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3DNA holds promise as a carrier for drugs that can be intercalated into its core or linked to surface arms. Coupling 3DNA to an antibody targeting intercellular adhesion molecule 1 (ICAM-1) results in high lung-specific biodistributions in vivo. While the role of individual parameters on ICAM-1 targeting has been studied for other nanocarriers, it has never been examined for 3DNA or in a manner capable of revealing the hierarchic interplay among said parameters. In this study, we used 2-layer vs. 4-layer anti-ICAM 3DNA and radiotracing to examine biodistribution in mice. We found that, below saturating conditions and within the ranges tested, the density of targeting antibodies on 3DNA is the most relevant parameter driving lung targeting over liver clearance, compared to the number of antibodies per carrier, total antibody dose, 3DNA dose, 3DNA size, or the administered concentration, which influenced the dose in organs but not the lung specific-over-liver clearance ratio. Data predicts that lung-specific delivery of intercalating (core loaded) drugs can be tuned using this biodistribution pattern, while that of arm-linked (surface loaded) drugs requires a careful parametric balance because increasing anti-ICAM density reduces the number of 3DNA arms available for drug loading.

Background Like most protein macromolecular drugs, the half-life of rhIFNɑ-2b is short, with a low drug utilization rate, and the preparation and release conditions significantly affect its stability. Methods A nanoporous ion-responsive targeted drug delivery system (PIRTDDS) was designed to improve drug availability of rhIFNα-2b and target it to the lung passively with sustained release. Chitosan rhIFNα-2b carboxymethyl nanoporous microspheres (CS-rhIFNα-2b-CCPM) were prepared by the column method. Here, an electrostatic self-assembly technique was undertaken to improve and sustain rhIFNα-2b release rate. Results The size distribution of the microspheres was 5~15 μm, and the microspheres contained nanopores 300~400 nm in diameter. The in vitro release results showed that rhIFNα-2b and CCPM were mainly bound by ionic bonds. After self-assembling, the release mechanism was transformed into being membrane diffusion. The accumulative release amount for 24 hrs was 83.89%. Results from circular dichrogram and SDS-PAGE electrophoresis showed that there was no significant change in the secondary structure and purity of rhIFNα-2b. Results from inhibition rate experiments for A549 cell proliferation showed that the antitumor activity of CS-rhIFNα-2b-CCPM for 24 hrs retained 91.98% of the stock solution, which proved that the drug-loaded nanoporous microspheres maintained good drug activity. In vivo pharmacokinetic experimental results showed that the drugs in CS-rhIFNα-2b-CCPM can still be detected in vivo after 24 hrs, equivalent to the stock solution at 6 hrs, which indicated that CS-rhIFNα-2b-CCPM had a certain sustained-release effect in vivo. The results of in vivo tissue distribution showed that CS-rhIFNα-2b-CCPM was mainly concentrated in the lungs of mice (1.85 times the stock solution). The pharmacodynamics results showed that CS-rhIFNα-2b-CCPM had an obvious antitumor effect, and the tumor inhibition efficiency was 29.2%. Conclusion The results suggested a novel sustained-release formulation with higher drug availability and better lung targeting from CS-rhIFNα-2b-CCPM compared to the reference (the stock solution of rhIFNα-2b), and, thus, should be further studied.

Adeno-associated virus (AAV)-mediated gene delivery holds great promise for gene therapy. However, the non-invasive delivery of AAV for lung tissues has not been adequately established. Here, we revealed that the intratracheal administration of an appropriate amount of AAV2/8 predominantly targets lung tissue. AAV-mediated gene delivery that we used in this study induced the expression of the desired protein in lung parenchymal cells, including alveolar type II cells. We harnessed the technique to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-susceptible mice. Three kinds of immune function-relevant gene knockout (KO) mice were transduced with AAV encoding human angiotensin-converting enzyme 2 (hACE2) and then injected with SARS-CoV-2. Among these mice, type I interferon receptor (IFNAR) KO mice showed increased viral titer in the lungs compared to that in the other KO mice. Moreover, nucleocapsid protein of SARS-CoV-2 and multiple lesions in the trachea and lung were observed in AAV-hACE2-transduced, SARS-CoV-2-infected IFNAR KO mice, indicating the involvement of type I interferon signaling in the protection of SARS-CoV-2. In this study, we demonstrate the ease and rapidness of the intratracheal administration of AAV for targeting lung tissue in mice, and this can be used to study diverse pulmonary diseases., Graphical abstract, We found that non-invasive intratracheal administration of AAV2/8 targets pulmonary parenchymal cells, including AT2 cells. We used this system for the delivery of hACE2 to the lungs of various immune function-relevant gene KO mice and identified type I interferon signaling to create a protective effect against SARS-CoV-2 pathogenesis.

In this review, the potential future role of microRNA-based therapies and their specific application in lung diseases is reported with special attention to pulmonary hypertension. Current limitations of these therapies will be pointed out in order to address the challenges that they need to face to reach clinical applications. In this context, the encapsulation of microRNA-based therapies in nanovectors has shown improvements as compared to chemically modified microRNAs toward enhanced stability, efficacy, reduced side effects, and local administration. All these concepts will contextualize in this review the recent achievements and expectations reported for the treatment of pulmonary hypertension.

Acute respiratory distress syndrome (ARDS), a catastrophic illness of multifactorial etiology, involves a rapid upsurge in inflammatory cytokines that leads to hypoxemic respiratory failure. Dexamethasone, a synthetic corticosteroid, mitigates the glucocorticoid-receptor-mediated inflammation and accelerates tissue homeostasis towards disease resolution. To minimize non-target organ side effects arising from frequent and chronic use of dexamethasone, we designed biodegradable, lung-targeted microspheres with sustained release profiles. Dexamethasone-loaded lipopolymeric microspheres of PLGA (Poly Lactic-co-Glycolic Acid) and DPPC (Dipalmitoylphosphatidylcholine) stabilized with vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate) were prepared by a single emulsion technique that had a mean diameter of 8.83 ± 0.32 μm and were spherical in shape as revealed from electron microscopy imaging. Pharmacokinetic and biodistribution patterns studied in the lungs, liver, and spleen of Wistar rats showed high selectivity and targeting efficiency for the lung tissue (re 13.98). As a proof-of-concept, in vivo efficacy of the microspheres was tested in the lipopolysaccharide-induced ARDS model in rats. Inflammation markers such as IL-1β, IL-6, and TNF-α, quantified in the bronchoalveolar lavage fluid indicated major improvement in rats treated with dexamethasone microspheres by intravenous route. Additionally, the microspheres substantially inhibited the protein infiltration, neutrophil accumulation and lipid peroxidation in the lungs of ARDS bearing rats, suggesting a reduction in oxidative stress. Histopathology showed decreased damage to the pulmonary tissue upon treatment with the dexamethasone-loaded microspheres. The multipronged formulation technology approach can thus serve as a potential treatment modality for reducing lung inflammation in ARDS. An improved therapeutic profile would help to reduce the dose, dosing frequency and, eventually, the toxicity.

Ion‐pairing a lifesaving drug such as theophylline with a targeting moiety could have a significant impact on medical emergencies such as status asthmaticus or COVID‐19 induced pneumomediastinum. However, to achieve rapid drug targeting in vivo the ion‐pair must be protected against breakdown before the entry into the target tissue. This study aims to investigate if inserting theophylline, when ion‐paired to the polyamine transporter substrate spermine, into a cyclodextrin (CD), to form a triplex, could direct the bronchodilator to the lungs selectively after intravenous administration. NMR demonstrates that upon the formation of the triplex spermine protruded from the CD cavity and this results in energy‐dependent uptake in A549 cells (1.8‐fold enhancement), which persists for more than 20 min. In vivo, the triplex produces a 2.4‐fold and 2.2‐fold increase in theophylline in the lungs 20 min after injection in rats and mice, respectively (p, This article demonstrates that ion‐pairing theophylline, a drug used in medical emergencies such as status asthmaticus or COVID‐19 induced pneumomediastinum, with a polyamine, can direct delivery to the lung. Such an approach is effective when the ion‐pair is stabilized as a triplex with cyclodextrin, which increases the in vivo ion‐pair life‐time to facilitate active accumulation in the lung.

A simple and sensitive LC-UV method to investigate the pharmacokinetics and biodistribution pattern of baicalin in rabbits was established and validated. Baicalin and the internal standard, rutin, were extracted from biosamples using acetonitrile as protein precipitation after pretreated with ammonium acetate buffer (pH 3.5; 1 M) to obtain a pure chromatographic peak and high extraction recovery. Chromatographic separation was achieved on a reverse-phase C18 column with a gradient elution at flow rate of 1.0 mL/min. UV absorption was set at 278 nm. Chromatographic response was linear over the ranges of 0.05–10.00 μg/mL in plasma and 0.05–300.00 μg/g in tissues with the limits of quantification of 50.0 ng/mL in plasma and tissues, and the limit of detection of baicalin in bio-samples of 15 ng/mL. The RSD of intra-and inter-day for the biosamples were from 4.19% to 10.84% and from 4.37% to 10.93%, respectively. The accuracy of plasma and tissue samples ranged from 81.6% to 95.2% and 80.8% to 98.4%, respectively. The extraction recoveries ranged from 81.5% to 88.3% for plasma, from 73.1% to 93.2% for tissues, respectively. Baicalin was stable in rabbit biosamples. The validated method was successfully applied to the study of the pharmacokinetics and tissue distribution of baicalin after intravenous administration of liposomal and injectable formulations to rabbits. Compared to baicalin injection, the pharmacokinetics and biodistribution behavior of baicalin was altered significantly in rabbits treated with its liposomes and drug concentration in the lungs was greatly increased.

Hui Meng, Yong XuDepartment of Pharmaceuticals, 85th People’s Liberation Army Hospital, Shanghai, People’s Republic of China Background: The purpose of this study was to develop novel pirfenidone (PFD)-loaded liposomes for targeting to the lung.Methods: The liposomes were prepared by the film hydration method, and their in vitro/vivo characteristics were evaluated.Results: The PFD liposomes appeared visually as green to yellowish suspensions and were spherical in shape. The particle size was 582.3±21.6 nm and the entrapment efficiency was relatively high (87.2%±5.7%). The liposomes showed typical sustained and prolonged drug-release behavior in vitro and fitted well with the Weibull distribution equation. The relatively slower time taken to reach a minimal plasma PFD concentration in vivo suggests that PFD liposomes have a sustained-release profile, which is consistent with the results of the in vitro release study. The PFD liposomes showed the largest area under the curve for the lung. The high distribution of PFD achieved in the lungs using this liposomal formulation may be explained by physical entrapment of the liposomes in the vascular network of the lung. Histopathological results indicated that liposomal PFD could alleviate pathological injury in lung tissue.Conclusion: This liposomal formulation can enable sustained release of PFD and increase targeting to the lung. Keywords: pirfenidone, liposomes, lung targeting, in vivo, histopathological&nbsp

A previous study has shown that lipophilic prodrugs can be delivered efficiently to normal lung endothelium by incorporation into liposomes covalently conjugated to monoclonal antibody (mAb) 34A against the lung endothelial anticoagulant protein thrombomodulin. In the present study, the potential use of these lung-targeted immunoliposomes (34A-liposomes) for delivery of a lipophilic prodrug, 3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine (dpFUdR), to the tumor-bearing lung was examined using BALB/c mice bearing experimental lung metastasis induced by i.v. injection of EMT-6 mouse mammary tumor cells. Immunohistochemical examination of the tumor-bearing lung showed specificity of mAb 34A to lung endothelium. Tumor cells appeared to localize just outside of the normal blood vessels and were within a small diffusion distance from the mAb 34A-binding sites. In-111-labeled 34A-liposomes containing monosialoganglioside (G(M1)) were prepared that included [H-3]-dpFUdR at 3.0 mol% in the lipid mixture. In vitro cell binding studies further demonstrated that 34A-liposomes bound specifically to normal mouse lung cells that expressed thrombomodulin but not to EMT-6 cells. Biodistribution study showed efficient and immunospecific accumulation of [H-3]-dpFUdR incorporated into 34A-liposomes in the lung at a level parallel with that of In-111-labeled 34A-liposomes, indicating that the drug is delivered to the target organ in intact liposomes. Liposomal dpFUdR appeared to be metabolized in the lung to the parent drug FUdR at a rate slower than in the liver and spleen, Furthermore, treatment of lung-metastasis-bearing mice with dpFUdR incorporated into 34A-liposomes on days 1 and 3 after tumor cell injection resulted in a significant increase in the median survival time of treated mice as compared with control mice (%T/C value, 165%). dpFUdR either dispersed in emulsion or incorporated into antibody-free liposomes was ineffective in prolonging the survival of mice. These results indicate the potential effectiveness of organ-specific immunoliposomes containing a lipophilic prodrug for the targeted therapy of metastatic tumors.

Pulmonary delivery of locally-acting drugs encapsulated in nanocarriers provides several advantages for the treatment of respiratory diseases such as asthma, chronic obstructive pulmonary diseases, cystic fibrosis, tuberculosis and lung cancer. These advantages include, among others, sustained drug delivery to the lungs, reduced therapeutic dose and improved patient compliance. The aim of this review is to give an updated overview on recent advances recorded in the last few years in this field as well as on the major challenges still existing and that remain to be overcome before any clinical application. After an outline on the cellular and extracellular barriers affecting drug delivery to the airways both in physiological and pathological conditions, the significant developments recorded using inhaled polymeric- and lipid-based nanocarriers for drug and gene delivery to the lung are presented. In this discussion, the major challenges existing in the field are evidenced including the understanding of the factors governing the mucus penetration capability of these nanocarriers and the identification of new technologies for delivering drugs to specific regions or cell types of the lungs. In this regard, the recognition of receptor expressed only at lung level may facilitate drug targeting to this organ and it should improve the therapeutic efficacy of nanocarrier-based treatments for respiratory diseases.