Nanocarriers Used Most in Drug Delivery and Drug Release: Nanohydrogel, Chitosan, Graphene, and Solid Lipid/Ilac Dagitim ve Ilac Saliminda En Cok Kullanilan Nanotasiyicilar: Nanohidrojel, Kitosan, Grafen ve Kati Lipit.
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. (11-13) 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 Fukumori (20) 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 Fukumori (20) stated that the mentioned shell could change and revert to its initial size with temperature changes between 30[degrees]C and 50[degrees]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 Patel (21) produced MC nanohydrogels by a tip probesonicator 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[R]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 -N[H.sub.2] 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, Fernandez-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) Aktas 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) Perez-Alvarez 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
GRAPHENE AND GRAPHENE OXIDE NANOCARRIERS
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. (54-58)
Following the discovery, scientists began to reveal GR's unique characteristics provided by its submicron dimension and the [pi]-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 [m.sup.2] [g.sup.-1]), layer number, lateral dimension, surface chemistry, and purity. (60-62) 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 NaN[O.sub.3]. 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)
SOLID LIPID NANOPARTICLES
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." (9)
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)
DISCUSSION AND CONCLUSION
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.
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[iD] Sibel Aysil OZKAN (1*), [iD] Aylin DEDEOGLU (1), [iD] Nurgul KARADAS BAKIRHAN (2), [iD] Yalcin OZKAN (3)
(1) Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, Ankara, Turkey
(2) University of Health Sciences, Gulhane Faculty of Pharmacy, Department of Analytical Chemistry, Ankara, Turkey
(3) University of Health Sciences, Gulhane Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara, Turkey
(*) Correspondence: E-mail: firstname.lastname@example.org, Phone: +90 533 818 36 35 ORCID: orcid.org0000-0001-7494-3077
Received: 13.06.2019, Accepted: 01.08.2019
Table 2. A literature summary of CSNs Date Drug Nanocarrier design & advantages 1999 Insulin Blood glucose control nasal absorption pH selective release 2005 Epirubicin Chemotherapy chitosan-bound magnetic nanocarrier 2005 BSA Carboxymethyl konjac glucomannan--chitosan nanoparticles 2005 Z-DEVD-FMK Cerebral Ischemia Therapy CS-PEG-BIO-SA/OX26 2005 Insulin Oral/Nasal Drug Carrier CS nanoparticles, CS nanocapsules and CS-coated lipid nanoparticles 2006 Triclosan Higher solubility in water hydroxypropyl Furoscmide cyclodextrin containing chitosan nanocarrier 2006 Protein complex P1 Transmucosal drug carrier glucomannan-coated chitosan nanoparticles 2006 Salmon calcitonin Oral drug carrier carrier for peptide drugs through the intestinal epithelium 2007 - Transmucosal drug carrier hydrophilic cyclodextrin-chitosan core and chitosan coating 2008 Indomethacin Ophthalmic Drug Delivery 2009 HP-b-CD complex Oral delivery of drugs that are insoluble in simvastatin water 2010 Bleomycin Chemotherapy [Fe.sub.3][O.sub.4] containing chitosan nanoparticles 2010 siRNA PEGylated Chitosan Nanocarriers Imidazole-modified chitosan-IAA nanoparticles 2010 Glutathione Oral Drug Carrier Chitosan and Chitosan /cyclodextrin NPs 2010 Mesalazine Colon Specific Drug Delivery Superparamagnetic chitosan-dextran sulfate NPs 2011 Silver NPs Colon Cancer Apoptosis Chitosan-based nanocarrier of silver NPs 2011 Curcumin Hydrophobic drug delivery for cancer treatment Carboxymethyl chitosan nanocarriers 2014 100% iron Osteoarthritis treatment saturated-bovine lactoferrin 2014 Rosmarinic acid Antioxidant delivery 2015 Paclitaxel Chitosan based glycolipid-like nanocarrier 2019 Polyoxometalates Breast cancer therapy pH selective release Date Drug CS nanoparticle production Reference 1999 Insulin Ionotropic gelation with 31 Pentasodium tri-polyphosphate 2005 Epirubicin Carboxymethylated Chitosan 32 covalently bound onto Fe3O4 nanoparticles 2005 BSA Dropping method 33 2005 Z-DEVD-FMK Chitosan acetylation 13.7% 34 2005 Insulin Ionotropic gelation 35 2006 Triclosan Ionotropic gelation 36 Furoscmide 2006 Protein complex P1 Ionotropic gelation 37 2006 Salmon calcitonin Ionotropic gelation 38 2007 - Ionotropic gelation 39 2008 Indomethacin Ionotropic gelation by 40 addition of TPP anions 2009 HP-b-CD complex Ionotropic gelation 41 simvastatin with Pentasodium tri-polyphosphate 2010 Bleomycin Ionotropic gelation 42 with Pentasodium tri-polyphosphate 2010 siRNA Complex coacervation of 43 nonmodified chitosan or chitosan-IAA with siRNA 2010 Glutathione Ionotropic gelation 44 2010 Mesalazine Ionotropic gelation 45 2011 Silver NPs Ionotropic gelation 46 with Pentasodium tri-polyphosphate 2011 Curcumin Ionic cross linking between 47 carboxyl group 2014 100% iron - 48 saturated-bovine lactoferrin 2014 Rosmarinic acid Ionotropic gelation 49 with Pentasodium tri-polyphosphate 2015 Paclitaxel 50 2019 Polyoxometalates Crosslinked in inverse 51 microemulsion medium CSN: Chitosan nanocarriers Table 3. A literature summary of GR/GO nanocarriers Date Drug Nanocarrier 2010 Camptothecin (CPT) FA-GONS-p-amino Doxorubicin (DOX) benzenesulfonic acid 2011 Ellagic acid (EA) GONS-Pluronic F38(F38), GONS - Tween 80(T80), GONS-Maltodextrin (MD) 2011 Doxorubicin (DOX) PEG-GONS 2011 Tamoxifen Citrate Pyridinium bromide (TmC) (PY+-Chol)-Graphene (GR) 2013 Doxorubicin (DOX) Polyethylene Glycol-Branched Polyethyleneimine-Reduced GO (PEG-BPEI-rGO) 2013 5-fluorouracil (5-FU) Fe3O4-GONS 2013 Doxorubicin (DOX) PVP-GONS-FA 2013 Doxorubicin (DOX) FA-GONS-Chitosan (CHI) 2014 Doxorubicin (DOX) GO/integrin aVb3 mono-antibody (Abs) /polyethyleneimine (PEI)/citraconic anhydride functionalized poly(allylamine) (PAH-Cit) 2014 Doxorubicin (DOX) Hyaluronic acid (HA)-GONS 2014 Doxorubicin (DOX) PEG-Poly (allylamine hydrochloride) (PAH)-2,3-dimethylmaleic anhydride (DA)-GONS 2015 Paclitaxel (PTX) PEG-GO 2015 Irinotecan (IRI) Poloxamer 188-GONS Doxorubicin (DI) 2015 Indomethacin (IMC) poly(N-isopropylacrylamide) Doxorubicin (DOX) (PNIPAM)-GO 2016 Doxorubicin (DOX) Gold Nanoparticle (AuNP) - Folic Acid-GONS 2018 Doxorubicin (DOX) Folic acid (FA)-Graphene Oxide Camptothecin (CPT) Nanosheet (GONS) 2018 Tetracycline (TC) Carboxymethylcellulose(CMC)-Zn-Based Metal-Organic Framework (MOF-5)-GO 2018 Doxorubicin (DOX) Carboxymethylcellulose (CMC)-Zn-Based Metal-Organic Framework (MOF-5)-GONS 2019 Quercetin (QSR) Polyvinylpyrrolidone Gefitinib (GEF) (PVP)-GO 2019 Cis Maghemitey-F[e.sub.2] -diamminedichloroplatinum [O.sub.3]-GO (II) (CisPt) 2019 Methotrexate (MTX) Polyethylene Glycol bis Amin (PEGA)- GO Magnetic NS (GOMNS) 2019 5-Fluorouracil (5-FU) Chitosan-rGO Curcumin (CUR) 2019 Doxorubicin (DOX) K-Carrageenan (K-Car)-GONS-biotin Date Nanocarrier design & GR or go Nanocarrier size advantages synthesis on average 2010 Sulfonic acid groups Hummer's GONS (thickness) render stability in method < 150 nm physiological solutions Target: human breast cancer cells 2011 High drug loading (For Hummer's GONS-F38 GO-T80, 1.22 g per 1 g) method (thickness)=6-7 nm GONS-T80 (thickness)=7-8 nm GONS-MD (thickness) =5-6 nm 2011 Both chemotherapy Hummer's and near infrared (NIR) method photothermal therapy Lower systematic toxicity 2011 Enhanced the apoptosis - PY+-Chol-GR of cancer cells (hydrodynamic diameter)=150-200 nm 2013 Photothermally Reduction 100-200 nm controlled anti-cancer by hydrazine drug delivery monohydrate Higher cancer cell death 2013 pH dependent Hummer's chemotherapy method High drug loading capacity of up to 0.35 mg [mg.sup.-1] 2013 pH sensitive nanocarrier Hummer's GONS=100 nm Both chemotherapy method and near infrared (NIR) photothermal therapy 2013 High drug loading Hummer's efficiency (0.98 mg/mg) method & prolonged drug release rate pH sensitive drug release 2014 Charge-reversal, target Hummer's GO/PEI/PAH-Cit specific nanocarrier method /DOX=20-200 nm Drug release in acidic intracellular organelles 2014 Targeted and pH Hummer's GONS sensitive drug delivery method (lateral)=10-200 High loading efficiency nm of drug (42.9%) 2014 pH sensitive drug Hummer's PEG-PAH-DA release method -GONS=70 nm Both chemotherapy and photothermal therapy 2015 Nontoxic chemotherapy Hummer's PEG-GO-PTX carrier method (lateral)=50-200 Increased biocompatibility nm and physiological stability 2015 Photothermal Hummer's GONS=200 nm therapy with dual method chemotherapies in one system 2015 Enhanced thermal Hummer's GONS=0.85 nm stability method NIPAM-GONS=3.2 Improved dispersibility in nm aqueous and cell medium 2016 Targeted chemotherapy AuNP-FA-GONS and photothermal (Hydrodynamic ablation size)=188.2[+ or -] 7.2 nm AuNP-GO (diagonal)=135 nm 2018 FA linked GONS for high Hummer's 2.7 nm affinity to method folate receptor 2018 Efficient oral drug Hummer's CMC/MOF-5/GO delivery method (diameter)=344 nm Effective protection against stomach pH 2018 Targeted delivery and Hummer's GONS controlled release of method (Thickness)=30 nm chemotherapy human CMC/MOF-5 blood cancer cell lines /GONS=80 nm 2019 High biocompatibility Hummer's GO=166.5 nm Enhanced anticancer method PVP-GO=300-400 activity within a dosage nm range 2019 Efficient Malignant Hummer's GO (width)=80-100 glioma chemotherapy method nm GONP accumulates in GO (thickness)=6.3 U87 human glioblastoma nm subcutaneous tumor xenografts 2019 Magnetic Iron NPs Hummer's Increased efficacy in method chemotherapy with pH dependent drug release and biocompatibility 2019 Increased efficiency of - - chemotherapy against colon cancer 2019 Targeted therapy for Hummer's x-Car-GONS-biotin cervical cancer method (thickness)=219 nm pH-sensitive drug release Date Reference 2010 64 2011 65 2011 66 2011 67 2013 68 2013 69 2013 70 2013 71 2014 72 2014 73 2014 74 2015 75 2015 76 2015 77 2016 78 2018 79 2018 80 2018 81 2019 82 2019 83 2019 84 2019 85 2019 86