Advances in nanotechnology-based drug delivery in targeting PI3K signaling in respiratory diseases

NanomedicineVol. 16, No. 16 CommentaryOpen AccessAdvances in nanotechnology-based drug delivery targeting PI3K signaling respiratory diseasesYinghan Chan, Ronan MacLoughlin, Flavia C Zacconi, Murtaza M Tambuwala, Ritesh Pabari, Sachin Kumar Singh, Terezinha de Jesus Andreoli Pinto, Gaurav Gupta, Dinesh Chellappan & Kamal DuaYinghan Chan https://orcid.org/0000-0001-8405-8637School of Pharmacy, International Medical University (IMU), Bukit Jalil, 57000 Kuala Lumpur, MalaysiaSearch for more papers by this author, MacLoughlin https://orcid.org/0000-0002-3164-1607Aerogen, IDA Business Park, Dangan, Galway H91 HE94, IrelandSchool Pharmacy Biomolecular Sciences, Royal College Surgeons Ireland, Dublin D02 YN77, Pharmaceutical Trinity College, PN40, IrelandSearch Zacconi https://orcid.org/0000-0002-3676-0453Departamento Química Orgánica, Facultad y Farma-cia, Pontificia Universidad Católica deChile, Av Vicuña Mackenna 4860, Macul, Santiago 7820436, ChileSearch Tambuwala https://orcid.org/0000-0001-8499-9891School Ulster University, Coleraine, Londonderry, Northern UKSearch Pabari https://orcid.org/0000-0002-1386-5199School Singh https://orcid.org/0000-0003-3823-6572School Lovely Professional Jalandhar-Delhi GT Road, Phagwara, 144411, Punjab, IndiaSearch Pinto https://orcid.org/0000-0002-0238-8227Department Faculty São Paulo, Paulo 05508-000, BrazilSearch Gupta https://orcid.org/0000-0001-7941-0229School Suresh Gyan Vihar Jagatpura, Jaipur 302017, **Author correspondence: Tel.: +60 126361308; E-mail Address: [email protected]://orcid.org/0000-0001-5567-6663Department Life School Jalil author Dua *Author +6129 514 7387; [email protected]://orcid.org/0000-0002-7507-1159Discipline Graduate Health, Technology Sydney, NSW 2007, AustraliaPriority Research Centre Healthy Lungs, Hunter Institute (HMRI), Newcastle, New Lambton Heights, 2305, AustraliaSearch authorPublished Online:17 May 2021https://doi.org/10.2217/nnm-2021-0087AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: chronic diseasedrug deliverynanomaterialsphosphoinositide 3-kinaseInflammation is the natural defense mechanism within human body combat and eliminate hazardous stimuli, such as irritants, pathogens damaged cells. Although inflammation can be beneficial resolution injury, a concern, chronically inflamed tissues often amplify inflammatory response recruiting immune cells from bloodstream, leading excessive self-targeted aggressiveness that results disease. With respect system, airway hallmark various CRDs, including asthma, obstructive pulmonary disease (COPD), cystic fibrosis acute distress syndrome [1,2]. CRDs are among main contributors major public health burdens they account significant proportion global morbidity mortality, thereby warranting development new targeted therapeutic approaches tackle increasing impact brought these diseases. PI3Ks one families kinases play central role mediating cascades lead initiation maintenance responses. As aberrant result selective individual isoforms promising approach regulation responses [3]. Nanomaterials offer great prospects developed advanced versatile platforms treatment owing their unique physicochemical properties, at same time, have been shown improve pharmacokinetics existing therapeutics [4,5]. This commentary describes roles pathogenesis applications systems management CRDs.PI3Ks pathwaysPI3Ks intracellular proteins involved myriad cellular events widely considered potential targets The family divided into three subtypes depending on structure, namely classes I, II III. Class I further classified class IA which comprises PI3Kα, PI3Kβ PI3Kδ, well IB PI3Kγ isoform. While III currently not fully understood, many studies reported multiple steps cascades. Structurally, exist heterodimeric complexes where p110, catalytic subunit, associated with particular regulatory p85, p55, p50, p101, p84 [6,7]. Upon activation cell surface receptors insulin, growth factors G-protein-coupled (GPCRs), initiate pathways phosphorylating phosphoinositol lipids D-3 position inositol ring, then converts phosphatidylinositol-4,5-biphosphate (PI-4,5-P2) phosphatidylinositol-3,4,5-triphosphate (PI-3,4,5-P3) acts second messenger recruitment cytosolic possessing pleckstrin homology domains specific locations plasma membrane or endomembrane. Representative effectors include protein serine/threonine (protein kinase B/Akt), C, PDK1 MAPK. In summary, regarded hub signals first relayed prior specialization secondary [6–8].Significance CRDsAsthma an example CRD characterized hyper-responsiveness inflammation, increased expression cytokines, chemokines, adhesion molecules, enzymes. Typically, exposure allergens induces Th2 differentiation T leads release cytokines promote allergic inflammation. It has demonstrated activation, proliferation cells, PI3Kδ being predominant isoforms. engagement receptor antigens, will activated tyrosine cascades; recruited G via GPCRs chemokine [7,9]. also smooth muscles epithelial contraction accumulation contractile typically modulated Rho kinase. Further, secretion IL-6 regulated PI3K, cytokine remodeling asthma [9]. addition, promotes IL-17 NF-κB cascade, proven study Park et al., were attenuated suppression [10]. Increased eosinophils induction pro-inflammatory chemokines reactive oxygen species (ROS) another key feature whereby it found inhibition suppresses eosinophil chemotaxis. led reduced eosinophilia models allergen challenge. Studies revealed both responsible mast function cascade acting initial IgE, followed maximize degranulation [7,9,11]. crucial molecule almost all aspects pathogenesis, thus, may therapeutically advantageous prevent degranulation, inhibit suppress mucus hyperproduction, facilitate bronchodilation.A similar strategy employed manage other COPD. contrast COPD primarily involves Th1-induced neutrophils macrophages. established strongly induced correlated susceptibility lung infection. necessary migration infiltration monocytes lung. Moreover, ROS dependent biphasic manner [8,12]. Cystic mutation gene encoding transmembrane conductance regulator. fibrosis, lungs patients rapidly develop influx polymorphonuclear imbalance between anti- mediators. ability modulating mediators documented COPD, exploited alternative [8,13].Applications systemsDue involvement responses, explored design CRDs. PI3K-targeted compounds developed, some them face limitations poor bioavailability pharmacokinetic variability, incidences adverse reactions, ability.In recent years, using nanomaterials gained attention due sustained profile when compared unconjugated compounds. Nanotechnological advancements allowed functionalization site-selective ligands, toward isoform while enhancing uptake, bioavailability, biodistribution biocirculation time loaded possess intrinsic biological activities synergistic benefits along those Overall, utilization highly novel allows customization engineering nanovehicles tailored meet [5,14,15].There performed years evaluate feasibility managing A Oliveira al. formulated resveratrol (RSV)-loaded lipid-core nanocapsules (RSV-LNCs) composed biodegradable polymers efficacy attenuating injury. was RSV-LNCs remarkably improved preventing leucocytes tissue blockade PI3K/Akt pathway. Conversely, unloaded RSV ineffective production [16]. Similarly, Gholizadeh dactolisib, potent inhibitor polymeric nanoparticles evaluated anti-inflammatory potential. could effectively deliver dactolisib TNF-α suggesting [17]. Jang investigated effects silver Results indicated administration significantly expressions tissues, hyperproduction downregulation PI3K/HIF-1α/VEGF pathway [18]. On hand, Poerio liposomes phosphatidylinositol-5-phosphate (PI-5-P) limiting tissue-damaging infections [19]. PI-5-P bacterial phagocytosis showed downregulated IL-1β, TNF-α. reduced, phagosome acidification killing Taken together, findings suggest liposomal enable ameliorate Furthermore, Pooladanda engineered iRGD peptide-conjugated nimbolide (iRGD-NIMLip), phytomedicine, treating syndrome, shares clinical manifestations outbreak COVID-19 [20]. iRGD-NIMLip lipopolysaccharide-induced genes PI3K/Akt/mTOR Oxidative stress storm suppressed free nimbolide. Thus, system pathological consequences [20].ConclusionAlthough regulate processes against damage infections, dysregulated augmented self-perpetuating damage, resulting Advanced nano-based vectors approaches, advantages attributed characteristics conventional therapeutics. Additionally, modern nanotechnological allow structural systems, capability efficacies. Unfortunately, date, conducted area research remain relatively scarce. Hence, in-depth should elucidate exact mechanisms involved, future translation safe effective CRDs.Financial competing interests disclosureThe authors no relevant affiliations financial any organization entity interest conflict subject matter materials discussed manuscript. includes employment, consultancies, honoraria, stock ownership options, expert testimony, grants patents received pending, royalties.No writing assistance utilized manuscript.Open accessThis work licensed under Attribution 4.0 License. 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