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Recent Advances in Oral Nano-Antibiotics for Bacterial Infection Therapy

Abstract Bacterial infections are the main infectious diseases and cause of death worldwide. Antibiotics are used to treat various infections ranging from minor to life-threatening ones. The dominant route to administer antibiotics is through oral delivery and subsequent gastrointestinal tract (GIT) absorption. However, the delivery efficiency is limited by many factors such as low drug solubility and/or permeability, gastrointestinal instability, and low antibacterial activity. Nanotechnology has emerged as a novel and efficient tool for targeting drug delivery, and a number of promising nanotherapeutic strategies have been widely explored to overcome these obstacles. In this review, we explore published studies to provide a comprehensive understanding of the recent progress in the area of orally deliverable nano-antibiotic formulations. The first part of this article discusses the functions and underlying mechanisms by which nanomedicines increase the oral absorption of antibiotics. The second part focuses on the classification of oral nano-antibiotics and summarizes the advantages, disadvantages and applications of nanoformulations including lipid, polymer, nanosuspension, carbon nanotubes and mesoporous silica nanoparticles in oral delivery of antibiotics. Lastly, the challenges and future perspective of oral nano-antibiotics for infection disease therapy are discussed. Overall, nanomedicines designed for oral drug delivery system have demonstrated the potential for the improvement and optimization of currently available antibiotic therapies.


Introduction
Infectious diseases refer to the illnesses that are caused by organisms such as bacteria, fungi, viruses, and parasites. 1 With the resurgence of known ones and the emergence of new ones, infectious diseases continue to cause high morbidity and mortality in recent years all over the world, especially in developing countries. 2 The overall morbidity of 39 notable infectious diseases in China increased from 3,906,566 cases (7248 deaths) in 2004 to 6,944,240 cases (18,237 deaths) in 2016. 3 The global burden of disease study (GBD) 2017 report showed that four infectious diseases were listed in the top 10 causes of death globally, including lower respiratory infections (ranked fourth), diarrheal diseases (5th), AIDS (8th) and malaria (10th). 4 Bacteria are the most common pathogenic organisms that can invade organs such as facial features, respiratory tract, gastrointestinal tract (GIT), and genitourinary system, whereas the symptoms range from minor illnesses such as strep throat or ear infections to life-threatening conditions. [5][6][7][8][9] Statistics shows that the annual death toll caused by bacterial infections could reach 14 million, 10 most of which are caused by Staphylococcus aureus, Pseudomonas aeruginosa, Clostridium labile and some drug-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA), third-generation cephalosporin-resistant Escherichia coli and vancomycin-resistant Enterococci (VRE). 11 Furthermore, bacterial infections pose significant economic burden on the healthcare system. In the United States, the medical costs and labor losses caused by antibiotic resistance alone amount to U$55 billion per year, while the cost for non-resistant bacteria further adds up to this stunning number. 12 Most bacterial infections require treatment with antibiotics although some of them may resolve by themselves. Since the discovery of penicillin by Alexander Fleming in 1928, 13 numerous antibiotic drugs have been isolated and identified that can kill bacteria (bactericidal) or prevent their reproduction or proliferation (bacteriostatic) through different mechanisms (Table 1). 14 As a result, infections that are previously severe or fatal can now be managed effectively. However, the worldwide overuse and misuse of antibiotics led to the rapid emergence of drug-resistant bacteria, which are now reversing the therapeutic miracles and threatening the effective prevention and treatment of infectious diseases. 15,16 Furthermore, the development of novel antibiotics has dropped by 30% over the last 30 years due to weakened economic incentives and more stringent regulations. Only six antibiotics were approved by the Food and Drug Administration of the United States between 2015 and 2018, and most of them only target Gram-positive bacteria and cause antimicrobial resistance (AMR) nonetheless. [17][18][19] On the other hand, novel treatments including monoclonal antibodies, bacteriophages, stem cells, etc. have so far been unsuccessful in clinical trials or bedside applications due to various reasons. 11 In summary, the aforementioned challenges in the treatment of bacterial infections still warrant further development of antibiotic formulations.
Antibiotics can be administered via oral, intravenous, transpulmonary, and transdermal routes. [20][21][22] Oral administration is the most popular route due to its safety, convenience, and excellent patient compliance, especially for longterm medications. 23 However, its efficiency is complexed by many physical and chemical barriers in GIT including mucus layer, epithelial tight junction, drug metabolic enzymes, P-glycoprotein, etc. [24][25][26] On the other hand, according to the biopharmaceutical classification system (BCS), many highly effective antibiotics, eg ciprofloxacin, vancomycin, cefpodoxime, rifampicin, and clarithromycin belong to BCS class II (low solubility) or IV (low solubility and low permeability) drugs. The poor solubility of most antibiotics also hinders their absorption through GIT and therefore significantly restricted their bioavailability. [27][28][29][30] Although a variety of formulation strategies including micronization, salt formation, solid dispersion, and emulsion have been explored to improve the bioavailability of insoluble antibiotics, only limited success has been achieved due to difficulties in production, batch-to-batch consistency, and quality control. 18 Nanotechnology offers new opportunities for drug dosing and delivery. 31 With unique structural, chemical, mechanical, magnetic, electrical, and biological properties, 32 nanomedicine demonstrates numerous advantages over 'free' therapeutic molecules. For example, the large specific surface area of nanomedicine increases drug solubility and gastrointestinal contact area. 31,33 The encapsulated drug payloads are also protected from degradation in GIT by the nanoscale carrier. The nanocarriers can be further modified to improve the profiles of delivery, penetration, and controlled release of encapsulated drugs, and thereby achieve desirable characteristics including higher antibiotic uptake, 34,35 less adverse reactions, alleviated drug resistance, shorter treatment duration, lower dose, and lower cost, especially for patients with severe infections. 36,37 The palatability of antibiotics can be improved as well. 38 Despite the great promise brought by orally deliverable nano-antibiotic formulations, the understanding of these formulations is still lacking compared to those of antineoplastic and biomolecules. In this review, we will discuss the present state-of-art and future prospects of the nanotechnology-based approaches to orally deliverable antibiotics.

Improved Oral Absorption of Poorly Soluble Antibiotics by Nano-Drug Delivery System
The orally administered antibiotics face a number of challenges before they can function properly. First, the absorption of antibiotics is physically barricaded by the tight connection of mucus layer lining the GIT. Drug capture by the mucus layer along with the fast turn-over of mucus layer cells also limits the efficiency of drug absorption. 39 Some antibiotics are substrates of P-glycoprotein (P-gp) and therefore can be re-shuttled back into the GIT. In addition, pH values in the GIT, gastrointestinal motility, and intestinal contents also affect drug absorption. 40 Second, the antibiotics need to retain their structural integrity before being absorbed. Some glycopeptide and lipopeptide antibiotics are especially vulnerable to the endo-or exo-peptidase secreted in the GIT. 41 The extensive metabolism by cytochrome P450 enzymes expressed in small intestine or liver may also lead to premature destruction of the antibiotics. 42 Researchers have designed different nano-drug delivery systems in order to overcome these challenges ( Figure 1).

Increase the Stability and Solubility in the GIT
Peptide-based antibiotics can be degraded by various enzymes in GIT, while acid-or base-labile antibiotics are prone to the gastrointestinal pH variations. Encapsulation of antibiotics in nanocarriers forms a protective shell for the active ingredient. For example, liposomes composed of bile salt-loaded cefotaxime effectively prevented the damage from bile acids toward the payload, and subsequently improved the drug stability. 43 The large surface area of nanoformulations also improves drug solubility.

Promote the Mucus Adhesion
Positively charged polymers like chitosan-coated clarithromycin can interact with the negatively charged mucus layer to promote the adhesion and subsequent absorption of the polymer. 44 Carriers containing thiol functionality can form disulfide bonds with the mucosa, 45 which prolongs the exposure time of antibiotic payload in the small intestine, and thereby increase the probability of mucosa penetration.

Facilitate Translocation Across the Mucus Layers
In general, the rapid secretion and shedding of mucus cover the epithelium surface with a tenacious layer of viscoelastic hydrogel that lubricates and protects the exposed epithelium from external threats and enzymatic degradation. The mucus is composed of mucin glycoproteins with negatively charged sialic residues. The mucin monomers can also be crosslinked into a multimer network with hydrophobic pockets via disulfide bonds between the cysteine-rich domains of different monomers. This tenacious, negatively charged, hydrophobic viscoelastic hydrogel can quickly capture foreign substances via physical, electrostatic, or hydrophobic interactions, and subsequently remove them when the mucus layer is shed off. 39 Polyethylene glycol (PEG) coating, on the other hand, imbues the nanoparticles with an electrically neutral and hydrophilic surface, and therefore can prevent the hydrophobic and electrostatic interactions between the nanoparticles and the mucus layer. 46,47 Enhance Permeation Across the Enteric Epithelia The permeation across the enteric epithelia can be increased by using absorption enhancer, eg chitosan and its derivatives. 48 On the other hand, some natural and synthetic excipients, such as Cremophor EL, Tween-80, Tween-20, D-α-tocopherol polyethylene glycol 2000 succinate (TPGS), and cetyltrimethylammonium bromide (CTAB) can inhibit the P-gp efflux pumps, and therefore promote drug infiltration through the intestinal epithelia. [49][50][51][52] Enhance Ligand-Mediated Endocytosis and Uptake by Microfold Cells (M Cells) Nanocarriers can target specific receptors on the enteric epithelia through receptor-specific ligands, thereby enhancing the cellular uptake and transepithelial transport of payloads. The receptor-mediated endocytosis is generally mediated by reticulin and caveolin. 53 For instance, folateconjugated liposomes facilitate the endocytic delivery of vancomycin via the folate receptors that are ubiquitously expressed on intestinal epithelial cells. 54 Microfold cells (M cells) presented in Peyer's patches are epithelial cells with specialized antigen-sampling ability. With high endocytic rate and low degradation ability, M cell can take up foreign substances, and move them to the intraepithelial pocket beneath the M-cell basolateral membrane to be processed in the lymphoid tissues. Although fewer than enterocytes, the high transcytosis ability of M cells makes them an excellent target for antibiotic delivery, including the delivery of dapsone-loaded solid lipid nanoparticles. [55][56][57] Classification of Oral Nano-Antibiotics Lipid-Based Nano-Antibiotics Lipid-based nanoparticles in antibiotic delivery can be categorized into self-nanoemulsifying drug delivery system (SNEDDS), liposomes, niosomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) (Figure 1).
Lipids are biocompatible and biodegradable. In addition to protecting drugs from gastrointestinal damage and controlling drug release, lipids also promote drug absorption through transcellular, paracellular and lymphatic transport, and eventually increase the bioavailability. [58][59][60][61] The properties of lipidbased nano-antibiotics are summarized in Table 2.

SNEDDS
Developed on the concept of nanoemulsion, SNEDDS is a stable complex composed of oil, water, surfactants, cosurfactants and fat-soluble drugs. While the nanoemulsions are sensitive and metastable, SNEDDS spontaneously form oilin-water nanoemulsions after oral administration under the mechanical force in the GIT with a particle size between 20 and 200 nm. 62,63 SNEDDS promotes drug transportation through the intestinal lymphatic system and prevent their degradation in the digestive tract. 64 In SNEDDS, mediumor long-chain triglycerides with different degrees of saturation constitute the oil phase, while Tween-80 or Span-20 function as surfactants to reduce the surface tension and increase the degree of dispersion. Medium chain alcohols (C3-C8), including propylene glycol and 1, 2-octanediol, are used as cosurfactants. 65 Appropriate choice of excipients and their ratios are critical to optimize particle size, drug-loading efficiency, encapsulation efficiency, and profile of drug release. 66 The advantages of using SNEDDS for antibiotic delivery include solubilization of insoluble drugs, reduction of P-gp-mediated active efflux and first-pass metabolism, promotion of drug transcellular, paracellular or intestinal lymphatic transport, and reduction of drug resistance. [67][68][69] To further improve the storage stability, solid self-nanoemulsifying drug delivery system (SSNEDDS) can be prepared by adding re-dispersants to the liquid preparations, and then curing the mixture by solid carrier adsorption, spray drying, etc. 70 Cefpodoxime proxetil (CP) is a prodrug of cefpodoxime, a BCS IV class β-lactam antibiotic with low oral bioavailability. Bajaj et al 52 encapsulated CP with different SNEDDS formulations using Tween-80, propylene glycol and tocopherol polyethylene glycol succinate (TPGS) as the surfactants/co-surfactants, and Capmul MCM as the oil compared with conventional formulations, CP-SNEDDS had significantly faster dissolution and higher permeability in vitro. The minimum inhibitory concentration (MIC) of CP-SNEDDS against Escherichia coli, Staphylococcus aureus and Bacillus subtilis were 1500 ng/mL, 100 ng/mL and 750 ng/mL, respectively; while the MIC of the conventional preparation were 2250 ng/mL, 250 ng/mL and 1000    International Journal of Nanomedicine 2020:15 submit your manuscript | www.dovepress.com DovePress ng/mL, respectively. The AUC 0-∞ value of CP-SNEDDS was 5.36-fold higher than that of commercial CP (75.55 ± 2.8 µg·h/mL vs 14.07 ± 2.4 µg·h/mL), whereas its oral bioavailability was 4 times higher. The liquid CP-SNEDDS was further spray-dried to form solid CP-SSNEDDS to improve storage stability. The improved bioavailability of CP-SNEDDS can be attributed to the Tween 80 and TPSG that increased membrane permeability, as well as the SNEDDS formulation that minimized P-gp efflux and cytochrome enzyme pre-absorption metabolism, promoted lymphatic transport, and increased gastrointestinal membrane permeability. Rifampicin (RIF) is a first-line anti-Mycobacterium tuberculosis drug. Liquid RIF-SNEDDS was prepared by preconcentration method using Labrasol as the surfactant, Cremophor-EL as the cosurfactant and Capmul MCM C8 as the oil phase. RIF-SSNEDDS was obtained via adsorption technology where RIF-SNEDDS was adsorbed to the adsorbent Aerosil 200. These preparations dramatically promoted osmosis in vitro. Their relative bioavailability was significantly improved compared with RIF suspension, and the oral bioavailability of RIF-SSNEDDS reached as high as 96.83%. 71,72 Liposome and Niosome Liposomes have been explored for oral delivery antibiotics for more than 40 years. 73 Conventional liposomes are composed of phospholipids and cholesterol, and exhibit a bilayer vesicle structure from 25 to 1000 nm in size. Drugs are distributed in the hydrophilic or hydrophobic compartments of liposomes according to their lipophilicity. 74,75 The resemblance to cell membrane imbues liposomes with excellent biocompatibility. Liposomes have shown promising properties for drug delivery, such as high entrapment efficiency, controlled drug release, satisfactory safety profile, convenient drug loading and surface modification, and protection of drug payloads. [76][77][78] On the other hand, they are also facing several challenges for antibiotic delivery. For example, gastric acid, bile salts, and digestive enzymes in GIT may compromise the liposome structure and cause premature drug release. 79 The large size of liposomes may hinder their penetration through the gastrointestinal barriers. 80 The industrial large-scale production of liposomal drug formulation may also present a technical difficulty. 81 These challenges can be overcome by surface modification and composition adjustment.
Surface modification is an important method to overcome the drug destruction in the gastrointestinal tract. Anderson et al 54 prepared a liposome formulation of vancomycin and conjugated folic acid as well as poly (ethylene glycol) (PEG) onto the liposome surface. The GIT specific and pH-dependent absorption of folic acid through receptor-mediated endocytosis increased drug bioavailability by 12.5-fold. As a type of surfactant secreted by hepatocytes, bile salts have been considered to be the main factor for the disruption of liposomes in GIT and lead to reduced concentrations of intact liposomes and release incorporated drugs. Paradoxically, studies also revealed that prior incorporation of bile salts into liposomal bilayers during liposome preparation stabilized the membrane to resist the destructive effects of physiological bile salts. 79,82 Daniela et al modified Tween 80, linolenic acid, and dioleoylphosphatidylethanolamine (DOPE) to synthesize liposomes encapsulating amoxicillin for the treatment of Helicobacter pylori infection. Tween 80 can separate the outer membrane of Helicobacter pylori. As an unsaturated fatty acid, linolenic acid can play an anti-Helicobacter pylori effect by disrupting the integrity of the bacterial membrane. In addition, because of the presence of phosphatidylethanolamine receptors in these bacteria, DOPE was added as a targeting agent for Helicobacter pylori. The results showed that the nanoparticles (F4) modified by Tween 80, linolenic acid and DOPE are stable for at least 6 months at 4°C. At the same time, the nanoparticles have high tolerance to harsh conditions including acidic pH and physiological temperature. Nanoparticles have low cytotoxicity in fibroblasts and gastric cell lines, and increase the residence time of the infection site (gastric mucosa). Figure 2 shows the overall design of this liposome. Four formulations of LNPs have been studied and characterized, which are distinguished by the presence or absence of linolenic acid and DOPE. 83 Arafat et al 43 prepared sodium deoxycholate-containing liposomes to encapsulate cefotaxime, a BCS III drug. The resultant formulation maintained good stability in gastric juice or even more destructive intestinal fluid. In vivo pharmacokinetics experiments showed that, compared with free cefotaxime, the sodium deoxycholate-containing liposomal drug increased the maximum concentration (C max ) by 3.39-fold (1.71 ± 0.3 vs 0.51 ± 0.2 µg/mL), and the area-under-the plasma concentration-time curve from 0 to infinity (AUC 0-∞ ) by 5.12-fold (5.73 ± 0.7 vs 1.12 ± 0.5 µg·h/mL). Notably, the oral bioavailability of the sodium deoxycholate-modified submit your manuscript | www.dovepress.com

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International Journal of Nanomedicine 2020:15 liposomes was five fold and two fold higher than that of free drug and unmodified liposome, respectively.
Solid proliposome is another tool to improve the stability of oral formulation. Daptomycin is a semisynthetic cyclic lipopeptide antibiotic with broad-spectrum activity against a variety of Gram-positive bacteria. It was incorporated into the proliposomes by hydrating a film of daptomycin, soybean phosphatidylcholine (SPC) and cholesterol. Stearylamine (SA) was also added provide a positive surface charge, which significantly increased the entrapment efficiency to 92% through interaction with daptomycin. Compared with daptomycin solution, the C max and AUC 0-∞ of solid proliposomes were 8.35 ± 0.64 µg/mL and 46.39 ± 5.69 µg·h/mL, respectively, while DPT solution below lower limit of quantification (LLOQ), representing a significantly higher oral bioavailability. 81

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Phospholipids are prone to oxidative degradation in GIT in addition to its high cost of manufacture. As a result, efforts have been attempted to replace phospholipids with various nonionic surfactants, such as creatinine, creatinine derivatives, bergenin (3,4,8,10-tetrahydroxy-2-hydroxymethyl-9-meth-oxy-2,3,4,4a-tetrahydropyrano[3,2-c] isochromen-6-one), a-tocopherol, and other renewable resources. These novel formulations are collectively known as niosomes, 84 and have shown promising properties including low toxicity, low cost, good biocompatibility and biodegradability, and stable physical/chemical properties. [85][86][87][88] Cefixime is the third-generation cephalosporin against a variety of Gram-negative and Gram-positive bacteria, but its acidity results in poor solubility and low oral bioavailability. Imran et al 87,89 synthesized two glycosidebased niosomal nanocarriers for cefixime delivery: LRC-BG (lauroyl chloride, bergenin) and BRM-BG (bromoundecane, bergenin). Cell viability and hemolysis assay showed that both had good biocompatibility. Compared with cefixime suspension, the C max and AUC 0-24 of LRC-BG increased by 1.72 and 4.58 times, respectively; while those of BRM-BG increased by 1.9 and 4.97 times, respectively. In addition to niosomal cefixime, niosomes with other antibiotics, eg daptomycin, levofloxacin, clarithromycin and azithromycin, have all shown promising results after oral administration. 85,86,88,90 Solid Matrix Mediated Lipid Nanoparticle Formulations (LNFs) Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are two types of LNFs mainly used for antibiotic delivery. The unique shell-core structure of LNFs makes them suitable for delivering drugs of different lipophilicity or different composition, and subsequently increase the solubility, permeability, and bioavailability of encapsulated drugs.

Solid Lipid Nanoparticles (SLNs)
Solid lipid nanoparticles (SLNs) were first designed in the 1990s by Schwarzetal et al. 91 These are composed of medium-or long-chain lipids eg anisodylglycerol, tripalmitin, and stearic acid that have high melting points and are electrically neutral, SLNs are shell-core structured with a particle size between 10 and 1000 nm. 92,93 SLNs are particularly effective in avoiding the first-pass metabolism and increasing the intestinal lymphatic transport via paracellular and transcellular pathways of enterocytes, and endocytosis of phagocytic cells. 94,95 In addition to the solid lipids, surfactants such as Tween-80, PVA and Pluronic F-68 are also used in SLNs. The composition and properties of LNFs for oral delivery of antibiotics are listed in Table 2.
Sharma et al 96 loaded the BCS II drug clarithromycin (CLA) in SLNs. The optimal feature of CLA-SLNs was achieved when Pluronic F-68 was used as the surfactant, and the ratio of stearic acid to trisearin was 1:1. These highly hydrophobic, negatively charged, sub-micron SLNs were conducive to M cell uptake and accumulation, and easily released from Peyer's patches to the lymphatic system. Compared to free CLA, the C max of CLA-SLNs increased by 2.3-fold, and its relative bioavailability increased by 5-fold. Öztürk et al studied the effect of lipid skeletons, ie glyceryl behenate, tripalmitin, and stearic acid, on the properties and antibacterial activity of CLA-SLNs. Besides the improvement in bioavailability, drug loading and release efficiency are significantly related to carbon chain length. 97 Rifabutin (RFB), with poor solubility, is a semisynthetic antibiotic to treat Mycobacterium tuberculosis and Mycobacterium avium. By loading RFB into glyceryl monostearate (GMS) via solvent diffusion evaporation, the oral bioavailability of resultant RFB-SLNs increased by 5-fold. 98 Ion pairing of unsaturated fatty acids (FAs) with antibiotics is another method to improve the antibacterial activity and entrapment efficiency of SLN. 99 Linoleic acid (LA), an unsaturated fatty acid, exhibits antibacterial activity. 100 Kalhapure et al 99 constituted VCM-LA2-SLNs by wrapping ion pair agent LA and vancomycin (VCM) in SLNs. The minimum inhibitory concentration (MICs) of vancomycin hydrochloric (VCM-HCL) SLNs to Staphylococcus aureus and MRSA were 250 g/mL and 500 g/mL, respectively, while those of VCM-LA2 SLNs were 31.25 g/mL and 15.62 g/mL, respectively. Unsaturated fatty acids exhibit antibacterial activity. The main target of unsaturated fatty acids action is the cell membrane, where it interferes with cell energy production by disrupting the electron transport chain and oxidative phosphorylation. Other mechanisms include a decrease in transfer frequency of conjugal DNA and an inhibition of bacterial enoyl-acyl carrier protein reductase FabI. 100 was stable for at least 8 weeks, indicating the potential of SLNs as oral formulations for leprosy treatment. For antibiotics with poor palatability, fluctuating oral bioavailability and photo-instability, wrapping the coating on SLNs' surface is likely a good strategy (Figure 3). 38 Nanostructured Lipid Carriers (NLCs) NLCs are the second generation of LNFs. They are composed of both solid and liquid lipids at a defined ratio, although the carriers maintain solid features at room temperature or body temperature. 103 By the adjustment in lipid composition, NLCs can encapsulate more antibiotics with higher entrapment efficiency and better biocompatibility compared to conventional SLNs.
First-line anti-tuberculosis drugs rifampicin and isoniazid are often used together in clinic, but rifampicin exhibits significant first-pass metabolism and gastric degradation. Rifampicin and isoniazid-loaded SLNs or NLCs were prepared using a modified multi-emulsification method. Although rifampicin and isoniazid showed similar compatibility in the matrices of both SLNs and NLCs, the NLCs system had higher drug loading and entrapment efficiency (Table 2), slower chemical degradation, and therefore exhibited great potential to increase the oral bioavailability of rifampicin. 104

Polymer-Based Nanomedicines
Polymers used for oral drug delivery are expected to have good biocompatibility, biodegradability, high drug loading, gastrointestinal stability, safety and controlled release. The carrier composition and properties of polymer-based nanocarriers for oral delivery of antibiotics are listed in Table 3.

Polymeric Micelle
Polymeric micelles are composed of amphiphilic copolymers that spontaneously assemble into 5 to 100 nm colloidal particles when their concentrations are above the critical micelle concentration (CMC) (Figure 1). 105,106 Antibiotics are encapsulated in the hydrophobic core of micelles, which were stabilized by a hydrophilic corona. 107 Polymeric micelles play an important role in the oral delivery of antibiotics not only because of its good solubilization, high drug-loading, and controlled drug release, but also due to its ability to reduce the non-specific uptake by the reticuloendothelial system (RES) and to remain stable in the GIT. 28,108 Pyrinezolid, an oxazolidinone-based drug, is effective against many Gram-positive bacteria including methicillinresistant Staphylococcus aureus (MRSA) and vancomycinresistant Enterococcus albeit with poor solubility. Methoxy poly (ethylene glycol)-poly (lactide) (mPEG-PLLA) diblock copolymers were used to improve the oral bioavailability and lung targeting of pyrinezolid. 28 While the hydrophilic mPEG block inhibited pyrinezolid elimination by RES, and increasing its stability and retention time in the body, 109,110 the hydrophobic block PLLA had good biocompatibility and degradability. 111 The pyrinezolid micelles were 57.8 ± 0.8 nm with a polydispersity index (PDI) of 0.68 ± 0.019 and an entrapment efficiency of 89.76 ± 3.19%. In vivo experiments showed that the oral bioavailability of pyrinezolid-micelles was 99.7%, significantly higher than that of free pyrinezolid (75.8%). Furthermore, higher lung tissue-targeted aggregation was beneficial to the treatment of MRSA-associated pneumonia.
Micelles with more complicated structure, including mixed micelles and "flower-like" structures, are also used for antibiotic delivery. For example, micelles made of block copolymer with different structures or molecular weights showed better thermodynamic and kinetic stability. 112,113 Ciprofloxacin, a P-gp substrate, was delivered by syntheticmixed micelles made of poloxamer, phosphatidylcholine, and cholesterol. In addition to an outstanding drug-loading capability at 88%, the micelles also significantly increased the drug transport across Caco-2 cells. 114 Arafat et al prepared micelles using phosphatidylcholine and sodium deoxycholate, and loaded them with a complex of cefotaxime and 3a,7a-dihydroxy-12-keto-5b-cholanate. The drugloading capability was 10.5% to 18.9%, and the micelles increased the oral bioavailability of drugs by 4-fold. 115 "Flower-like" micelles can be prepared from triblock copolymers. 116,117 For example, poly(ε-caprolactone)-b-polyethylene glycol-b-poly(ε-caprolactone) (PCL-b-PEG-b-PCL) micelles were prepared using co-solvent/evaporation method for the delivery of rifampicin. The hydrophobic-hydrophilichydrophobic triblock copolymer spontaneously formed a "flower structure" micelle in the aqueous solution, which encapsulated rifampicin in a hydrophobic core, controlled its release, and protected rifampicin from isoniazid and the highly acidic environment in the stomach. Moreover, even in the presence of isoniazid, the oral bioavailability of rifampicin micelles was a 3.3-fold higher than that of free drugs. 118

Polymeric Nanoparticles
Biodegradable polymers for antibiotics delivery include chitosan, alginate, gelatin of natural origin, and poly (lactic-co-glycolic acid) (PLGA), and polylactic acid (PLA) of synthetic origin can be used to encapsulate insoluble antibiotics ( Figure 1). 119,120 The gastrointestinal localization and paracellular or lymphoid transport can be improved by adjusting the molecular weight, hydrophobicity, and adhesion of polymers. 121,122 As a natural cationic polysaccharide, chitosan (CS) has been used for the delivery of small molecules, proteins, polypeptides, polysaccharides, and genes. [123][124][125] At the same time, many chitosan derivatives with better delivery properties have been developed such as trimethyl chitosan, carboxymethyl chitosan, and thiolated chitosan, all of which played an important role in the development of oral drug delivery systems. [126][127][128] First, chitosan causes the relaxing of tight junctions between epithelial cells, and subsequently allows more drugs to pass through the epithelial barriers. Second, the positively charged chitosan interacts with the negatively charged mucus to improve the adhesion of the carrier on the mucus layer and promote the transcellular and paracellular transport of encapsulated antibiotics 129,130 The reactive functional groups of chitosan and chitosan derivatives also provide a good opportunity for improving the stability in the stomach area and the permeability in the intestine. Gentamicin (GM) is a wellknown aminoglycoside antibiotic, but its oral absorption is limited by enzymatic degradation and low bioavailability. Optimizing the oral controlled-release dosage form of GM submit your manuscript | www.dovepress.com

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International Journal of Nanomedicine 2020:15 Table 3 Composition and Properties of Polymer-Based Nanocarriers for Oral Delivery of Antibiotics  Chitosan-modified GM-PLGA nanoparticles has the potential to improve the oral absorption of GM. 131 PLGA nanoparticles coated with chitosan were used to load clarithromycin. Both PLGA and chitosan exhibit good biocompatibility and degradability, while the positively charged chitosan also had excellent stability and the ability to cross intestinal epithelial tight junction. 48,132 Furthermore, studies showed that chitosan has antibacterial activity. 133 In the nanoparticles containing chitosan and PLGA, the zeta potential increased significantly to a positive value, and the encapsulation efficiency was up to 85%. Antibacterial activity test results showed that mixing of natural and synthetic polymers significantly increases the antibacterial activity of clarithromycin against Staphylococcus aureus (ATCC 25,923), Listeria monocytogenes (ATCC 1911), and Klebsiella pneumoniae (ATCC 700,603). 44 Similar improvement was also observed when clofazimine and clindamycin hydrochloride were loaded into PLGA polymeric nanoparticles. 134 In another example, rifampicin-gantrez-ethylcellulose nanoparticles are prepared with particle sizes ranging from 400 to 500 nm. Compared with rifampicin-gantrez AN-119 nanoparticles, the incorporation of ethylcellulose increased the contact angle and decreased the adhesion, which are beneficial for Peyer's patches uptake and lymphatic transport. As a result, the relative bioavailability of rifampicin-Gantrez-ethylcellulose nanoparticles nearly tripled, and more drugs accumulated in lung. 122 Helicobacter pylori is a micro-aerobic gram-negative bacterium that colonizes the deep layer of human gastric mucus with acidic pH values. 135,136 Therefore, therapeutic agents not only need to penetrate the gastric mucus layer but also need to be protected from the acidic environment. Since the solubility of chitosan is pH-dependent, Arif et al prepared pHresponsive sulfhydryl chitosan/poly (malic acid) nanoparticles to encapsulate amoxicillin for the treatment of Helicobacter pylori (H. pylori) infection. The sulfhydryl chitosan/poly (malic acid) was selected based on their mucoadhesive and anticoagulant properties, so that the formulated nanoparticles can adhere and then penetrate the mucous layer at the infection site. Amoxicillincysteine-CS/poly (malic acid) nanoparticles have good pH sensitivity and can delay the presence of amoxicillin in gastric acid. The release of the drug enables the drug to be effectively delivered and targeted to the survival area of H. pylori. 137 Similarly, new pH-sensitive urea-based coupled chitosan/tripolyphosphate nanoparticles have also been designed for targeted therapy of H. pylori. 138 Other Nanopreparations Nanosuspension Nanosuspension is a no-carrier two-phase dispersion system composed of surfactant, co-surfactant, and aqueous solution. Its size is generally smaller than 1000 nm ( Figure 1). 139,140 Sucrose, lactose, mannose and other redispersants can be added and then dried to form solid preparations. 141,142 Cefdinir is the third-generation cephalosporin antibiotics with poorsolubility and permeability. Sawant et al prepared nanosuspensions with Poloxamer 407 as stabilizers and zirconia as the abrasive by a media milling method to improve cefdinir solubility. The saturated solubility of cefdinir nanosuspension in physiological saline was 1985.3 ± 10.2 mg/mL, while the pure drug was 352.2 ± 6.5 mg/mL. In the case of improved solubility, in vivo results showed that C max and T max of the marketed suspension were 6.37 mg/mL and 2.1 h, while nanosuspension were 28.45 mg/mL and 1.6 h, respectively. In addition, the oral bioavailability of nanosuspension was 3-fold higher than that of marketed suspension. 143 Tetracycline, as a well-known, broad-spectrum, effective and cheap antibiotic for the treatment of diarrhea, is very popular in developing countries with limited medical budgets. However, the emergence of bacterial resistance is gradually eroding its market competitiveness. Mukherjee

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Tet-CPNP (4.5 µg/kg b.w.) showed better Shigellainfected mice treatment effect compared with the same dose of free tetracycline. 144,145 Carbon Nanotubes Carbon nanotubes are allotropes of carbon with an inner diameters as small as 1 nm (Figure 1). 146 Multiwalled carbon nanotubes (MWCNTs) exhibited satisfactory properties such as small particle size, acid stability, high strength, high toughness, and non-swelling. 147,148 MWCNTs, encapsulated by liquid crystalline molecularly imprinted polymer (LC-MIP), namely MWCNT@LCMIP, was prepared for oral drug delivery of levofloxacin (LVF). 149,150 LC-MIP has the ability to float on an aqueous medium by its solventresponsive deformation. This elastic structure had good gastric floating and controlled release characteristics, which prolonged the gastric residence time of drugs, and increased the half-life of levofloxacin. Since MWCNT@LC-MIP had a smaller size (average layer thickness was 60 nm), a higher pore property (171.10 × 10 −3 cm 3 g −1 ), as well as a longer sustained release time (15.6 h), compared with bared MWCNT, the relative bioavailability of MWCNT@LCMIP was increased by 578.9%, whereas only 11.7% of the former.

Mesoporous Silica Nanoparticles (MSNs)
Since 2001, mesoporous materials have been gradually used as drug delivery vehicles due to their smaller size (2-50 nm) and larger specific surface area (above 1000 m 2 /g) (Figure 1). In addition to low toxicity, large pore size and high drug loading, it also has good thermal stability, strong controlled release ability and acid stability. [151][152][153][154] Synthetic lipid-coated mesoporous silica nanoparticles (L-MSNs) were used to improve the antibacterial activity of ciprofloxacin by Mudakavi et al. 155 The submicron MSN has a surface area of more than 1000 m 2 g −1 , which is beneficial for loading more drugs and being absorbed by M cells and macrophages present in Peyer's patches. Results showed that ciprofloxacin coated with L-MSN had the same or even higher antibacterial activity than free drugs at low doses, and the carriercontrolled drug release also prolongs antibiotic courses. In addition, rifampicin-loaded MSN also showed positive results. 156

Conclusion
Numerous studies have shown that the advantages of nanoantibiotics in overcoming multiple gastrointestinal barriers and improving drug stability, solubility, permeability and oral bioavailability (Table 4). However, few review articles have been published to provide an overview on oral nanoantibiotics. To date, some new functional nanomaterials such as nano-selenium, nano-ZnO/TiO 2 /CuO/Cu 2 O, dendrimers, graphene, fullerenes, nano-carries for nitric oxide, nano-hydroxyapatite, and bioinspired nanomedicines have been explored in other routes of antibiotic administration, all of these provide scholars with more choices for in-depth exploration and design of convenient

Nanomedicine Types Advantages Disadvantages Reference
Other nanopreparations Nanosuspension Simple preparation, ease of scale-up and little batch-to-batch variation.
Expand the formulation technology to the level of industrial production, and the cost is relatively low.
The wide application of stabilizers is limited by the difficulty of choosing the most effective stabilize.
Lack of basic knowledge about particleparticle interaction in nanosuspensions, and unable to obtain high efficiency and high throughput stabilizer screening technology. 140,169,170 Carbon nanotubes The structure is much more stable than polymer materials.

Good flexibility and hardness
Has certain cytotoxicity and causes inflammation to human organs.

147-150
Mesoporous silica nanoparticles (MSNs) Adjust the pharmacokinetic release profile through diffusion or other mechanisms.
Release drugs for specific tissues. Improve the bioavailability of candidate pHsensitive drugs.

Controlled drug release
The surface density of silanol groups interacting with the surface of the phospholipids of the red blood cell membranes resulting in hemolysis.

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and effective oral nano-antibiotics. Although there are many studies on oral nano-antibiotics, few of them are translated to the clinic. Regardless of its effectiveness, there are many issues that need to be considered in the clinical translation of nanomedicine. The first is the synthesis, such as physical and chemical stability, biodegradability, and formulation design. We should work hard to solve the obstacles of large-scale production, such as repeatability and high cost, as well as the obstacles of quality control analysis for characterization, such as polydispersity, scalability, complexity, final product consistency and storage stability. The second issue is pre-clinical evaluation. We should conduct a systematic and effective nanomedicine evaluation to determine the pharmacodynamics, pharmacokinetics and toxicology. Finally, after entering the clinical evaluation stage, the design of nanomedicine, the safety of the human body, the toxicity, and the evaluation of the patient's therapeutic effect should all minimize time and cost.