Nanocarriers Used Most in Drug Delivery and Drug Release: Nanohydrogel, Chitosan, Graphene, and Solid Lipid


  • Sibel Ayşıl ÖZKAN
  • Aylin DEDEOĞLU
  • Yalçın ÖZKAN

Received Date: 13.06.2019 Accepted Date: 01.08.2019 Turk J Pharm Sci 2019;16(4):481-492 PMID: 32454753

Over the past few years, nanocarriers have become an ideal solution for safe and efficient drug delivery and release. This is mainly due to the extraordinary characteristics that nanomaterials exhibit when compared with their larger scaled forms. A variety of these carriers are more popular due to their high biocompatibility, ensuring greater efficacy especially in cancer treatments. Nanocrystal, liposomal, and micelle designs of these materials as nanocarriers for drug delivery and release have been extensively researched throughout the past 50 years. Successful applications have not only ensured a greater focus on therapeutic development but also created a new solution available in the pharmaceutical market. Herein, a brief review of research studies focused on nanocarrier materials and designs to achieve superior benefits of drugs for disease treatments is presented. Nanohydrogels, chitosan, graphene oxide, and solid lipid nanoparticle nanocarrier designs and applications are selectively given due to the great attention they have gained from being highly biocompatible and easy-to-manipulate nanocarrier options from organic and inorganic nanocarrier materials. Each summary exhibits the progress that has been achieved to date. With greater understanding of the current state in the development process of these nanomaterials, there is a rising chance to provide better treatment to patients, which is a desperate need in pharmaceutical technologies.

Keywords: Nanocarrier, drug delivery, nanomaterials, controlled drug release, targeting


Materials that have one or more dimensions lower than 100 nm are considered nanomaterials.1 To be more specific, in 2011 the European Commission defined a nanomaterial as follows:

“A natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm-100 nm.”2

Nanomaterials have great research and development/product development potential in medical applications. Some of these applications include DNA/RNA nanotechnology, diagnosis by molecular imaging, biosensing, nanomedicine, and nanocarriers for drug delivery.3 A considerable number of nanomaterials have been developed, produced, and utilized for these application fields, such as nanohydrogels, chitosan/starch/cellulose nanoparticles, graphene (GR)/GR oxide (GO) nanosheets, iron oxide nanoparticles, gold nanoparticles, cerium oxide nanoparticles, and carbon nanotubes/nanoparticles.

Nanomaterials exhibit extraordinary optical, electronic, and/or mechanical properties when compared with their greater scaled forms. They can differ in color, conductivity, reactivity, surface area to volume ratio, and surface tension from macro forms. Due to this, nanomaterials have attracted the attention of scientists for their potential utilization in vaccines, drug development, and drug delivery.4 Over many years, many nanomaterials have been adopted as nanocarriers, i.e. nanohydrogels, oil-in-water (O/W) emulsions, liposomes, and nanoparticles based on synthetic polymers or natural macromolecules.5 The very first studies were conducted by Couvreur et al.6 and Kreuter and Speiser.7 in the late 70s, where the team exploited polymeric nanocapsules as lysosomotropic carriers and adjuvants.

Drug nanocarriers usually serve two main purposes: targeted drug delivery to specific tissue, organ, or cells and controlled drug release. The foundation of drug delivery is based on biocompatible nanoparticles or nanocapsules and targeting molecules. Biocompatible materials are selected and incorporated to enhance the hydrophilicity of hydrophobic carrier systems or drugs. Targeting molecules are generally antibodies or avidin/biotins that directly target tissue, organs, or cells. Drug release features of nanocarrier systems are provided by the environmentally sensitive structure of the carrier. Controlling drug release ensures paramount therapeutic effect by releasing the delivered drug with high efficiency in the targeted area and preventing any healthy tissue damage that could be caused by some drugs such as chemotherapy agents.8 Nanocarriers that have been designed from polymer-based nanoparticles are solid colloidal particles that are approximately 10-500 nm in size.4 Drug incorporation into nanocarriers is based on 5 methods: dissolution, entrapment, adsorption, attachment, or encapsulation.9 Herein a brief review of nanocarrier systems is given. A summary of the literature including easily manipulated popular nanomaterials that have been adopted as nanocarriers (nanohydrogels, chitosan (CS) nanoparticles, GR/GO nanocarriers, and solid lipid nanoparticles) is given. Nanohydrogels and CS nanoparticle derivatives are the most heavily rotated amphiphilic nanocarrier materials. GR/GO nanomaterials are favored nanocarriers since they are present in a wide range of carrier designs. Finally, solid lipid nanocarriers (SLNs) are currently the most promising and novel lipophilic drug carriers.10


Nanohydrogels can be defined starting with the descriptions of macro-scaled hydrogels. Hydrogels are three-dimensional hydrophilic polymer chain networks that are crosslinked. These networks can consist of natural or synthetic polymers and display swelling behavior when introduced to water or physiological fluids. Moreover, they are able to revert to their initial state when removed from the presence of water/biological fluids.11,12,13 Due to this unique behavior, hydrogels have gained attention and been adopted in biomedical applications such as drug delivery, drug release, and vaccine design.14

Drug delivery and drug release system designs that utilize hydrogels have been and are still considered appealing in medicine due to their crosslink-controlled pore structures. Moreover, physiochemically, hydrogels are very similar to the extracellular matrix of the human body. With also a very high content of water, hydrogels are known to have very high biocompatibility. A main disadvantage is their viscosity, which created an alternative solution: nanohydrogels. These submicron particles made excellent drug carriers that could easily be extruded through an injector needle. In addition, decreasing size ensures an increase in surface area that provides further bioconjugation.11,15

Nanogels, in the range of 10-100 nm size, are small enough to be used as sys­temic drug carriers. For designs that include clearance of nanogel carriers by kidney filtration the diameter is lower than 10 nm. Drug release to tissue, organs, or cells is through the meshes of nanohydrogels, which are typically between 5 and 100 nm in size.16 Mesh sizes in environmentally dependent designs such as temperature- and pH-sensitive ones change with the stimuli according to the crosslink bond concentration that forms or breaks.15 Regulating the breakages of crosslinking bonds that form the initial mesh size of the carriers will provide control of drug release acceleration. Other designs include utilization of the swelling capacity of nanohydrogels.17 As swelling continues, mesh sizes increase and gradually release the encapsulated drug.15

Nanohydrogel carriers that are environmentally dependent include designs sensitive to pH, temperature, electric field, light, enzyme, calcium, glucose, redox, etc.18 In this paper, some of these designs are summarized according to their sensitivity features as below. From this summary, it can be stated that as nanohydrogel carriers there are several popular materials that are prominent when compared with others. In Table 1, materials that receive the greatest attention from scientists are listed.

Temperature-sensitive nanohydrogel carriers

Temperature-sensitive nanohydrogel carriers are systems that exhibit swelling behavior that is dependent on temperature changes and are a widely studied field.19 A temperature-sensitive drug-release design was reported by Ichikawa and Fukumori20 in 1999. The design consists of a water-soluble hemostatic drug core inside a thermosensitive poly[N-isopropylacrylamide (NIPAAm)] nanohydrogel containing an ethyl cellulose shell. Ichikawa and Fukumori20 stated that the mentioned shell could change and revert to its initial size with temperature changes between 30°C and 50°C in water and that nanohydrogels exhibit positive thermosensitive swelling. The drug release rate is reported to be not only temperature dependent but also nanohydrogel concentration dependent.20 A very recent study introduced thermosensitive 5-fluorouracil (5-FU; a chemotherapeutic drug employed for solid tumor treatments) containing methyl cellulose (MC) nanohydrogels for decreased side effects of chemotherapy. In this 2018 study Dalwadi and Patel21 produced MC nanohydrogels by a tip probe-sonicator method from MC hydrogels. 5-FU release depends on both temperature and its biodegradability. Within 48 h the drug is released in the injected area, preventing a cytotoxic drug burst in a very large area as in conventional chemotherapy.21

pH- and/or ionic-strength-sensitive nanohydrogel carriers

pH and/or ionic strength sensitivity allows nanocarriers’ mesh size to be manipulated according to the environmental pH. Elsaeed et al.22 synthesized poly(NIPA-co-AAC) nanohydrogels by inverse microemulsion polymerization method in 2010. On average, the diameter of these nanohydrogels is reported to range between 60 and 80 nm. The team delivers a possible drug release methodology that is pH dependent through poly (NIPA-co-AAC) nanohydrogel by characterizing its swelling behavior between the pH values of 4.00 and 8.00 (ionic strength=0.4). That study shows that the nanohydrogels’ swelling capacity increased with environmental pH.22 In an earlier study, in 2004, Dufresne et al.23 reported pH-sensitive poly (N-isopropylacrylamide) derivative copolymers or poly(alkyl(meth)acrylate) diblock copolymers were produced as indomethacin (a nonsteroidal anti-inflammatory drug), fenofibrate (a drug for treating abnormal blood lipid levels), and doxorubicin (DOX) and aluminum chloride phthalocyanine carriers. PNIPAM copolymers were stated to be synthesized by free radical polymerization while the poly[alkyl(meth)acrylate] diblock copolymers were synthesized by atom transfer radical polymerization. The team carried out both in vitro and in vivo assays. Dufresne et al.23 refer to the PNIPAM derivatives as a potential safe alternative to Cremophor®EL, a common carrier for various poorly water-soluble drugs. Furthermore, poly[alkyl(meth)acrylate] derivative [polyethylene glycol (PEG)-b-(EA-co-MAA)] nanoparticles were stated to be excellent carriers for hydrophobic drugs that could be used orally. The carrier system is reported to exhibit dissociation behavior with increasing pH.23


Chitin is a long-chain polymer derivative [poly (b-(1-4)-N-acetyl-D-glucosamine)] of glucose with significance as the raw material of CS nanocarriers (CSNs). When chitin is deacetylated up to about 50%, it transforms into CS, which has a linear backbone linked through glycosidic bonds.24,25 CS’s efficient bio-adhesiveness and permeabilization capacity make it one of the most popular nanocarrier materials amongst other hydrophilic polymers.26 Moreover, CS is a nanocarrier that has a high loading efficiency of drugs. Based on the protonation of -NH2 at the C-2 position of the D-glucosamine repeat, one of the most important characteristics of CS is its solubility in aqueous acidic media as given in Figure 1.24 Thus, CS nanocapsules provide an effective solution for the delivery of hydrophobic drugs.27 All the mentioned features of CS nanoparticles make it an excellent nanocarrier material.

Moreover, CS exhibits pH-sensitive behavior due to the percentage of its acetylated monomers and their distribution in the chains.28 This behavior is utilized for controlled drug release by scientists. A common example for this is drug delivery to tumor cells and controlling release since the pH of tumor cells is significantly lower than that of healthy cells.29 A summary of the literature that features CSNs as drug delivery systems is provided in Table 2 in chronological order. Production methods for CS carriers differ however, the most common method used being ionotropic gelation, which is based on the capability of polyelectrolytes to crosslink in the presence of counter ions.30

As can be seen in Table 2, Fernández-Urrusuno et al.31 proposed the use of CS nanoparticles as potential drug carriers for transmucosal delivery in 1999. In their design the team loads insulin into CS nanoparticles to be given nasally to conscious normoglycemic rabbits. It is reported that there was a 40% reduction in the serum glucose levels.31 Aktaş et al.34 reported the use of PEG-grafted CS nanoparticles as peptide drug carriers. They observed nanoparticle formation through intermolecular hydrogen bonding in an aqueous solution. The incorporation and release of insulin were dependent on the degree of introduction of the PEG chain on CS and observed sustained release phenomenon over time.52,53 Pérez-Álvarez et al.51 reported one of the most recent studies in this field revealing the state of art in 2019. Their work exploits the designed CSN as a great candidate for polyoxometalate delivery into tumoral cells. CSN production is achieved by dissolving low molecular weight CS in 1% (v/v) acetic acid solutions for crosslinking in inverse microemulsion medium, which results in the attainment of nanometric CS gel particles. Utilizing the pH-sensitive characteristics the team managed to inhibit cytotoxic drug release.51


Professor Andre Geim and Professor Kostya Novoselov made a groundbreaking disclosure by finally discovering a production method for GR in 2004. The research was outstanding since it had not been possible previously to produce a single layer of graphite (carbon atoms with sp2 bonds in the shape of honeycomb). Later, GR became known as the basic building block of graphitic materials such as spherical nanoparticles that are also known as 0D fullerenes, 1D carbon nanotubes, and 3D graphite.54,55,56,57,58

Following the discovery, scientists began to reveal GR’s unique characteristics provided by its submicron dimension and the π-conjugation in its structure. GR is revealed to exhibit extraordinary thermal, mechanical, and electrical properties.57 Further research provided a better understanding of the physical and chemical structure of GR’s surface, which has created interest in medical and pharmaceutical technologies as well as other fields of science. GR is researched and utilized for nanoscaffolds, chemical/biosensing, imaging, drug delivery and controlled drug release.59 In the area of nanomedicine and nanocarriers, GR and its composites are important due to its large surface area where every single atom is exposed on the surface (2600 m2 g-1), layer number, lateral dimension, surface chemistry, and purity.60,61,62 Hereby, GR could be considered a superior candidate as an ideal nanocarrier with the mentioned characteristics that allows a high drug load capacity.58

One of the most popular derivatives of GR is GO, GR with oxygen-containing functionalities (epoxide, carbonyl, carboxyl, and hydroxyl groups). GR and GO have a major difference that affects their drug delivery performance when used as nanocarriers: GO is highly hydrophilic, whereas GR is hydrophobic so that it requires surface modifications for use in biological fluids. Thus, any nanocarrier design that uses GR should take into consideration the possible impurities and negative effects such as cytotoxicity.61,63 This leads researchers to gravitate towards GO-containing designs rather than GR nanocarrier designs.

In Table 3, a summary of GR/GO nanocarrier designs is given. As can be seen, Hummer’s method for production is the most popular choice, where graphite oxidative exfoliation is applied with NaNO3. Although Hummer’s production method is usually opted for rather than other complicated methods, over the years it can be seen that nanocarrier designs have evolved into more complex systems that apply chemotherapy and photothermal therapy for treating cancer.

In 2008, Liu et al.87 published a study that demonstrates PEG-functionalized GO nanocarriers used as a noncovalent physisorption chemotherapy drug delivery system. The team reveals that the nanocarriers have an adequate in vitro cellular uptake capacity.87 A very recent study by Bullo et al.88 examined the state of the art in GO nanocarriers. GO is reported to be synthesized by Hummer’s method. GO is modified with PEG for higher biocompatibility and loaded with two chemotherapeutic drugs: protocatechuic acid and chlorogenic acid. The carrier is then coated with folic acid to target cancer cells since tumor surface membranes have a greater number of folate receptors. The final size of the nanocarrier system is stated to be 9-40 nm with a median of 8 nm. The team reveals that drug release of this design took more than 100 h, which ensures a steady therapeutic effect.88


Nanocarriers designed with a polymer foundation have a certain advantage in terms of the wealth of possible chemical modifications, including the synthesis of block and comb polymers.89 Designs that use SLNs exploit this advantage by combining the advantages and avoiding the disadvantages of other colloidal carriers.

Lipids are defined as molecules that are hydrophobic or consisting of both hydrophilic and hydrophobic parts that are insoluble in water and soluble in organic solvents.90 IUPAC gave the following further detailed definition in 1995:

A loosely defined term for substances of biological origin that are soluble in nonpolar solvents. They consist of saponifiable lipids, such as glycerides (fats and oils) and phospholipids, as well as nonsaponifiable lipids, principally steroids.”91

SLNs are developed by researchers as a substitute colloidal carrier with a spherical morphology for drug delivery and drug release.5 SLNs have an average size of between 150 and 300 nm but could reach up to 1000 nm according to the surfactant used during production and are composed of roughly 0.1-30 (% w/w) solid fat.92 Size and solid to liquid fat ratio affect the long-term stability, drug-loading capacity, and drug-release behavior of SLNs.93 As mentioned, SLNs have several favored assets such as low to no toxic effect on healthy tissue and ease of production in greater units of production, ability to load both lipophilic and hydrophilic therapeutic agents, and high drug load capacity.5 The most common use of SLNs as nanocarriers is for oral drug delivery. Other than this example, several drugs have been loaded using SLNs for drug delivery, such as doxorubicin and idarubicin,94 thymopentin,95 and camptothecin.96


Nanocarriers provide researchers with a highly applicable alternative method for targeted drug delivery and controlled drug release. The first and foremost reason that nanocarriers have become such a great focus in pharmaceutical technologies is that nanomaterials demonstrate extraordinary characteristics when compared with their larger scaled forms. These characteristics are summarized in this review as color, visible light, reactivity, surface area to volume ratio, conductivity, and surface tension. A variety of these carriers are more popular due to their high biocompatibility, ensuring greater efficacy especially in cancer treatments. Successful applications have not only ensured a greater focus on therapeutic development but also created a new solution available in the pharmaceutical market. In this paper, nanocarrier materials that have gained the most attention in drug delivery and release are summarized under the titles of nanohydrogels carriers, CSNs, GR and GO nanocarriers, and SLNs. Besides these nanomaterials there are also a great number of different nanocarrier designs that are not included in this review, such as gold nanocarriers,97 starch and/or cellulose nanocarriers,98 cerium oxide nanocarriers,99 and carbon nanotube incorporated nanocarriers.100 It is clear that, with further information gathered on nanocarriers for drug delivery and the current state in the development process of these nanomaterials, there is a high possibility to deliver better treatment to patients desperate in need of efficient treatment strategies.

Conflict of interest: No conflict of interest was declared by the authors.

  1. Grimsdale AC, Müllen K. The chemistry of organic nanomaterials. Angew Chem Int Ed Engl. 2005;44:5592-5629.
  2. EU Definition of a Nanomaterial [Internet]. [cited 2019 May 27]. Available from:
  3. Nalwa HS. A special issue on reviews in nanomedicine, drug delivery and vaccine development. J Biomed Nanotechnol. 2014;10:1635-1640.
  4. Han J, Zhao D, Li D, Wang X, Jin Z, Zhao K. Polymer-based nanomaterials and applications for vaccines and drugs. Polymers (Basel). 2018;10(1).
  5. Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. Eur J Pharm Biopharm. 2000;50:161-177.
  6. Couvreur P, Kante B, Roland M, Guiot P, Bauduin P, Speiser P. Polycyanoacrylate nanocapsules as potential lysosomotropic carriers: preparation, morphological and sorptive properties. J Pharm Pharmacol. 1979;31:331-332.
  7. Kreuter J, Speiser PP. In vitro studies of poly(methyl methacrylate) adjuvants. J Pharm Sci. 1976;65:1624-1627.
  8. De Jong WH, Borm PJ. Drug delivery and nanoparticles: applications and hazards. Int J Nanomedicine. 2008;3:133-149.
  9. Ochekpe NA, Olorunfemi PO, Ngwuluka NC. Nanotechnology and Drug Delivery Part 2: Nanostructures for Drug Delivery. Trop J Pharm Res. 2009;8:275-287.
  10. Lombardo D, Kiselev MA, Caccamo MT. Smart nanoparticles for drug delivery application: development of versatile nanocarrier platforms in biotechnology and nanomedicine. Journal of Nanomaterials. 2019;2019:1-26.
  11. Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer. 2008;49:1993-2007.
  12. Choudhary B, Paul SR, Nayak SK, Qureshi D, Pal K. Synthesis and biomedical applications of filled hydrogels. In: Pal K, Banerjee I, eds. Polymeric Gels: Characterization, Properties and Biomedical Applications (1st ed). United Kingdom; Elsevier, 2018:283-302.
  13. Klouda L, Mikos AG. Thermoresponsive hydrogels in biomedical applications. Eur J Pharm Biopharm. 2008;68:34-45.
  14. Wang ZG, Ding B. DNA-based self-assembly for functional nanomaterials. Adv Mater. 2013;25:3905-3914.
  15. Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat Rev Mater. 2016;1:16071.
  16. Lin CC, Metters AT. Hydrogels in controlled release formulations: network design and mathematical modeling. Adv Drug Deliv Rev. 2006;58:1379-1408.
  17. Brannon-Peppas L, Peppas NA. Equilibrium swelling behavior of pH-sensitive hydrogels. Chemical Engineering Science. 1991;46:715-722.
  18. Garg T, Singh S, Goyal AK. Stimuli-sensitive hydrogels: an excellent carrier for drug and cell delivery. Crit Rev Ther Drug Carrier Syst. 2013;30:369-409.
  19. Liu J, Yin Y. Temperature responsive hydrogels: construction and applications. Polym Sci. 2015;1:1.
  20. Ichikawa H, Fukumori Y. A novel positively thermosensitive controlled-release microcapsule with membrane of nano-sized poly(N-isopropylacrylamide) gel dispersed in ethylcellulose matrix. J Control Release. 2000;63:107-119.
  21. Dalwadi C, Patel G1. Thermosensitive nanohydrogel of 5-fluorouracil for head and neck cancer: preparation, characterization and cytotoxicity assay. Int J Nanomedicine. 2018;13(T-NANO 2014 Abstracts):31-33.
  22. Elsaeed SM, Farag RK, Maysour NS. Synthesis and characterization of pH-sensitive crosslinked (NIPA-co-AAC) nanohydrogels copolymer. J Appl Polym Sci. 2012;124:1947-1955.
  23. Dufresne MH, Garrec DL, Sant V, Leroux JC, Ranger M. Preparation and characterization of water-soluble pH-sensitive nanocarriers for drug delivery. Int J Pharm. 2004;277:81-90.
  24. Rinaudo M. Chitin and chitosan: properties and applications. Progress in Polymer Science. 2006;31:603-632.
  25. Ravi Kumar MNV. A review of chitin and chitosan applications. React Funct Polym. 2000;46:1-27.
  26. de la Fuente M, Csaba N, Garcia-Fuentes M, Alonso MJ. Nanoparticles as protein and gene carriers to mucosal surfaces. Nanomedicine (Lond). 2008;3:845-857.
  27. Calvo P, Remuñán-López C, Vila-Jatu JL, Alonso MJ. Novel hydrophilic chitosan-polyethylene oxide nanoparticles as protein carriers. J. Appl. Polym. Sci. 1997;63:125-132.
  28. Csaba N, Garcia-Fuentes M, Alonso MJ. The performance of nanocarriers for transmucosal drug delivery. Expert Opin Drug Deliv. 2006;3:463-478.
  29. Zhang X, Lin Y, Gillies RJ. Tumor pH and its measurement. J Nucl Med. 2010;51:1167-1170.
  30. Giri TK. Alginate containing nanoarchitectonics for improved cancer therapy. In: Holban AM, Grumezescu AM, eds. Nanoarchitectonics for Smart Delivery and Drug Targeting. Elsevier, 2016;565-588.
  31. Fernández-Urrusuno R, Calvo P, Remuñán-López C, Vila-Jato JL, Alonso MJ. Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharm Res. 1999;16:1576-1581.
  32. Chang YC, Shieh DB, Chang CH, Chen DH. Conjugation of monodisperse chitosan-bound magnetic nanocarrier with epirubicin for targeted cancer therapy. J Biomed Nanotechnol. 2005;1:196-201.
  33. Du J, Sun R, Zhang S, Zhang LF, Xiong CD, Peng YX. Novel polyelectrolyte carboxymethyl konjac glucomannan-chitosan nanoparticles for drug delivery. I. Physicochemical characterization of the carboxymethyl konjac glucomannan-chitosan nanoparticles. Biopolymers. 2005;78:1-8.
  34. Aktaş Y, Yemisci M, Andrieux K, Gürsoy RN, Alonso MJ, Fernandez-Megia E, Novoa-Carballal R, Quiñoá E, Riguera R, Sargon MF, Celik HH, Demir AS, Hincal AA, Dalkara T, Capan Y, Couvreur P. Development and brain delivery of chitosan−PEG nanoparticles functionalized with the monoclonal antibody OX26. Bioconjug Chem. 2005;16:1503-1511.
  35. Prego C, García M, Torres D, Alonso MJ. Transmucosal macromolecular drug delivery. J. Control. Release. 2005;101:151-162.
  36. Maestrelli F, Garcia-Fuentes M, Mura P, Alonso MJ. A new drug nanocarrier consisting of chitosan and hydoxypropylcyclodextrin. Eur J Pharm Biopharm. 2006;63:79-86.
  37. Cuña M, Alonso-Sandel M, Remuñán-López C, Pivel JP, Alonso-Lebrero JL, Alonso MJ. Development of phosphorylated glucomannan-coated chitosan nanoparticles as nanocarriers for protein delivery. J Nanosci Nanotechnol. 2006;6:2887-2895.
  38. Prego C, Fabre M, Torres D, Alonso MJ. Efficacy and mechanism of action of chitosan nanocapsules for oral peptide delivery. Pharm Res. 2006;23:549-556.
  39. Trapani A, Garcia-Fuentes M, Alonso MJ. Novel drug nanocarriers combining hydrophilic cyclodextrins and chitosan. Nanotechnology. 2008;19:185101.
  40. Badawi AA, El-Laithy HM, El Qidra RK, El Mofty H, El dally M. Chitosan based nanocarriers for indomethacin ocular delivery. Arch Pharm Res. 2008;31:1040-1049.
  41. Vyas A, Saraf S, Saraf S. Encapsulation of cyclodextrin complexed simvastatin in chitosan nanocarriers: a novel technique for oral delivery. J Incl Phenom. 2009;66:251-259.
  42. Kavaz D, Odabaş S, Güven E, Demirbilek M, Denkbaş EB. Bleomycin loaded magnetic chitosan nanoparticles as multifunctional nanocarriers. J. Bioact. Compat. Polym. 2010;25:305-318.
  43. Ghosn B, Singh A, Li M, Vlassov AV, Burnett C, Puri N, Roy K. Efficient gene silencing in lungs and liver using imidazole-modified chitosan as a nanocarrier for small interfering RNA. Oligonucleotides. 2010;20:163-172.
  44. Trapani A, Lopedota A, Franco M, Cioffi N, Ieva E, Garcia-Fuentes M, Alonso MJ. A comparative study of chitosan and chitosan/cyclodextrin nanoparticles as potential carriers for the oral delivery of small peptides. Eur J Pharm Biopharm. 2010;75:26-32.
  45. Saboktakin MR, Tabatabaie R, Maharramov A, Ramazanov MA. Synthesis and characterization of superparamagnetic chitosan-dextran sulfate hydrogels as nano carriers for colon-specific drug delivery. Carbohydr. Polym. 2010;81:372-376.
  46. Sanpui P, Chattopadhyay A, Ghosh SS. Induction of apoptosis in cancer cells at low silver nanoparticle concentrations using chitosan nanocarrier. ACS Appl Mater Interfaces. 2011;3:218-228.
  47. Anitha A, Maya S, Deepa N, Chennazhi KP, Nair SV, Tamura H, Jayakumar R. Efficient water soluble O-carboxymethyl chitosan nanocarrier for the delivery of curcumin to cancer cells. Carbohydr. Polym. 2011;83:452-461.
  48. Samarasinghe RM, Kanwar RK, Kanwar JR. The effect of oral administration of iron saturated-bovine lactoferrin encapsulated chitosan-nanocarriers on osteoarthritis. Biomaterials. 2014;35:7522-7534.
  49. da Silva SB, Amorim M, Fonte P, Madureira R, Ferreira D, Pintado M, Sarmento B. Natural extracts into chitosan nanocarriers for rosmarinic acid drug delivery. Pharm Biol. 2015;53:642-652.
  50. Hu YW, Du YZ, Liu N, Liu X, Meng TT, Cheng BL, He JB, You J, Yuan H, Hu FQ. Selective redox-responsive drug release in tumor cells mediated by chitosan based glycolipid-like nanocarrier. J Control Release. 2015;206:91-100.
  51. Pérez-Álvarez L, Ruiz-Rubio L, Artetxe B, Vivanco MD, Gutiérrez-Zorrilla JM, Vilas-Vilela JL. Chitosan nanogels as nanocarriers of polyoxometalates for breast cancer therapies. Carbohydr Polym. 2019;213:159-167.
  52. Kumar MN, Muzzarelli RA, Muzzarelli C, Sashiwa H, Domb AJ. Chitosan chemistry and pharmaceutical perspectives. Chem Rev. 2004;104:6017-6084.
  53. Ahmed TA, Aljaeid BM. Preparation, characterization, and potential application of chitosan, chitosan derivatives, and chitosan metal nanoparticles in pharmaceutical drug delivery. Drug Des Devel Ther. 2016;10:483-507.
  54. Geim AK, Novoselov KS. The rise of graphene. Nat Mater. 2007;6:183-191.
  55. Geim AK. Graphene: status and prospects. Science. 2009;324:1530-1534.
  56. Stankovich S, Dikin DA, Dommett GH, Kohlhaas KM, Zimney EJ, Stach EA, Piner RD, Nguyen ST, Ruoff RS. Graphene-based composite materials. Nature. 2006;442:282-286.
  57. Allen MJ, Tung VC, Kaner RB. Honeycomb carbon: a review of graphene. Chem Rev. 2010;110:132-145.
  58. Liu J, Cui L, Losic D. Graphene and graphene oxide as new nanocarriers for drug delivery applications. Acta Biomater. 2013;9:9243-9257.
  59. Shao Y, Wang J, Wu H, Liu J, Aksay IA, Lin Y. Graphene based electrochemical sensors and biosensors: A review. Electroanalysis 2010;22:1027-1036.
  60. Shen H, Zhang L, Liu M, Zhang Z. Biomedical applications of graphene. Theranostics. 2012;2:283-294.
  61. Wang Y, Li Z, Wang J, Li J, Lin Y. Graphene and graphene oxide: biofunctionalization and applications in biotechnology. Trends Biotechnol. 2011;29:205-212.
  62. Liu Z, Sun X, Nakayama-Ratchford N, Dai H. Supramolecular chemistry on water-soluble carbon nanotubes for drug loading and delivery. ACS Nano. 2007;1:50-56.
  63. Pumera M. Nanotoxicology: the molecular science point of view. Chem Asian J. 2011;6:340-348.
  64. Zhang L, Xia J, Zhao Q, Liu L, Zhang Z. Functional graphene oxide as a nanocarrier for controlled loading and targeted delivery of mixed anticancer drugs. Small. 2010;6:537-544.
  65. Kakran M, Sahoo NG, Bao H, Pan Y, Li L. Functionalized graphene oxide as nanocarrier for loading and delivery of ellagic acid. Curr Med Chem. 2011;18:4503-4512.
  66. Zhang W, Guo Z, Huang D, Liu Z, Guo X, Zhong H. Synergistic effect of chemo-photothermal therapy using PEGylated graphene oxide. Biomaterials. 2011;32:8555-8561.
  67. Misra SK, Kondaiah P, Bhattacharya S, Rao CN. Graphene as a nanocarrier for tamoxifen induces apoptosis in transformed cancer cell lines of different origins. Small. 2012;8:131-143.
  68. Kim H, Lee D, Kim J, Kim TI, Kim WJ. Photothermally triggered cytosolic drug delivery via endosome disruption using a functionalized reduced graphene oxide. ACS Nano. 2013;7:6735-6746.
  69. F an X, Jiao G, Zhao W, Jin P, Li X. Magnetic Fe3O4-graphene composites as targeted drug nanocarriers for pH-activated release. Nanoscale. 2013;5:1143-1152.
  70. Qin XC, Guo ZY, Liu ZM, Zhang W, Wan MM, Yang BW. Folic acid-conjugated graphene oxide for cancer targeted chemo-photothermal therapy. J Photochem Photobiol B. 2013;120:156-162.
  71. Wang Z, Zhou C, Xia J, Via B, Xia Y, Zhang F, Li Y, Xia L. Fabrication and characterization of a triple functionalization of graphene oxide with Fe3O4, folic acid and doxorubicin as dual-targeted drug nanocarrier. Colloids Surf B Biointerfaces. 2013;106:60-65.
  72. Zhou T, Zhou X, Xing D. Controlled release of doxorubicin from graphene oxide based charge-reversal nanocarrier. Biomaterials. 2014;35:4185-4194.
  73. Song E, Han W, Li C, Cheng D, Li L, Liu L, Zhu G, Song Y, Tan W. Hyaluronic acid-decorated graphene oxide nanohybrids as nanocarriers for targeted and pH-responsive anticancer drug delivery. ACS Appl Mater Interfaces. 2014;6:11882-11890.
  74. Feng L, Li K, Shi X, Gao M, Liu J, Liu Z. Smart pH-responsive nanocarriers based on nano-graphene oxide for combined chemo- and photothermal therapy overcoming drug resistance. Adv Healthc Mater. 2014;3:1261-1271.
  75. Xu Z, Zhu S, Wang M, Li Y, Shi P, Huang X. Delivery of paclitaxel using pegylated graphene oxide as a nanocarrier. ACS Appl Mater Interfaces. 2015;7:1355-1363.
  76. Tran TH, Nguyen HT, Pham TT, Choi JY, Choi HG, Yong CS, Kim JO. Development of a graphene oxide nanocarrier for dual-drug chemo-phototherapy to overcome drug resistance in cancer. ACS Appl Mater Interfaces. 2015;7:28647-28655.
  77. Kundu A, Nandi S, Das P, Nandi AK. Fluorescent graphene oxide via polymer grafting: an efficient nanocarrier for both hydrophilic and hydrophobic drugs. ACS Appl Mater Interfaces. 2015;7:3512-3523.
  78. Chauhan G, Chopra V, Tyagi A, Rath G, Sharma RK, Goyal AK. “Gold nanoparticles composite-folic acid conjugated graphene oxide nanohybrids” for targeted chemo-thermal cancer ablation: in vitro screening and in vivo studies. Eur J Pharm Sci. 2017;96:351-361.
  79. He H, Li S, Shi X, Wang X, Liu X, Wang Q, Guo A, Ge B, Khan NU, Huang F. Quantitative nanoscopy of small blinking graphene nanocarriers in drug delivery. Bioconjug Chem. 2018;29:3658-3666.
  80. Karimzadeh Z, Javanbakht S, Namazi H. Carboxymethylcellulose/MOF-5/graphene oxide bio-nanocomposite as antibacterial drug nanocarrier agent. Bioimpacts. 2019;9:5-13.
  81. Javanbakht S, Pooresmaeil M, Namazi H. Green one-pot synthesis of carboxymethylcellulose/Zn-based metal-organic framework/graphene oxide bio-nanocomposite as a nanocarrier for drug delivery system. Carbohydr Polym. 2019;208:294-301.
  82. Tiwari H, Karki N, Pal M, Basak S, Verma RK, Bal R, Kandpal ND, Bisht G, Sahoo NG. Functionalized graphene oxide as a nanocarrier for dual drug delivery applications: the synergistic effect of quercetin and gefitinib against ovarian cancer cells. Colloids Surf B Biointerfaces. 2019;178:452-459.
  83. Makharza SA, Cirillo G, Vittorio O, Valli E, Voli F, Farfalla A, Curcio M, Iemma F, Nicoletta FP, El-Gendy AA, Goya GF, Hampel S. Magnetic graphene oxide nanocarrier for targeted delivery of cisplatin: a perspective for glioblastoma treatment. Pharmaceuticals (Basel). 2019;12(2).
  84. Abdollahi Z, Taheri-Kafrani A, Bahrani SA, Kajani AA. PEGAylated graphene oxide/superparamagnetic nanocomposite as a high-efficiency loading nanocarrier for controlled delivery of methotrexate. J Biotechnol. 2019;298:88-97.
  85. Dhanavel S, Revathy TA, Sivaranjani T, Sivakumar K, Palani P, Narayanan V, Stephen A. 5-Fluorouracil and curcumin co-encapsulated chitosan/reduced graphene oxide nanocomposites against human colon cancer cell lines. Polym Bull. 2019 Mar 15. doi:10.1007/s00289-019-02734-x
  86. Vinothini K, Rajendran NK, Munusamy MA, Alarfaj AA, Rajan M. Development of biotin molecule targeted cancer cell drug delivery of doxorubicin loaded κ-carrageenan grafted graphene oxide nanocarrier. Mater Sci Eng C Mater Biol Appl. 2019;100:676-687.
  87. Liu Z, Robinson JT, Sun X, Dai H. PEGylated nanographene oxide for delivery of water-insoluble cancer drugs. J Am Chem Soc. 2008;130:10876-10877.
  88. Bullo S, Buskaran K, Baby R, Dorniani D, Fakurazi S, Hussein MZ. Dual drugs anticancer nanoformulation using graphene oxide-PEG as nanocarrier for protocatechuic acid and chlorogenic acid. Pharm Res. 2019;36:91.
  89. Mehnert W, Mäder K. Solid lipid nanoparticles. Advanced Drug Delivery Reviews. 2012;64:83-101.
  90. Gordillo-Galeano A, Mora-Huertas CE. Solid lipid nanoparticles and nanostructured lipid carriers: a review emphasizing on particle structure and drug release. Eur J Pharm Biopharm. 2018;133:285-308.
  91. Moss GP, Smith PAS, Tavernier D. Glossary of class names of organic compounds and reactivity intermediates based on structure (IUPAC Recommendations 1995). Pure &App Chem. 1995;67:1307-1375.
  92. Naseri N, Valizadeh H, Zakeri-Milani P. Solid lipid nanoparticles and nanostructured lipid carriers: structure, preparation and application. Adv Pharm Bull. 2015;5:305-313.
  93. Yoon G, Park JW, Yoon IS. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs): recent advances in drug delivery. J Pharm Investig. 2013;43:353-362.
  94. Cavalli R, Caputo O, Gasco MR. Solid lipospheres of doxorubicin and idarubicin. Int J Pharm.  1993;89:R9-R12.
  95. Morel S, Ugazio E, Cavalli R, Gasco MR. Thymopentin in solid lipid nanoparticles. Int J Pharm. 1996;132:259-261.
  96. Yang S, Zhu J, Lu Y, Liang B, Yang C. Body distribution of camptothecin solid lipid nanoparticles after oral administration. Pharm Res. 1999;16:751-757.
  97. Choi WI, Kim JY, Kang C, Byeon CC, Kim YH, Tae G. Tumor regression in vivo by photothermal therapy based on gold-nanorod-loaded, functional nanocarriers. ACS Nano. 2011;5:1995-2003.
  98. Kang B, Okwieka P, Schöttler S, Winzen S, Langhanki J, Mohr K, Opatz T, Mailänder V, Landfester K, Wurm FR. Carbohydrate-based nanocarriers exhibiting specific cell targeting with minimum influence from the protein corona. Angew Chem Int Ed Engl. 2015;54:7436-7440.
  99. Sack M, Alili L, Karaman E, Das S, Gupta A, Seal S, Brenneisen P. Combination of conventional chemotherapeutics with redox-active cerium oxide nanoparticles—a novel aspect in cancer therapy. Mol Cancer Ther. 2014;13:1740-1749.
  100. Hampel S, Kunze D, Haase D, Krämer K, Rauschenbach M, Ritschel M, Leonhardt A, Thomas J, Oswald S, Hoffmann V, Büchner B. Carbon nanotubes filled with a chemotherapeutic agent: a nanocarrier mediates inhibition of tumor cell growth. Nanomedicine (Lond). 2008;3:175-182.