Self-Assembled chitosan/phospholipid nanoparticles: from fundamentals to preparation for advanced drug delivery

Figures & data

Table 1. Summary of nanoparticles as drug delivery systems.

Types	Advantages	Disadvantages	Applicatons
Mesoporous silica nanoparticles	Amorphous structure with high porosity and enormous surface area.	Potential toxicity in vitro and in vivo and certain biohazards.	Deliver anticancer drugs (carboplatin, doxorubicin), Di Pasqua et al., 2009; He et al., 2011 antibiotics (amoxicillin), Li et al., 2010 and heart disease drugs (captopril) Popovici et al., 2011.
Carbon nanoparticles	Enormous surface area; excellent electronic and thermal conductivity; drug degradation protection; release only in specific conditions.	Carcinogenic potential; low biocompatibility and biodegradability; need complex chemical modifications to improve biocompatibility.	Deliver anti-inflammatory drugs (dexamethasone) Luo et al., 2011. anticancer drugs (cisplatin, doxorubicin) Di Crescenzo et al., 2011; Tripisciano et al., 2010 and antibacterial drugs (sulfamethoxazole) Zhang et al., 2011
Solid lipid nanoparticles	Good physical stability; drug degradation protection; controlled drug release; good tolerability.	Low loading capacity; drug expulsion after crystallization; a relatively high water content of the dispersions.	Delivery of lipophobic drugs for dermal (Abdel-Mottaleb et al., 2011), peroral (Muchow et al., 2008), parenteral (Nayak et al., 2010), ocular (Attama et al., 2007), plumonary (Liu et al., 2008), and rectal (Sznitowska et al., 2001) delivery.
Magnetic nanoparticles	Easy handling under external magnetic fields; visualization possibility; enhanced uptake by the target tissue resulting in effective treatment at the therapeutically optimal doses.	Aggregation into larger clusters loses the properties associated with their small dimensions and making physical handling difficult; inadequate magnet system.	Deliver antimetabolites (gemcitabine, 5-fluorouracil) Tong et al., 2011; Arias et al., 2010, anticancer drugs (cisplatin, paclitaxel) Hua et al., 2010; Yang et al., 2006, anti-infective agents (ciprofloxacin) Bajpai & Gupta, 2011.
Polymeric nanoparticles	Incorporation of biodegradable polymers; improved aqueous stability and photostability of the encapsulated drug.	Require chemical modifications with nonionic surfactants to reduce immunological interactions and intermolecular interactions between the surface chemical groups.	Delivery antitubercular drugs (rifampicin) Saraogi et al., 2010, antineoplastic drug (carboplatin) Rejinold et al., 2011, antifungal drug (clotrimazole) Pandey et al., 2005.

Figure 1. Schematic representation of chitosan-phospholipid interaction and the self-assembly of SACPNs.

Figure 2. Schematic illustration of the preparation of SACPNs by the classic solvent injection method.

Figure 3. (a) Schematic illustration of quercetin-loaded SACPNs. (b) TEM images of quercetin-loaded SACPNs. (c) Visual observation of crude quercetin in water (left) and quercetin-loaded SACPNs suspension (right). (a, b, c) Reproduced with permission (Tan et al., 2011). Copyright 2011, Informa PLC.

Figure 4. (a) Transmission electron micrographs of SACPNs. (b) Atomic force microscopy images of SACPNs. (c) FTIR spectra of SACPNs and of the two components separately. (d) Comparison of the mean square hydrogen fluctuation differences of a dry SACPNs (open triangles) and a pure phospholipid one (closed triangles). (e) FTIR spectra of (e1) chitosan, (e2) phospholipid, (e3) natamycin and (e4) natamycin-loaded SACPNs. (a, b, c) Reproduced with permission (Sonvico et al., 2006). Copyright 2006, Elsevier. (d) Reproduced with permission (Sonvico et al., 2006). Copyright 2006, Elsevier. (e) Reproduced with permission (Bhatta et al., 2012). Copyright 2012, Elsevier.

Figure 5. (a) Schematic illustrations of the mesoscopic models of SACPNs. The yellow spheres represent the hydrophobic part of the phospholipid, while the red spheres represent the hydrophilic part. The chitosan are assembled in a random configuration around the phospholipid. (b) Distribution of chitosan on the xy plane. (b1) 50 chains of chitosan; (b2) 100 chains of chitosan; (b3) 150 chains of chitosan; (b4) 200 chains of chitosan. (c) Cryo-TEM image of SACPNs containing tamoxifen (c1) and progesterone (c2). (a, b) Reproduced with permission (Terrón-Mejía et al., 2018). Copyright 2018, MDPI. (c) Reproduced with permission (Gerelli et al., 2008). Copyright 2007, IOP Publishing.

Figure 6. Schematic illustrations of drug release mechanisms of SACPNs.

Table 2. Summary of recent studies of SACPNs as drug delivery systems.

APIs	Encapsulation efficiency (%)	Size of SACPNs (nm)	Drug loading (%)	Characteristics	Application	References
Tamoxifen citrate	81.3 ± 2.1	94.8 ± 7.2	30.2 ± 0.3	Release can be triggered by enzymatic attack of lipase and lysozyme.	Oral administration	Barbieri et al., 2013
Insulin	94.69 ± 0.20	128.3 ± 9.45	4.60 ± 0.16	Improve oral bioavailability, time-dependent release, and therapeutic activity of insulin.	Oral administration	Liu et al., 2016
Melatonin	7. 1 ± 0.2	122.8 ± 0.8	4.8 ± 0.2	The SACPNs can be stored in solid form for 7 months while retaining physico-chemical properties and the encapsulated drug.	Oral administration	Hafner et al., 2011
Capsaicin	96.80 ± 0.59	18.04 ± 0.95	96.0	Simulation investigation about the interaction between capsaicin and CS is very weak compared to that with lecithin.	Transmucosal administration	Terrón-Mejía et al., 2018
β-lapachone	52.4 ± 2.4	330.1 ± 3.5	25.8 ± 7.4	Can obtain no parasite reduction while stop the lesion progression.	Transdermal administration	Moreno et al., 2015
Clobetasol propionate	92.2 ± 0.5	248.25 ± 15.1	10.9	Use of SACPNs in chitosan gel can significantly improve the risk-benefit ratio.	Transdermal administration	Şenyiğit et al., 2016
Simvastatin	98.52 ± 1.33	146.7 ± 26.2	90.7 ± 0.87	Enzyme triggered drug release and permeation across mucosal surfaces through physiological biodegradation processes.	Nasal administration	Clementino et al., 2016, 2018
Amphotericin-B	74.6 ± 0.75	282.7 ± 5.2	5.71	Achieved higher AUC and MRT in comparison with marketed formulation.	Ocular administration	Chhonker et al., 2015
Doxorubicin & piperine	45.96 ± 2.63 for DOX; 52.91 ± 3.56 for PIP	157.7 ± 4.53	8.93 ± 0.82 for DOX; 8.46 ± 0.57 for PIP	Co-delivery and sustained release of DOX and PIP, with the potential to be used to treat MDR cancer cells.	Multiple administrations	Alkholief, 2019
Cisplatin	89.2 ± 0.5	181.0 ± 0.43	2.11 ± 0.7	Controlled delivery of cisplatin in cancer therapy.	Multiple administrations	Khan et al., 2019

Figure 7. (a, b) SEM images of the clobetasol propionate-loaded SACPNs at 80 Kx (a) and 500 Kx (b) magnifications. (c) Histology of the rat skin samples: (c1) control; (c2) commercial cream; (c3) SACPNs; (c4) Na-DOC gel. (d) Amount of DFV accumulated from formulations in the SC + epidermis (dark bars) and dermis (light bars). (e) Changes in the paw thickness of the rats with respect to time after formulation applications. (a, b, c) Reproduced with permission (Şenyiğit et al., 2016). Copyright 2017, MDPI. (d, e) Reproduced with permission (Özcan et al., 2013). Copyright 2013, Dove Press.

Figure 8. (a) Simvastatin release profile from simvastatin-loaded SACPNs (filled circle) and a control simvastatin suspension (open circle) in simulated nasal fluid (b) Radioactivity biodistribution in rats 90 minutes after the nasal instillation of 20 μL (10 μL in each nostril) of 99 mTc-labeled simvastatin-loaded SACPNs, simvastatin suspension, and pertechnetate (TcO_4–) (a, b) Reproduced with permission (Clementino et al., 2016). Copyright 2016, Dove Press.

Figure 9. (a, b) Zone of inhibition of amphotericin-B, Fungizone and amphotericin-B-laded SACPNs against A. fumigates. (c) Bar graphs represent zone of inhibition of different formulations against A. fumigates. (d) Cular pharmacokinetic profile of amphotericin-B following topical instillation in rabbit eyes. (a, b, c, d) Reproduced with permission (Chhonker et al., 2015). Copyright 2015, Elsevier.

Figure 10. (a) In vitro time-dependent release profiles of insulin-loaded SACPNs with different phospholipid/chitosan ratios. (b) Time-dependent reduction in blood glucose levels in diabetic rats. (a, b) Reproduced with permission (Liu et al., 2016). Copyright 2016, Dove Press.

Figure 11. (a) Morphological characterization of curcumin-loaded SACPNs by TEM (left) and SEM (right). (b) The inhibition of Nitric oxide activity (left) and H₂O₂ activity (right) in blank nanoparticles (Blank), curcumin powder (CP) and curcumin-loaded SACPNs. (a, b) Reproduced with permission (Pathak et al., 2015). Copyright 2015, Springer Nature.

Figure 12. (a) Schematic illustration of KAE-SACPNs. (b) Morphology and dispersivity of KAE-SACPNs. (c) Effect of KAE-SACPNs and pure KAE on the radial growth of Fusarium oxysporium in time dependent manner. (a, b, c) Reproduced with permission (Ilk et al., 2017). Copyright 2016, Taylor & Francis Group.

Di Pasqua AJ, Wallner S, Kerwood DJ, Dabrowiak JC. (2009). Adsorption of the Pt(II) anticancer drug carboplatin by mesoporous silica. Chem Biodivers 6:1343–9.

 PubMed Web of Science ®Google Scholar

He Q, Gao Y, Zhang L, et al. (2011). A pH-responsive mesoporous silica nanoparticles-based multi-drug delivery system for overcoming multi-drug resistance. Biomaterials 32:7711–20.

 PubMed Web of Science ®Google Scholar

Li Z, Su K, Cheng B, et al. (2010). Organically modified MCM-type material preparation and its usage in controlled amoxicillin delivery. J. Colloid Interface Sci 342:607–13.

 PubMed Web of Science ®Google Scholar

Popovici R, Seftel E, Mihai G, et al. (2011). Controlled drug delivery system based on ordered mesoporous silica matrices of captopril as angiotensin-converting enzyme inhibitor drug. J Pharma Sci 100:704–14.

 PubMed Web of Science ®Google Scholar

Luo X, Matranga C, Tan S, et al. (2011). Carbon nanotube nanoreservior for controlled release of anti-inflammatory dexamethasone. Biomaterials 32:6316–23.

 PubMed Web of Science ®Google Scholar

Di Crescenzo A, Velluto D, Hubbell JA, Fontana A. (2011). Biocompatible dispersions of carbon nanotubes: a potential tool for intracellular transport of anticancer drugs. Nanoscale 3:925–8.

 PubMed Web of Science ®Google Scholar

Tripisciano C, Costa S, Kalenczuk R, Borowiak-Palen E. (2010). Cisplatin filled multiwalled carbon nanotubes–a novel molecular hybrid of anticancer drug container. Eur Phys J B 75:141–6.

 Web of Science ®Google Scholar

Zhang D, Pan B, Wu M, et al. (2011). Adsorption of sulfamethoxazole on functionalized carbon nanotubes as affected by cations and anions. Environ. Pollut 159:2616–21.

 PubMed Web of Science ®Google Scholar

Abdel-Mottaleb MM, Neumann D, Lamprecht A. (2011). Lipid nanocapsules for dermal application: a comparative study of lipid-based versus polymer-based nanocarriers. Eur. J. Pharm. Biopharm 79:36–42.

 PubMed Web of Science ®Google Scholar

Muchow M, Maincent P, Müller RH. (2008). Lipid nanoparticles with a solid matrix (SLN®, NLC®, LDC®) for oral drug delivery. Drug Dev Ind Pharm 34:1394–405.

 PubMed Web of Science ®Google Scholar

Nayak AP, Tiyaboonchai W, Patankar S, et al. (2010). Curcuminoids-loaded lipid nanoparticles: novel approach towards malaria treatment. Colloids Surf. B. Biointerfaces 81:263–73.

 PubMed Web of Science ®Google Scholar

Attama A, Schicke B, Paepenmüller T, Müller-Goymann C. (2007). Solid lipid nanodispersions containing mixed lipid core and a polar heterolipid: characterization. Eur. J. Pharm. Biopharm 67:48–57.

 PubMed Web of Science ®Google Scholar

Liu J, Gong T, Fu H, et al. (2008). Solid lipid nanoparticles for pulmonary delivery of insulin. Int J Pharma 356:333–44.

 PubMed Web of Science ®Google Scholar

Sznitowska M, Gajewska M, Janicki S, et al. (2001). Bioavailability of diazepam from aqueous-organic solution, submicron emulsion and solid lipid nanoparticles after rectal administration in rabbits. Eur. J. Pharm. Biopharm 52:159–63.

 PubMed Web of Science ®Google Scholar

Tong Q, Li H, Li W, et al. (2011). In vitro and in vivo anti-tumor effects of gemcitabine loaded with a new drug delivery system. J Nanosci Nanotech 11:3651–8.

 PubMed Web of Science ®Google Scholar

Arias JL, López-Viota M, Delgado ÁV, Ruiz MA. (2010). Iron/ethylcellulose (core/shell) nanoplatform loaded with 5-fluorouracil for cancer targeting. Colloids Surf. B. Biointerfaces 77:111–6.

 PubMed Web of Science ®Google Scholar

Hua M-Y, Yang H-W, Chuang C-K, et al. (2010). Magnetic-nanoparticle-modified paclitaxel for targeted therapy for prostate cancer. Biomaterials 31:7355–63.

 PubMed Web of Science ®Google Scholar

Yang J, Park S-B, Yoon H-G, et al. (2006). Preparation of poly ɛ-caprolactone nanoparticles containing magnetite for magnetic drug carrier. Int J Pharma 324:185–90.

 PubMed Web of Science ®Google Scholar

Bajpai A, Gupta R. (2011). Magnetically mediated release of ciprofloxacin from polyvinyl alcohol based superparamagnetic nanocomposites. J Mater Sci: Mater Med 22:357–69.

 PubMed Web of Science ®Google Scholar

Saraogi GK, Gupta P, Gupta U, et al. (2010). Gelatin nanocarriers as potential vectors for effective management of tuberculosis. Int J Pharma 385:143–9.

 PubMed Web of Science ®Google Scholar

Rejinold NS, Chennazhi K, Nair S, et al. (2011). Biodegradable and thermo-sensitive chitosan-g-poly (N-vinylcaprolactam) nanoparticles as a 5-fluorouracil carrier. Carbohydr. Polym 83:776–86.

 Web of Science ®Google Scholar

Pandey R, Ahmad Z, Sharma S, Khuller G. (2005). Nano-encapsulation of azole antifungals: potential applications to improve oral drug delivery. Int J Pharma 301:268–76.

 PubMed Web of Science ®Google Scholar

Tan Q, Liu W, Guo C, Zhai G. (2011). Preparation and evaluation of quercetin-loaded lecithin-chitosan nanoparticles for topical delivery. Int J Nanomed 6:1621–30.

 PubMed Web of Science ®Google Scholar

Sonvico F, Cagnani A, Rossi A, et al. (2006). Formation of self-organized nanoparticles by lecithin/chitosan ionic interaction. Int J Pharma 324:67–73.

 PubMed Web of Science ®Google Scholar

Bhatta RS, Chandasana H, Chhonker YS, et al. (2012). Mucoadhesive nanoparticles for prolonged ocular delivery of natamycin: in vitro and pharmacokinetics studies. Int J Pharma 432:105–12.

 PubMed Web of Science ®Google Scholar

Terrón-Mejía K, Martínez-Benavidez E, Higuera-Ciapara I, et al. (2018). Mesoscopic modeling of the encapsulation of capsaicin by lecithin/chitosan liposomal nanoparticles. Nanomaterials 8:425.

 Web of Science ®Google Scholar

Gerelli Y, Di Bari M, Deriu A, et al. (2008). Structure and organization of phospholipid/polysaccharide nanoparticles. J Phys Condens Mat 20:104211.

 Web of Science ®Google Scholar

Barbieri S, Sonvico F, Como C, et al. (2013). Lecithin/chitosan controlled release nanopreparations of tamoxifen citrate: Loading, enzyme-trigger release and cell uptake. J Con Release 167:276–83.

 PubMed Web of Science ®Google Scholar

Liu M, Zhang J, Zhu X, et al. (2016). Efficient mucus permeation and tight junction opening by dissociable “mucus-inert” agent coated trimethyl chitosan nanoparticles for oral insulin delivery. J Con Release 222:67–77.

 PubMed Web of Science ®Google Scholar

Hafner A, Dürrigl M, Pepić I, Filipović-Grčić J. (2011). Short- and long-term stability of lyophilised melatonin-loaded lecithin/chitosan nanoparticles. Chem Pharm Bull 59:1117–23.

 PubMed Web of Science ®Google Scholar

Moreno E, Schwartz J, Larrea E, et al. (2015). Assessment of β-lapachone loaded in lecithin-chitosan nanoparticles for the topical treatment of cutaneous leishmaniasis in L. major infected BALB/c mice. Nanomed Nanotechnol Biol Med 11:2003–12.

 PubMed Web of Science ®Google Scholar

Şenyiğit T, Sonvico F, Rossi A, et al. (2016). In vivo assessment of clobetasol propionate-loaded lecithin-chitosan nanoparticles for skin delivery. Int J Mol Sci 18:32.

 PubMed Web of Science ®Google Scholar

Clementino A, Batger M, Garrastazu G, et al. (2016). The nasal delivery of nanoencapsulated statins–an approach for brain delivery. Indian J. Nephro 11:6575–90.

 Google Scholar

Clementino A, Pozzoli M, Botti E, Sonvico F. (2018). Lecithin/chitosan-based nanoparticles for the nasal delivery of statins: enzyme-trigger controlled release and cellular transport. Respiratory Drug Del 2:589–594.

 Google Scholar

Chhonker YS, Prasad YD, Chandasana H, et al. (2015). Amphotericin-B entrapped lecithin/chitosan nanoparticles for prolonged ocular application. Int J Bio Macromol 72:1451–8.

 PubMed Web of Science ®Google Scholar

Alkholief M. (2019). Optimization of Lecithin-Chitosan nanoparticles for simultaneous encapsulation of doxorubicin and piperine. J. Drug Deliv. Sci. Technol 52:204–14.

 Web of Science ®Google Scholar

Khan MM, Madni A, Torchilin V, et al. (2019). Lipid-chitosan hybrid nanoparticles for controlled delivery of cisplatin. Drug Delivery 26:765–72.

 PubMed Web of Science ®Google Scholar

Özcan I, Azizoğlu E, Senyiğit T, et al. (2013). Enhanced dermal delivery of diflucortolone valerate using lecithin/chitosan nanoparticles: in-vitro and in-vivo evaluations. Int J Nanomedicine 8:461–75,

 PubMed Web of Science ®Google Scholar

Pathak L, Kanwal A, Agrawal Y. (2015). Curcumin loaded self assembled lipid-biopolymer nanoparticles for functional food applications. J Food Sci Technol 52:6143–56.

 PubMed Web of Science ®Google Scholar

Ilk S, Saglam N, Özgen M. (2017). Kaempferol loaded lecithin/chitosan nanoparticles: preparation, characterization, and their potential applications as a sustainable antifungal agent. Artif Cells Nanomed Biotechnol 45:907–16.

 PubMed Web of Science ®Google Scholar