, and AIDS, threaten the health of human beings globally. New viruses, drug-resistant bacteria, and fungi continue to challenge the human efficacious drug bank. Researchers have developed a variety of new antiviral and antibacterial drugs in response to the infectious disease crisis. Meanwhile, the development of functional materials has also improved therapeutic outcomes. As a natural material, chitosan possesses good biocompatibility, bioactivity, and biosafety. It has been proven that the cooperation between chitosan and traditional medicine greatly improves the ability of anti-infection. This review summarized the application and design considerations of chitosan-composed systems for the treatment of infectious diseases, looking forward to providing the idea of infectious disease therapy.
Antimicrobial nanomedicine for ocular bacterial and fungal infection
Wenjie Fan, Haijie Han, Yaoyao Chen, Xiaobo Zhang, Yifan Gao, Su Li, Qiao Jin, Jian Ji & Ke Yao
doi : 10.1007/s13346-021-00966-x
Drug Delivery and Translational Research volume 11, pages1352–1375 (2021)
Ocular infection induced by bacteria and fungi is a major cause of visual impairment and blindness. Topical administration of antibiotics remains the first-line treatment, as effective eradication of pathogens is the core of the anti-infection strategy. Whereas, eye drops lack efficiency and have relatively low bioavailability. Intraocular injection may cause concurrent ocular damage and secondary infection. In addition, antibiotic-based management can be limited by the low sensitivity to multidrug-resistant bacteria. Nanomedicine is proposed as a prospective, effective, and noninvasive platform to mediate ocular delivery and combat pathogen or even resistant strains. Nanomedicine can not only carry antimicrobial agents to fight against pathogens but also directly active microbicidal capability, killing pathogens. More importantly, by modification, nanomedicine can achieve enhanced residence time and release time on the cornea, and easy penetration through corneal tissues into anterior and posterior segments of the eye, thus improving the therapeutic effect for ocular infection. In this review, several categories of antimicrobial nanomedicine are systematically discussed, where the efficiency and possibility of further embellishment and improvement to adapt to clinical use are also investigated. All in all, novel antimicrobial nanomedicine provides potent and prospective ways to manage severe and refractory ocular infections.
Topographical nanostructures for physical sterilization
Yujie Cai, Wei Bing, Xiao Xu, Yuqi Zhang, Zhaowei Chen & Zhen Gu
doi : 10.1007/s13346-021-00906-9
Drug Delivery and Translational Research volume 11, pages1376–1389 (2021)
The development in nanobiotechnology provides an in-depth understanding of cell-surface interactions at the nanoscale level. Particularly, several surface features have shown the ability to interrogate the bacterial behavior and fate. In the past decade, the mechanical and physical sterilization has attracted considerable attention, as paradigms of such do not rely on chemical substances to damage or kill bacteria, whereas it is associated with natural living organisms or synthetic materials. Of note, such antibacterial scenario does not cause bacterial resistance, as the morphology of nanometer can directly cause bacterial death through physical and mechanical interactions. In this review, we provide an overview of recently developed technologies of leveraging topographical nanofeatures for physical sterilization. We mainly discuss the development of various morphologic nanostructures, and colloidal nanostructures show casing the capacity of “mechanical sterilization.” Mechanically sterilized nanostructures can penetrate or cut through bacterial membranes. In addition, surface morphology, such as mechanical bactericidal nanoparticles and nanoneedles, can cause damage to the membrane of microorganisms, leading to cell lysis and death. Although the research in the field of mechanical sterilization is still in infancy, the effect of these nanostructure morphologies on sterilization has shown remarkable antibacterial potential, which could provide a new toolkit for anti-infection and antifouling applications.
Ovalbumin and cholera toxin delivery to buccal mucus for immunization using microneedles and comparison of immunological response to transmucosal delivery
Yu-Jeong Oh, Hye-Ran Cha, Su Jin Hwang, Dae-Sung Kim, Yu-Ji Choi, Yun-Seo Kim, Yu-Ra Shin, Thuy Trang Nguyen, Seong-O Choi, Jae Myun Lee & Jung-Hwan Park
doi : 10.1007/s13346-021-00964-z
Drug Delivery and Translational Research volume 11, pages1390–1400 (2021)
The oral mucosa is an effective site for vaccination. However, for oral mucosal vaccines, delivery of the right dose of vaccine is not possible due to the water-rich environment. In this study, the buccal mucosa, which is easy to access using a microneedle array in the oral cavity, was selected as the administration site. The immune responses to the use of microneedles to conventional transmucosal delivery were compared. In addition, the adjuvant effect of the addition of cholera toxin (CT) to the drug formulation was observed. Two kinds of patches were prepared: (1) Ovalbumin (OVA) was dip coated only on the tips of microneedles (C-OVA-MN) and (2) OVA was coated on the surface of a flat disk patch substrate without microneedles (C-OVA-D). The drug delivery properties of C-OVA-MN and C-OVA-D were investigated using fluorescent-labeled OVA (OVA/FITC). Each patch was administered to mice twice, 2 weeks apart, and then antibody titers were measured. A microneedle patch can deliver vaccine into the epithelium of the buccal mucosa in a short period of time compared to transmucosal delivery. A microneedle system of C-OVA-MN showed a high serum IgG titer. In addition, CT triggered CD8+ and CD4+ T cell-mediated immune responses. Through this study, we present the possibility of a new method of vaccination to the buccal mucosa using microneedles and CT adjuvant.
Advances in vaccine delivery systems against viral infectious diseases
Dongyoon Kim, Yina Wu, Young Bong Kim & Yu-Kyoung Oh
doi : 10.1007/s13346-021-00945-2
Drug Delivery and Translational Research volume 11, pages1401–1419 (2021)
Although vaccines are available for many infectious diseases, there are still unresolved infectious diseases that threaten global public health. In particular, the rapid spread of unpredictable, highly contagious viruses has recorded numerous infection cases and deaths, and has changed our lives socially or economically through social distancing and wearing masks. The pandemics of unpredictable, highly contagious viruses increase the ever-high social need for rapid vaccine development. Nanotechnologies may hold promise and expedite the development of vaccines against newly emerging infectious viruses. As potential nanoplatforms for delivering antigens to immune cells, delivery systems based on lipids, polymers, proteins, and inorganic nanomaterials have been studied. These nanoplatforms have been tested as a means to deliver vaccines not as a whole, but in the form of protein subunits or as DNA or mRNA sequences encoding the antigen proteins of viruses. This review covers the current status of nanomaterial-based delivery systems for viral antigens, with highlights on nanovaccines against recently emerging infectious viruses, such as severe acute respiratory syndrome coronavirus-2, Middle East respiratory syndrome coronavirus, and Zika virus.
Nanotechnology advances in pathogen- and host-targeted antiviral delivery: multipronged therapeutic intervention for pandemic control
Kai-Chieh Yang, Jung-Chen Lin, Hsiao-Han Tsai, Chung-Yao Hsu, Vicky Shih & Che-Ming Jack Hu
doi : 10.1007/s13346-021-00965-y
Drug Delivery and Translational Research volume 11, pages1420–1437 (2021)
The COVID-19 pandemic's high mortality rate and severe socioeconomic impact serve as a reminder of the urgent need for effective countermeasures against viral pandemic threats. In particular, effective antiviral therapeutics capable of stopping infections in its tracks is critical to reducing infection fatality rate and healthcare burden. With the field of drug delivery witnessing tremendous advancement in the last two decades owing to a panoply of nanotechnology advances, the present review summarizes and expounds on the research and development of therapeutic nanoformulations against various infectious viral pathogens, including HIV, influenza, and coronaviruses. Specifically, nanotechnology advances towards improving pathogen- and host-targeted antiviral drug delivery are reviewed, and the prospect of achieving effective viral eradication, broad-spectrum antiviral effect, and resisting viral mutations are discussed. As several COVID-19 antiviral clinical trials are met with lackluster treatment efficacy, nanocarrier strategies aimed at improving drug pharmacokinetics, biodistributions, and synergism are expected to not only contribute to the current disease treatment efforts but also expand the antiviral arsenal against other emerging viral diseases.
DNA-derived nanostructures selectively capture gram-positive bacteria
Chan-Jin Kim, Zhangyong Si, Sheethal Reghu, Zhong Guo, Kaixi Zhang, Jianghua Li & Mary B. Chan-Park
doi : 10.1007/s13346-021-00975-w
Drug Delivery and Translational Research volume 11, pages1438–1450 (2021)
We report the first demonstration of the efficient bacteria targeting properties of DNA-based polymeric micelles with high-density DNA corona. Nanoscale polymer micelles derived from DNA-b-polystyrene (DNA-b-PS) efficiently selected most tested Gram-positive strains over Gram-negative strains; single-strand DNAs were 20-fold less selective. We demonstrate that these targeting properties were derived from the interaction between densely packed DNA strands of the micelle corona and the peptidoglycan layers of Gram-positive bacteria. DNA-b-PS micelles incorporating magnetic nanoparticles (MNPs) can efficiently capture and concentrate Gram-positive bacteria suggesting the simple applications of these DNA block copolymer micelles for concentrating bacteria. Adenine (A), thymine (T), cytosine (C), and guanine (G)-rich nanostructures were fabricated, respectively, for investigating the effect of sequence on Gram-selective bacteria targeting. T-rich micelles showed the most efficient targeting properties. The targeting properties of these DNA nanostructures toward Gram-positive bacteria may have applications as a targeted therapeutic delivery system.
Self-luminescent photodynamic therapy and pathogen detection for infectious diseases
Endong Zhang, Yiming Huang & Shu Wang
doi : 10.1007/s13346-021-00989-4
Drug Delivery and Translational Research volume 11, pages1451–1455 (2021)
The importance of detection and treatments of infectious diseases has been stressed to the world by the ongoing COVID-19 pandemic. As a substitution of an external light source, self-luminescent therapeutics featuring in situ light emission aims to address the lack of tissue penetration in conventional photodynamic therapy (PDT). Luminol-based self-luminescent systems are successfully incorporated in PDT and detection of pathogens in infectious diseases. In these systems, luminol/hydrogen peroxide is served as luminescence source which can be activated by horseradish peroxidase (HRP). As a supplement strategy to the HRP-based bioluminescence, electrochemiluminescence (ECL) provided an electric-driven therapeutic solution and demonstrated potential capabilities of wearable healthcare devices with properly constructed transparent flexible hydrogels. Besides the diagnosis of infection and detection of bacteria, fungi and virus in solution or powder samples have been achieved by ATP-derived self-luminescence as the light source. In this inspirational note, we provide an overview on latest progress in the PDT and microbial detection by self-luminescent systems with an emphasis on the bioluminescence and ECL.
Titanium dioxide nanotubes as drug carriers for infection control and osteogenesis of bone implants
Kun Wang, Haoyu Jin, Qing Song, Jingjing Huo, Jing Zhang & Peng Li
doi : 10.1007/s13346-021-00980-z
Drug Delivery and Translational Research volume 11, pages1456–1474 (2021)
Titanium implants have been widely used as one of the most effective treatments of bone defects. However, the lack of osteogenesis and bacteria-resistant activities result in high infection and loosening rates of titanium implants. Anodic oxidation could easily construct titanium dioxide nanotubes (TNTs) array on the surface of titanium, and the rough surface of TNTs is beneficial to the growth of osteoblast-related cells on the surface. And TNTs could be excellent drug carriers because of their single-entry tubular hollow structure. In this review, we aim at detailing the application of TNTs as drug carriers in the field of bone implants. Starting from the topography of TNTs, we illustrated the biological activity of the TNTs surface, the drugs for loading in TNTs, and the controlled and responsive release strategies of drug-loaded TNTs, respectively. At the end of this review, the shortcomings of TNTs as the drug carrier in the field of bone implants are discussed, and the development direction of this research field is also prospected.
Inflammation-responsive delivery systems for the treatment of chronic inflammatory diseases
Zhengyu Deng & Shiyong Liu
doi : 10.1007/s13346-021-00977-8
Drug Delivery and Translational Research volume 11, pages1475–1497 (2021)
Inflammation is the biological response of immune system to protect living organisms from injurious factors. However, excessive and uncontrolled inflammation is implicated in a variety of devastating chronic diseases including atherosclerosis, inflammatory bowel disease (IBD), and rheumatoid arthritis (RA). Improved understanding of inflammatory response has unveiled a rich assortment of anti-inflammatory therapeutics for the treatment and management of relevant chronic diseases. Notwithstanding these successes, clinical outcomes are variable among patients and serious adverse effects are often observed. Moreover, there exist some limitations for clinical anti-inflammatory therapeutics such as aqueous insolubility, low bioavailability, off-target effects, and poor accessibility to subcellular compartments. To address these challenges, the rational design of inflammation-specific drug delivery systems (DDSs) holds significant promise. Moreover, as compared to normal tissues, inflamed tissue-associated pathological milieu (e.g., oxidative stress, acidic pH, and overexpressed enzymes) provides vital biochemical stimuli for triggered delivery of anti-inflammatory agents in a spatiotemporally controlled manner. In this review, we summarize recent advances in the development of anti-inflammatory DDSs with built-in pathological inflammation-specific responsiveness for the treatment of chronic inflammatory diseases.
Transdermal drug delivery systems for fighting common viral infectious diseases
Fang-Ying Wang, Yunching Chen, Yi-You Huang & Chao-Min Cheng
doi : 10.1007/s13346-021-01004-6
Drug Delivery and Translational Research volume 11, pages1498–1508 (2021)
Transdermal drug delivery systems (TDDS) have many advantages and represent an excellent alternative to oral delivery and hypodermic injections. TDDS are more convenient and less invasive tools for disease and viral infection treatment, prevention, detection, and surveillance. The emerging development of microneedles for TDDS has facilitated improved skin barrier penetration for the delivery of macromolecules or hydrophilic drugs. Microneedle TDDS patches can be fabricated to deliver virus vaccines and potentially provide a viable alternative vaccine modality that offers improved immunogenicity, thermostability, simplicity, safety, and compliance as well as sharp-waste reduction, increased cost-effectiveness, and the capacity for self-administration, which could improve vaccine distribution. These advantages make TDDS-based vaccine delivery an especially well-suited option for treatment of widespread viral infectious diseases including pandemics. Because microneedle-based bioassays employ transdermal extraction of interstitial fluid or blood, they can be used as a minimally invasive approach for surveying disease markers and providing point-of-care (POC) diagnostics. For cutaneous viral infections, TDDS can provide localized treatment with high specificity and less systemic toxicity. In summary, TDDS, especially those that employ microneedles, possess special attributes that can be leveraged to reduce morbidity and mortality from viral infectious diseases. In this regard, they may have considerable positive impact as a modality for improving global health. In this article, we introduce the possible role and summarize the current literature regarding TDDS applications for fighting common cutaneous or systemic viral infectious diseases, including herpes simplex, varicella or herpes zoster, warts, influenza, measles, and COVID-19.
Mannose-conjugated chitosan nanoparticles for delivery of Rifampicin to Osteoarticular tuberculosis
Pratiksha Prabhu, Trinette Fernandes, Pramila Chaubey, Parvinder Kaur, Shridhar Narayanan, Ramya VK & Sujata P. Sawarkar
doi : 10.1007/s13346-021-01003-7
Drug Delivery and Translational Research volume 11, pages1509–1519 (2021)
Tuberculosis (TB) is a potentially fatal contagious disease and is a second leading infectious cause of death in the world. Osteoarticular TB is treated using standard regimen of 1st and 2nd line anti-tubercular drugs (ATDs) for extensive period of 8–20 months. These drugs are commonly administered in high doses by oral route or by intravenous route, because of their compromised bioavailability. The common drawbacks associated with conventional therapy are poor patient compliance due to long treatment period, frequent and high dosing, and toxicity. This aspect marks for the need of formulations to eliminate these drawbacks. MTB is an intracellular pathogen of mononuclear phagocyte. This attribute makes nanotherapeutics an ideal approach for MTB treatment as macrophages capture nano forms. Polymeric nanoparticles are removed from the body by opsonization and phagocytosis, which forms an ideal strategy to target macrophage containing mycobacteria. To further improve targetability, the nanoparticles are conjugated with ligand, which serves as an easy substrate for the receptors present on the macrophage surface. The purpose of present work was to develop intra-articular injectable in situ gelling system containing polymeric nanoparticles, which would have promising advantages over conventional method of treatment. The rationale behind formulating nanoparticle incorporated in situ gel-based system was to ensure localization of the formulation in intra-articular cavity along with sustained release and conjugation of nanoparticles with mannose as ligand to improve uptake by macrophages. Rifampicin standard ATD was formulated into chitosan nanoparticles. Chitosan with 85% degree of deacetylation (DDA) and sodium tripolyphosphate (TPP) as the crosslinking agent was used for preparing nanoparticles. The percent entrapment was found to be about 71%. The prepared nanoparticles were conjugated with mannose. Conjugation of ligand was ascertained by performing Fourier transformed infrared spectroscopy. The particle size was found to be in the range of 130–140 nm and zeta potential of 38.5 mV. Additionally, we performed scanning electron microscopy to characterize the surface morphology of ligand-conjugated nanoparticles. The conjugated chitosan nanoparticles were incorporated into in situ gelling system comprising Poloxamer 407 and HPMC K4M. The gelling system was evaluated for viscosity, gelling characteristics, and syringeability. The drug release from conjugated nanoparticles incorporated in in situ gel was found to be about 70.3% at the end of 40 h in simulated synovial fluid following zero-order release kinetics. Based on the initial encouraging results obtained, the nanoparticles are being envisaged for ex vivo cellular uptake study using TB-infected macrophages
A triple combination 'nano' dry powder inhaler for tuberculosis: in vitro and in vivo pulmonary characterization
Manasi M. Chogale, Sagar B. Dhoble & Vandana B. Patravale
doi : 10.1007/s13346-021-01005-5
Drug Delivery and Translational Research volume 11, pages1520–1531 (2021)
Inhalation route of drug delivery is the most favorable for pulmonary infections wherein direct drug delivery is desired to the lungs. Tuberculosis is one such infection suffering from poor therapeutic efficacy because of low patient compliance due to high drug dosing and lengthy treatment protocols. The current research work was undertaken to develop a dry powder inhaler (DPI) for administration of three first-line antitubercular antibiotics directly to the lungs to improve the treatment rates. Nanoformulations of isoniazid, pyrazinamide, and rifampicin were prepared, spray-dried to obtain a dry powder system, and blended with inhalation grade lactose to develop the DPI. The DPI was evaluated for its flow properties, pulmonary deposition, dissolution profile, and stability. The DPI possessed excellent flow properties with a fine particle fraction of 45% and a mass median aerodynamic diameter of approximately 5 µm indicating satisfactory lung deposition. In vitro drug release exhibited a sustained release of the formulations. In vivo studies showed a prolonged deposition in the lung at elevated concentrations compared to oral therapy. Stability studies proved that the formulation remained stable at accelerated and long-term stability conditions. The DPI could complement the existing oral therapy in enhancing the therapeutic efficacy in patients.
Chitosan-based hydrogels to treat hydrofluoric acid burns and prevent infection
Shu-Wei Huang, Fang-Ching Yeh, You-Ren Ji, Ying-Fu Su, Ying-shih Su, Ming-Hsien Chiang, Shian-Chiuan Tzeng, Chien-Yao Fu, Aristine Cheng, Yung-Chi Wang & Yi-Tzu Lee
doi : 10.1007/s13346-021-01007-3
Drug Delivery and Translational Research volume 11, pages1532–1544 (2021)
There is an urgent need for treatments for hydrofluoric acid (HF) burns and their derivative problems that prevent hydrogen ion dissociation and fluoride ion binding to tissues. This study evaluated the ability of chitosan-based hydrogels combined with a buffer solution containing either boric acid or Tris and calcium gluconate (CHS-BA-CG and CHS-Tris-CG) to repair HF burn wounds and prevent wound infections. We assessed calcium release rates and biocompatability and constructed a mouse HF burn model to assess the tissue repair effects of the hydrogels. Finally, we performed disc diffusion tests from burn tissue and quantified the bacterial counts to assess the anti-infection properties of the hydrogels. Calcium was gradually released in the CHS-BA-CG and CHS-Tris-CG groups (73% and 43%, respectively, after 48 h). The cell viabilities at 48 h after HF burn in these groups were significantly higher than those in the phosphate-buffered saline (PBS) and CG-treated groups. Histopathological evaluation showed a clear boundary between the epidermal and dermal layers in both CHS-BA-CG and CHS-Tris-CG-treated groups, indicating their effectiveness in tissue repair. In the disc diffusion test, CHS-BA-CG and CHS-Tris-CG exhibited larger inhibition zones against Acinetobacter baumannii than those for PBS and CG. The bacterial counts on HF burn wounds were significantly lower in the CHS-BA-CG and CHS-Tris-CG-treated groups than those in the PBS and CG-treated groups. The in vitro studies demonstrated the biocompatibility and antimicrobial effects of the CHS-BA-CG and CHS-Tris-CG hydrogels. Both gels also demonstrated tissue repair and anti-infection effects. Thus, chitosan-based hydrogels may be candidates for HF burn therapy.
Therapy of infected wounds: overcoming clinical challenges by advanced drug delivery systems
Pia Kaiser, Jana Wächter & Maike Windbergs
doi : 10.1007/s13346-021-00932-7
Drug Delivery and Translational Research volume 11, pages1545–1567 (2021)
In recent years, the incidence of infected wounds is steadily increasing, and so is the clinical as well as economic interest in effective therapies. These combine reduction of pathogen load in the wound with general wound management to facilitate the healing process. The success of current therapies is challenged by harsh conditions in the wound microenvironment, chronicity, and biofilm formation, thus impeding adequate concentrations of active antimicrobials at the site of infection. Inadequate dosing accuracy of systemically and topically applied antibiotics is prone to promote development of antibiotic resistance, while in the case of antiseptics, cytotoxicity is a major problem. Advanced drug delivery systems have the potential to enable the tailor-made application of antimicrobials to the side of action, resulting in an effective treatment with negligible side effects. This review provides a comprehensive overview of the current state of treatment options for the therapy of infected wounds. In this context, a special focus is set on delivery systems for antimicrobials ranging from semi-solid and liquid formulations over wound dressings to more advanced carriers such as nano-sized particulate systems, vesicular systems, electrospun fibers, and microneedles, which are discussed regarding their potential for effective therapy of wound infections. Further, established and novel models and analytical techniques for preclinical testing are introduced and a future perspective is provided.
New perspectives on the topical management of recurrent candidiasis
Ana Carolina S. Ré, Jayanaraian F. Martins, Marcílio Cunha?Filho, Guilherme M. Gelfuso, Carolina P. Aires & Taís Gratieri
doi : 10.1007/s13346-021-00901-0
Drug Delivery and Translational Research volume 11, pages1568–1585 (2021)
Candidiasis is a common opportunistic infection caused by fungi of the Candida genus that affects mainly mucocutaneous tissues (e.g., vaginal, oral, and mammary). This condition has been known for a long time; thus, innumerous topical and systemic treatments are already available on the market worldwide. Yet, recurrent superficial candidiasis (RSC) is an expected outcome, still lacking effective and convenient treatments. Although several individual conditions may contribute to disease recurrence, biofilms’ presence seems to be the main etiological factor contributing to antifungal resistance. More than proposing novel antifungal agents, current research seems to be focusing on improving the pharmaceutical technology aspects of formulations to address such a challenge. These include extending and improving intimate contact of drug delivery systems with the mucocutaneous tissues, increasing drug loading dose, and enhancing topical drug permeation. This review discusses the current understanding of the RSC and the use of pharmaceutical technology tools in obtaining better results. Even though several drawbacks of conventional formulations have been circumvented with the help of nano- or microencapsulation techniques and with the use of mucoadhesive formulation excipients, many challenges remain. In particular, the need to mask the unpalatable taste of formulations for the treatment of oral candidiasis, and the necessity of formulations with a “dryer” sensorial feeling and improved performances in providing higher bioavailability for the treatment of mammary and vaginal candidiasis.
Polymeric micelles with anti-virulence activity against Candida albicans in a single- and dual-species biofilm
Yassamin N. Albayaty, Nicky Thomas, Paulina D. Ramírez-García, Thomas P. Davis, John F. Quinn, Michael R. Whittaker & Clive A. Prestidge
doi : 10.1007/s13346-021-00943-4
Drug Delivery and Translational Research volume 11, pages1586–1597 (2021)
Infections caused by fungal biofilms with rapidly evolving resistance against the available antifungal agents are difficult to manage. These difficulties demand new strategies for effective eradication of biofilms from both biological and inert surfaces. In this study, polymeric micelles comprised of di-block polymer, poly-(ethylene glycol) methyl ether methacrylate and poly 2-(N,N-diethylamino) ethyl methacrylate polymer, P(PEGMA-b-DEAEMA), were observed to exhibit remarkable inhibitory effects on hyphal growth of Candida albicans (C. albicans) and C. tropicalis, thus preventing biofilm formation and removing existing biofilms. P(PEGMA-b-DEAEMA) micelles showed biofilm removal efficacy of?>?40% and a 1.4-log reduction in cell viability of C. albicans in its single-species biofilms. In addition, micelles alone promoted high removal percentage in a mixed biofilm of C. albicans and C. tropicalis (~?70%) and remarkably reduced cell viability of both strains. Co-delivery of fluconazole (Flu) and amphotericin B (AmB) with micelles showed synergistic effects on C. albicans biofilms (3-log reduction for AmB and 2.2-log reduction for Flu). Similar effects were noted on C. albicans planktonic cells when treated with the micellar system combined with AmB but not with Flu. Moreover, micelle-drug combinations showed an enhancement in the antibiofilm activity of Flu and AmB against dual-species biofilms. Furthermore, in vivo studies using Caenorhabditis elegans nematodes revealed no obvious toxicity of the micelles. Targeting morphologic transitions provides a new strategy for defeating fungal biofilms of polymorphic resistance strains and can be potentially used in counteracting Candida virulence.
Nano-fats for bugs: the benefits of lipid nanoparticles for antimicrobial therapy
Chelsea R. Thorn, Nicky Thomas, Ben J. Boyd & Clive A. Prestidge
doi : 10.1007/s13346-021-00921-w
Drug Delivery and Translational Research volume 11, pages1598–1624 (2021)
Bacterial infections are an imminent global healthcare threat evolving from rapidly advancing bacterial defence mechanisms that antibiotics fail to overcome. Antibiotics have been designed for systemic administration to target planktonic bacteria, leading to difficulties in reaching the site of localized bacterial infection and an inability to overcome the biological, chemical and physical barriers of bacteria, including biofilms, intracellular infections and antimicrobial resistance. The amphiphilic, biomimetic and antimicrobial properties of lipids provide a promising toolbox to innovate and advance antimicrobial therapies, overcoming the barriers presented by bacteria in order to directly and effectively treat recalcitrant infections. Nanoparticulate lipid-based drug delivery systems can enhance antibiotic permeation through the chemical and physical barriers of bacterial infections, as well as fuse with bacterial cell membranes, release antibiotics in response to bacteria and act synergistically with loaded antibiotics to enhance the total antimicrobial efficacy. This review explores the barriers presented by bacterial infections that pose bio-pharmaceutical challenges to antibiotics and how different structural and functional mechanisms of lipids can enhance antimicrobial therapies. Different nanoparticulate lipid-based systems are presented as valuable drug delivery systems to advance the efficacy of antibiotics, including liposomes, liquid crystalline nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers and lipid nanocarriers. In summary, liquid crystalline nanoparticles are emerging with the greatest potential for clinical applications and commercial success as an “all-rounder” advanced lipid-based antimicrobial therapy that overcomes the multiple biological, chemical and physical barriers of bacteria.
Inhaled antibodies: formulations require specific development to overcome instability due to nebulization
Alexie Mayor, Béatrice Thibert, Sylvain Huille, Renaud Respaud, Héloïse Audat & Nathalie Heuzé-Vourc’h
doi : 10.1007/s13346-021-00967-w
Drug Delivery and Translational Research volume 11, pages1625–1633 (2021)
Respiratory infections are life-threatening and therapeutic antibodies (Ab) have a tremendous opportunity to benefit to patients with pneumonia due to multidrug resistance bacteria or emergent virus, before a vaccine is manufactured. In respiratory infections, inhalation of anti-infectious Ab may be more relevant than intravenous (IV) injection-the standard route-to target the site of infection and improve Ab therapeutic index. One major challenge associated to Ab inhalation is to prevent protein instability during the aerosolization process. Ab drug development for IV injection aims to design a high-quality product, stable to different environment stress. In this study, we evaluated the suitability of Ab formulations developed for IV injection to be extended for inhalation delivery. We studied the aerosol characteristics and the aggregation profile of three Ab formulations developed for IV injection after nebulization, with two mesh nebulizers. Although the formulations for IV injection were compatible with mesh nebulization and deposition into the respiratory tract, the Ab were more unstable during nebulization than exposition to a vigorous shaking. Overall, our findings indicate that Ab formulations developed for IV delivery may not easily be repurposed for inhalation delivery and point to the requirement of a specific formulation development for inhaled Ab.
Nanoparticle-mediated pulmonary drug delivery: state of the art towards efficient treatment of recalcitrant respiratory tract bacterial infections
Zheng Huang, Sylvia Natalie K?odzi?ska, Feng Wan & Hanne Mørck Nielsen
doi : 10.1007/s13346-021-00954-1
Drug Delivery and Translational Research volume 11, pages1634–1654 (2021)
Recalcitrant respiratory tract infections caused by bacteria have emerged as one of the greatest health challenges worldwide. Aerosolized antimicrobial therapy is becoming increasingly attractive to combat such infections, as it allows targeted delivery of high drug concentrations to the infected organ while limiting systemic exposure. However, successful aerosolized antimicrobial therapy is still challenged by the diverse biological barriers in infected lungs. Nanoparticle-mediated pulmonary drug delivery is gaining increasing attention as a means to overcome the biological barriers and accomplish site-specific drug delivery by controlling release of the loaded drug(s) at the target site. With the aim to summarize emerging efforts in combating respiratory tract infections by using nanoparticle-mediated pulmonary delivery strategies, this review provides a brief introduction to the bacterial infection-related pulmonary diseases and the biological barriers for effective treatment of recalcitrant respiratory tract infections. This is followed by a summary of recent advances in design of inhalable nanoparticle-based drug delivery systems that overcome the biological barriers and increase drug bioavailability. Finally, challenges for the translation from exploratory laboratory research to clinical application are also discussed and potential solutions proposed.
Formulation and evaluation of transdermal nanogel for delivery of artemether
Petra O. Nnamani, Agatha A. Ugwu, Ogechukwu H. Nnadi, Franklin C. Kenechukwu, Kenneth C. Ofokansi, Anthony A. Attama & Claus-Michael Lehr
doi : 10.1007/s13346-021-00951-4
Drug Delivery and Translational Research volume 11, pages1655–1674 (2021)
Artemether (ART) is second to artesunate in being the most widely used derivatives of artemisinin in combination therapy of malaria. Nanostructured lipid carrier (NLC) formulations were prepared following our previous report using optimized ART concentration of 0.25 g dissolved in 5% w/v mixture of solid (Gelucire 43/01 and Phospholipon 85G) and liquid (Transcutol) lipids at 90 °C. An aqueous surfactant phase at 90 °C was added (dropwise) under magnetic stirring (1000 rpm) for 5 min. The pre-emulsion was speedily homogenized at 28,000 rpm for 15 min and further probe sonicated at 60% amplitude (15 min). Resultant sample was cooled at room temperature and frozen at ? 80 °C prior to lyophilization. The freeze-dried sample was used for solid-state characterization as well as in the formulation of transdermal nanogels using three polymers (Carbopol 971P, Poloxamer 407, and Prosopis africana peel powder) to embed the ART-NLC, using ethanol as a penetration enhancer. Transdermal ART-nanogels were characterized accordingly (physical examination, pH, drug content, rheology, spreadability, stability, particle size and morphology, skin irritation, in vitro and ex vivo skin permeation, and analysis of permeation data), P?<?0.05. Results indicated that ART nanogels showed good encapsulation, drug release, pH-dependent swelling, stability, and tolerability. Overall, ART nanogels prepared from Poloxamer 407 showed the most desirable drug permeation, pH, swellability, spreadability, viscosity, and transdermal antiplasmodial properties superior to PAPP-ANG?>?C971P-ANG. A two-patch/week concurrent application of the studied nanogels could offer 100% cure of malaria as a lower-dose (50 mg ART) patient-friendly regimen devoid of the drug’s many side effects.
Engineering biomaterials to prevent post-operative infection and fibrosis
Aditya Josyula, Kunal S. Parikh, Ian Pitha & Laura M. Ensign
doi : 10.1007/s13346-021-00955-0
Drug Delivery and Translational Research volume 11, pages1675–1688 (2021)
Implantable biomaterials are essential surgical devices, extending and improving the quality of life of millions of people globally. Advances in materials science, manufacturing, and in our understanding of the biological response to medical device implantation over several decades have resulted in improved safety and functionality of biomaterials. However, post-operative infection and immune responses remain significant challenges that interfere with biomaterial functionality and host healing processes. The objectives of this review is to provide an overview of the biology of post-operative infection and the physiological response to implanted biomaterials and to discuss emerging strategies utilizing local drug delivery and surface modification to improve the long-term safety and efficacy of biomaterials.
Carboxymethyl-?-glucan/chitosan nanoparticles: new thermostable and efficient carriers for antigen delivery
Ana Sara Cordeiro, Yagmur Farsakoglu, José Crecente-Campo, María de la Fuente, Santiago F. González & María José Alonso
doi : 10.1007/s13346-021-00968-9
Drug Delivery and Translational Research volume 11, pages1689–1702 (2021)
In the last few decades, nanotechnology has emerged as an important tool aimed at enhancing the immune response against modern antigens. Nanocarriers designed specifically for this purpose have been shown to provide protection, stability, and controlled release properties to proteins, peptides, and polynucleotide-based antigens. Polysaccharides are particularly interesting biomaterials for the construction of these nanocarriers given their wide distribution among pathogens, which facilitates their recognition by antigen-presenting cells (APCs). In this work, we focused on an immunostimulant beta-glucan derivative, carboxymethyl-?-glucan, to prepare a novel nanocarrier in combination with chitosan. The resulting carboxymethyl-?-glucan/chitosan nanoparticles exhibited adequate physicochemical properties and an important protein association efficiency, with ovalbumin as a model compound. Moreover, thermostability was achieved through the optimization of a lyophilized form of the antigen-loaded nanoparticles, which remained stable for up to 1 month at 40 ºC. Biodistribution studies in mice showed an efficient drainage of the nanoparticles to the nearest lymph node following subcutaneous injection, and a significant co-localization with dendritic cells. Additionally, subcutaneous immunization of mice with a single dose of the ovalbumin-loaded nanoparticles led to induced T cell proliferation and antibody responses, comparable to those achieved with alum-adsorbed ovalbumin. These results illustrate the potential of these novel nanocarriers in vaccination.
Current status and future of delivery systems for prevention and treatment of infections in the oral cavity
Sevda ?enel, Ayben I??lay Özdo?an & Gülçin Akca
doi : 10.1007/s13346-021-00961-2
Drug Delivery and Translational Research volume 11, pages1703–1734 (2021)
Oral health reflects the general health, and it is fundamental to well-being and quality of life. An infection in the oral cavity can be associated with serious complications in human health. Local therapy of these infections offers many advantages over systemic drug administration, targeting directly to the diseased area while minimizing systemic side effects. Specialized drug delivery systems into the oral cavity have to be designed in such a fashion that they resist to the aqueous environment that is constantly bathed in saliva and subject to mechanical forces. Additionally, a prolonged release of drug should also be provided, which would enhance the efficacy and also decrease the repeated dosing. This review is aimed to summarize the current most relevant findings related to local drug delivery of various drug groups for prevention and treatment of infections (viral, bacterial, fungal) and infection-related manifestations in the oral cavity. Current therapeutic challenges in regard to effective local drug delivery systems will be discussed, and the recent approaches to overcome these obstacles will be reviewed. Finally, future prospects will be overviewed to promote novel strategies that can be implemented in clinical management for prevention and treatment of oral infections.
Pharmaceutical design of a delivery system for the bacteriocin lacticin 3147
Aoibhín Ryan, Pratikkumar Patel, Paula M. O’Connor, R. Paul Ross, Colin Hill & Sarah P. Hudson
doi : 10.1007/s13346-021-00984-9
Drug Delivery and Translational Research volume 11, pages1735–1751 (2021)
Lacticin 3147 is a dual-acting two-peptide bacteriocin which is generally active against Gram-positive bacteria, including Listeria monocytogenes and antimicrobial-resistant bacteria such as Closteroides difficile in the colon. L. monocytogenes infections can cause life-long effects in the elderly and vulnerable and can cause severe complications in pregnant women. C. difficile causes one of the most common healthcare-associated infections and can be fatal in vulnerable groups such as the elderly. Although lacticin 3147 is degraded by intestinal proteases and has poor aqueous solubility, encapsulation of the bacteriocin could enable its use as an antimicrobial for treating these bacterial infections locally in the gastrointestinal tract. Lacticin 3147 displayed activity in aqueous solutions at a range of pH values and in gastric and intestinal fluids. Exposure to trypsin and ?-chymotrypsin resulted in complete inactivation, implying that lacticin 3147 should be protected from these enzymes to achieve successful local delivery to the gastrointestinal tract. The amount of lacticin 3147 dissolved, i.e. its solution concentration, in water or buffered solutions at pH 1.6 and 7.4 was low and varied with time but increased and was stabilized in gastrointestinal fluids by the phospholipid and bile salt components present. Thus, the feasibility of a solid lipid nanoparticle (SLN) delivery system for local administration of lacticin 3147 was investigated. Bacteriocin activity was observed after encapsulation and release from a lipid matrix. Moreover, activity was seen after exposure to degrading enzymes. Further optimization of SLN delivery systems could enable the successful pharmaceutical development of active lacticin 3147 as an alternative to traditional antibiotics.
Testing of aerosolized ciprofloxacin nanocarriers on cystic fibrosis airway cells infected with P. aeruginosa biofilms
Jenny Juntke, Xabier Murgia, Nazende Günday Türeli, Akif Emre Türeli, Chelsea R. Thorn, Marc Schneider, Nicole Schneider-Daum, Cristiane de Souza Carvalho-Wodarz & Claus-Michael Lehr
doi : 10.1007/s13346-021-01002-8
Drug Delivery and Translational Research volume 11, pages1752–1765 (2021)
The major pathogen found in the lungs of adult cystic fibrosis (CF) patients is Pseudomonas aeruginosa, which builds antibiotic-resistant biofilms. Pulmonary delivery of antibiotics by inhalation has already been proved advantageous in the clinic, but the development of novel anti-infective aerosol medicines is complex and could benefit from adequate in vitro test systems. This work describes the first in vitro model of human bronchial epithelial cells cultivated at the air–liquid interface (ALI) and infected with P. aeruginosa biofilm and its application to demonstrate the safety and efficacy of aerosolized anti-infective nanocarriers. Such a model may facilitate the translation of novel therapeutic modalities into the clinic, reducing animal experiments and the associated problems of species differences. A preformed biofilm of P. aeruginosa PAO1 was transferred to filter-grown monolayers of the human CF cell line (CFBE41o-) at ALI and additionally supplemented with human tracheobronchial mucus. This experimental protocol provides an appropriate time window to deposit aerosolized ciprofloxacin-loaded nanocarriers at the ALI. When applied 1 h post-infection, the nanocarriers eradicated all planktonic bacteria and reduced the biofilm fraction of the pathogen by log 6, while CFBE41o- viability and barrier properties were maintained. The here described complex in vitro model approach may open new avenues for preclinical safety and efficacy testing of aerosol medicines against P. aeruginosa lung infection.
Spray-dried lactose-leucine microparticles for pulmonary delivery of antimycobacterial nanopharmaceuticals
Durairaj Thiyagarajan, Benedikt Huck, Birgit Nothdurft, Marcus Koch, David Rudolph, Mark Rutschmann, Claus Feldmann, Constantin Hozsa, Marcus Furch, Karen F. W. Besecke, Robert K. Gieseler, Brigitta Loretz & Claus-Michael Lehr
doi : 10.1007/s13346-021-01011-7
Drug Delivery and Translational Research volume 11, pages1766–1778 (2021)
Pulmonary delivery of nanocarriers for novel antimycobacterial compounds is challenging because the aerodynamic properties of nanomaterials are sub-optimal for such purposes. Here, we report the development of dry powder formulations for nanocarriers containing benzothiazinone 043 (BTZ) or levofloxacin (LVX), respectively. The intricacy is to generate dry powder aerosols with adequate aerodynamic properties while maintaining both nanostructural integrity and compound activity until reaching the deeper lung compartments. Microparticles (MPs) were prepared using vibrating mesh spray drying with lactose and leucine as approved excipients for oral inhalation drug products. MP morphologies and sizes were measured using various biophysical techniques including determination of geometric and aerodynamic mean sizes, X-ray diffraction, and confocal and focused ion beam scanning electron microscopy. Differences in the nanocarriers’ characteristics influenced the MPs’ sizes and shapes, their aerodynamic properties, and, hence, also the fraction available for lung deposition. Spay-dried powders of a BTZ nanosuspension, BTZ-loaded silica nanoparticles (NPs), and LVX-loaded liposomes showed promising respirable fractions, in contrast to zirconyl hydrogen phosphate nanocontainers. While the colloidal stability of silica NPs was improved after spray drying, MPs encapsulating either BTZ nanosuspensions or LVX-loaded liposomes showed the highest respirable fractions and active pharmaceutical ingredient loads. Importantly, for the BTZ nanosuspension, biocompatibility and in vitro uptake by a macrophage model cell line were improved even further after spray drying.
