**3. Various nanoscale drug delivery systems**

#### **3.1. Nanoparticles**

Indian craftsman and artisan used nanotechnology for designing weapons in early times. The first observation and size measurement of nanoparticle were carried out using an ultra microscope by Richard Zsigmondy in 1902. The term nanotechnology was first time used by a researcher named Norio Taniguchi in University of Tokyo in 1974. In 1980 the inventions of two atoms further advanced the field of Nanotechnology. In 1985 fullerene C60 was discovered by Kroto's and Smalley's research team. In 1991 carbon tubes were discovered by Saumio lijima and by 2000 National Nanotechnology Initiative (NNI), The United States was launched which

Nanotechnology may be considered as one of the main propellants for technological, econom‐ ical change as industrial competeition. Nanotechnology has integrated various disciplines including biomedicine, engineering and technology. Nanotechnology is being used for improving the existing products and to create new products. The strength can be varied accordingly with the requirements of engineering. It can be used to make the water cleaner by remediation to remove its pollutant. It has helped to clean the environment by removing pollutants and has generated cleaner and cheaper energy. It has improved the healthcare system by introducing new devices for diagnosis, monitoring, treatment of diseases and drug-

Nanomaterials have wide applications in pharmaceutical sciences and technology. Few other predominant areas of use of nanotechnology are in drug delivery, and as diagnostic imaging and biosensor. These devices of nanoscale size are popularly known as nanomedicine. Thus nanomedicines are sub-micron size materials (<1μm) which are used for treatment, monitoring and diagnostic purposses. In the present chapter we will discuss on the current status and

There are many reasons for which nanoscale size drug delivery systems are attractive to formulation scientists. The most important reason is that number of surface atoms or molecules to the total number of atoms or molecules increases in drug delivery systems. Thus the surface area increases. This helps to bind, adsorb and carry with other com‐ pounds such as drug, probes and proteins. The drug particles itself can be engineered to form nanoscale size materials too [4]. The nanosize device systems, sizes smaller than eukaryotic or prokaryotic cells, can eventually much more in amount reach in generally inaccessible areas such as cancer cells, inflamed tissues etc. due to their enhanced permea‐ bility and retention effect (EPR) and can impair lymphatic drainage thus that can be used for administration of genes, proteins through the peroral route of administration [5]. They can be used to target the reticuloendothelial cells, thereby facilitating passive targeting of drug to the macrophages of liver and spleen and thus enabling a natural system for treating intracellular infections [6]. The nanomaterials used for the purpose should be soluble, safe and biocompatible as well as bioavailable. They should not occlude blood vessel and less invasive and the toxicity associated with the nanomaterials for drug delivery should be

paved the way for future development in nanotechnology [2].

526 Application of Nanotechnology in Drug Delivery

future strategies of nanosize drug delivery systems.

**2. Significance of nanomaterials in drug delivery**

delivery [1].

Nanoparticles are submicron-sized polymeric colloidal particles with therapeutic agents of interest encapsulated or dispersed within their polymeric matrix or adsorbed or conjugated onto the surface. Commonly used synthetic polymers to prepare nanoparticles for drug delivery are generally biodegradable [10]. Nanoparticles may also be composed of or transport a variety of substances such as silica, gold or other heavy metals, medicaments, quantum dots, nanocrystals, quantum rods and various contrast agents [11]. Nanoparticle systems offer major improvements in therapeutics through site specificity, their ability to escape from multi-drug resistance and the efficient delivery of an agent. They can be used for active drug targeting attaching ligand such as antibody on their surface (Figure 1).

Solid lipid nanoparticles (SLNs) refer to as lipospheres or solid lipid nanospheres, or particles and are generally solid at human physiological temperature (37o C) and have a diameter less than 1000 nm [12]. They can be formed from a range of lipids, including mono-, di- and triglycerides, fatty acids, waxes and combinations there of. SLNs must be stabilized by surfactants to form administrable emulsions. SLNs form a strongly lipophilic matrix into which drugs can be loaded for subsequent release. SLNs have been investigated for the delivery of various cancer treatments like colon cancer, breast cancer [13].

Polymer-based nanoparticles have been extensively investigated as drug nanocarriers. The most widely researched synthetic polymers include polylactide (PLA), poly (D,L-lactide-co-

**Figure 2.** Endocytosis mediated cellular internalization of drug nanocarriers

Nanoliposomes are the nanosize vesicles made of bilayered phospholipid membranes generally unilamellar with an aqueous interior (Figure 1)[17]. They can be used for the delivery of low molecular weight drugs, imaging agents, peptides, proteins, and nucleic acids. Different anticancer, antiviral drugs are incorporated within the liposomes [18]. Nanoliposomes can also provide slow release of an encapsulated drug, resulting in sustained exposure to the site of action and enhanced efficacy. Usually hydrophilic drugs can be loaded in aqueous compart‐ ment and lipophilic drugs are incorporated in the phospholipid layer [19]. However unlike liposome nanoliposome does not undergo rapid degradation and clearance by liver macro‐ phages. As for the targeted drug delivery, nanoliposome plays an important role. It can be used for passive targeting or active targeting [20]. Due to the leaky vascular structure of the tumor tissue nanoliposomes get predominantly accumulated in the tumor and release the drug for a prolonged period of time in passive targeting. Active targeting is achieved by incorpo‐ rating antibody, ligands etc. on the nanoliposomal surface. By active targeting liposomes directly go to the targeted organs or tissues, and release drug for a prolonged period of time, so that the normal cells are not affected and only the diseased cells are affected [21]. Targeted nanoliposomal drug delivery is more efficacious than the non-targeted drug delivery systems. C6-ceremide ligand induced nanoliposome used to treat the blood cancer directly targets the over expressed lukemic cells and decreases the high epxpression of survivin protein in leukemic cells [22]. The concept of long-circulating or sterically stabilized nanoliposomes is derived for novelibility of delivery systems which can circulate in the blood for a long period of time. Nanoliposomal formulations containing polyethylene glycol (PEG) alter the pharma‐

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*3.1.1. Nanoliposomes*

**Figure 1.** Different Types of Nanocarriers for drug delivery

glycolide) (PLGA) and poly ethylene glycol (PEG). All three polymers are hydrolized *in vivo* and are biodegradable. Other polymers based on biological polysaccharides have been extensively investigated, including chitosan, Clycodextrin and dextrans [14].

Gold nanoparticles (NPs) consist of a core of gold atoms that can be functionalized by addition of a monolayer of moieties containing a thiol (SH) group. Gold NPs can be synthesized using NaBH4 to reduce AuCL4 salts in the presence of thiol containing moieties that subsequently form a monolayer around the core gold atom, depending on the stoichiometric gold/ thiol ratio [15]. Drug delivery using gold NPs has been made in DNA delivery for gene therapy and imaging [16]. PEG coated micelles containing drug are also used to deliver drug as new delivery system (Figure 1). Many other nanoparticulate synthetic, semisynthetic, natural and metals are under investigation to know their poten‐ tials as drug delivery materials.

Polymeric nanoparticles may adhere to the cell surface and release drug molecules by diffusion which may enter inside the cell to work. However the entire polymeric nanoparticles can also enter the cell by endocytosis. They bind with the cell surface receptor and formation of endosome takes place. Endosome may be lysed with the help of lysosomal enzymes and the nanoparticles release in the cytoplasm (Figure 2).

**Figure 2.** Endocytosis mediated cellular internalization of drug nanocarriers

#### *3.1.1. Nanoliposomes*

glycolide) (PLGA) and poly ethylene glycol (PEG). All three polymers are hydrolized *in vivo* and are biodegradable. Other polymers based on biological polysaccharides have been

Gold nanoparticles (NPs) consist of a core of gold atoms that can be functionalized by addition of a monolayer of moieties containing a thiol (SH) group. Gold NPs can be

that subsequently form a monolayer around the core gold atom, depending on the stoichiometric gold/ thiol ratio [15]. Drug delivery using gold NPs has been made in DNA delivery for gene therapy and imaging [16]. PEG coated micelles containing drug are also used to deliver drug as new delivery system (Figure 1). Many other nanoparticulate synthetic, semisynthetic, natural and metals are under investigation to know their poten‐

Polymeric nanoparticles may adhere to the cell surface and release drug molecules by diffusion which may enter inside the cell to work. However the entire polymeric nanoparticles can also enter the cell by endocytosis. They bind with the cell surface receptor and formation of endosome takes place. Endosome may be lysed with the help of lysosomal enzymes and the

salts in the presence of thiol containing moieties


extensively investigated, including chitosan, Clycodextrin and dextrans [14].

synthesized using NaBH4 to reduce AuCL4

**Figure 1.** Different Types of Nanocarriers for drug delivery

528 Application of Nanotechnology in Drug Delivery

nanoparticles release in the cytoplasm (Figure 2).

tials as drug delivery materials.

Nanoliposomes are the nanosize vesicles made of bilayered phospholipid membranes generally unilamellar with an aqueous interior (Figure 1)[17]. They can be used for the delivery of low molecular weight drugs, imaging agents, peptides, proteins, and nucleic acids. Different anticancer, antiviral drugs are incorporated within the liposomes [18]. Nanoliposomes can also provide slow release of an encapsulated drug, resulting in sustained exposure to the site of action and enhanced efficacy. Usually hydrophilic drugs can be loaded in aqueous compart‐ ment and lipophilic drugs are incorporated in the phospholipid layer [19]. However unlike liposome nanoliposome does not undergo rapid degradation and clearance by liver macro‐ phages. As for the targeted drug delivery, nanoliposome plays an important role. It can be used for passive targeting or active targeting [20]. Due to the leaky vascular structure of the tumor tissue nanoliposomes get predominantly accumulated in the tumor and release the drug for a prolonged period of time in passive targeting. Active targeting is achieved by incorpo‐ rating antibody, ligands etc. on the nanoliposomal surface. By active targeting liposomes directly go to the targeted organs or tissues, and release drug for a prolonged period of time, so that the normal cells are not affected and only the diseased cells are affected [21]. Targeted nanoliposomal drug delivery is more efficacious than the non-targeted drug delivery systems. C6-ceremide ligand induced nanoliposome used to treat the blood cancer directly targets the over expressed lukemic cells and decreases the high epxpression of survivin protein in leukemic cells [22]. The concept of long-circulating or sterically stabilized nanoliposomes is derived for novelibility of delivery systems which can circulate in the blood for a long period of time. Nanoliposomal formulations containing polyethylene glycol (PEG) alter the pharma‐ cokinetic properties of various drug molecules leading to long elimination half-life [23]. Nanoliposomes are expected to bring lots of change in drug delivery in near future.

*3.1.3. Nanoshells*

**3.2. Fullerenes and nanotubes**

within the tubes [34].

from pyrimidines [36].

**3.4. Quantum dots**

**3.3. Nanopores**

Nanoshells (100-200 nm) may be used for drug carrier of both imaging and therapy. Nanoshells consist of nanoparticles with a core of silica and a coating of thin metallic shell [29]. They can be targeted to a tissue by using immunological methods. Nanoshells can also be embedded in a hydrogel polymer [30]. Nanoshells are currently being investigated for prevention of micrometastasis of tumors and also for the treatment of diabetes. Nanoshells are useful for

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Fullerenes composed of carbon in the form of a hollow sphere or ellipsoid tube. These are also known as 'bucky balls' because of their resemblance to the geodesic dome design of Buck minster Fuller. Fullerenes are being investigated for drug transport of antiviral drugs, antibiotics and anticancer agents [32]. Fullerenes have the potential to stimulate host immune response and productions of fullerene specific antibodies. Soluble derivatives of fullerenes

Nanotubes are nanometer scale tube like structure and they are of different types like carbon nanotube, inorganic nanotube, DNA nanotube, membrane nanotube etc. [33]. Carbon nano‐ tubes can be made more soluble by incorporation of carboxylic or ammonium groups to their structures and can be used for the transport of peptides, nucleic acids and other drug mole‐ cules. The ability of nanotubes to transport DNA across cell membrane is used in studies involving gene therapy. DNA can be attached to the tips of nanotubes or can be incorporated

Nanopores (20 nm in diameter) consist of wafers with high density of pores which allow entry of oxygen, glucose and other chemicals such as insulin to pass through. Nanopores can be used as devices to protect transplanted tissues from the host immune system, at the same time, utilizing the benefit of transplantation [35]. β-Cells of pancreas can be enclosed within the nanopore device and implanted in the recipient's body. Nanopores can also be employed in DNA sequencing. Nanopores are also being developed with an ability to differentiate purines

Quantum dots (QD) are tiny semiconductor nanocrystals type of particles generally no larger than 10 nanometers that can be made to fluoresce in different colours when stimulated by light. The biomolecule conjugation of the QD can be modulated to target various biomarkers [37]. They can be tagged with biomolecules and used as highly sensitive probes. QD can also be used for imaging of sentinel node in cancer patients for tumour staging and planning of therapy. This technology also outlines some early success in the detection and treatment of breast cancer [38]. QD may provide new insights into understanding the pathophysiology of

diagnostic purposes in whole blood immunoassays [31].

such as C60 have shown great utility as pharmaceutical agents.

cancer and real time imaging and screening of tumors.

#### *3.1.2. Dendrimers*

Dendrimers are branched polymers, resembling the structure of a tree (Figure 1). Dendrimers represent three dimensional highly branched polymeric macromolecules with the diameter varying from 2.5 to 10 nm. It can be synthesized from both synthetic and natural monomers e.g. aminoacids, monosaccharides and nucleotides. Two classes of dendrimers commonly used for biomedical applications are polyamidoamines and polypropyleneimines [24]. A dendrimer is typically symmetric around the core, and when sufficiently extended it often adopts a spheroidal three-dimensional morphology in water. A central core can be recognized in their structure with at least two identical chemical functionalities. Starting from those groups, repeated units of other molecules can originate with at least one junction of branching. The repetitions of chains and branching result in a series of radially concentric layers with increased crowding [25].

The overall shapes of dendrimers range from spheres to flattened spheroids (disks) to amoebalike structures, especially in cases where surface charges exist and give the macromolecule a ''starfish''-like shape. Branching of dendrimers depends on the synthesis processes. Low molecular weight drugs can be placed into the cavities within the dendrimer molecules and are temporarily immobilized there with hydrophobic forces, hydrogen and covalent bonds [26]. The two processes for the synthesis of dendrimers are divergent and convergent methods. In the divergent method dendrimer grows outwords from a multifunctional core molecule. The core molecule reacts with monomer molecules containing one reactive and two dormant groups giving the first generation dendrimer. The convergent method is developed as a response to the weakness of the divergent synthesis. In the convergent approach, the den‐ drimer is constructed stepwise, starting from the end groups and progressing inwards. When the growing branched polymeric arms, called dendrons, are large enough, they are attached to a multifunctional core molecule. The convergent method is relatively easy to purify the desired product and the occurrence of defects in the final structure is minimised [27]. Due to classical polymerization dendrimers have a negligible degree of polydispersity. They are random in nature and produce molecules of various sizes. The size of dendrimers can be carefully controlled during the process of synthesis of dendrimers. Scientists are focusing on newer approaches for speeding up the synthesis process by preassembly of oligomeric branches which can be linked together to reduce the number of synthesis steps involved and also increase the dendrimer yield [28].

Dendrimers are popularly used for transfer of genetic materials in cancer therapy or other viral diseases in different organs because of their monodisperisity, high density of functional groups, well-defined shape and multivalency. In gene delivery polyamidoamines (PAMAM) dendrimer is widely used. Some other types of dendrimers are peptide dendrimers, glyco‐ dendrimers, polypropilimine dendrimers, Polyethyleneimine (PEI) dendrimers etc.

### *3.1.3. Nanoshells*

cokinetic properties of various drug molecules leading to long elimination half-life [23].

Dendrimers are branched polymers, resembling the structure of a tree (Figure 1). Dendrimers represent three dimensional highly branched polymeric macromolecules with the diameter varying from 2.5 to 10 nm. It can be synthesized from both synthetic and natural monomers e.g. aminoacids, monosaccharides and nucleotides. Two classes of dendrimers commonly used for biomedical applications are polyamidoamines and polypropyleneimines [24]. A dendrimer is typically symmetric around the core, and when sufficiently extended it often adopts a spheroidal three-dimensional morphology in water. A central core can be recognized in their structure with at least two identical chemical functionalities. Starting from those groups, repeated units of other molecules can originate with at least one junction of branching. The repetitions of chains and branching result in a series of radially concentric layers with increased

The overall shapes of dendrimers range from spheres to flattened spheroids (disks) to amoebalike structures, especially in cases where surface charges exist and give the macromolecule a ''starfish''-like shape. Branching of dendrimers depends on the synthesis processes. Low molecular weight drugs can be placed into the cavities within the dendrimer molecules and are temporarily immobilized there with hydrophobic forces, hydrogen and covalent bonds [26]. The two processes for the synthesis of dendrimers are divergent and convergent methods. In the divergent method dendrimer grows outwords from a multifunctional core molecule. The core molecule reacts with monomer molecules containing one reactive and two dormant groups giving the first generation dendrimer. The convergent method is developed as a response to the weakness of the divergent synthesis. In the convergent approach, the den‐ drimer is constructed stepwise, starting from the end groups and progressing inwards. When the growing branched polymeric arms, called dendrons, are large enough, they are attached to a multifunctional core molecule. The convergent method is relatively easy to purify the desired product and the occurrence of defects in the final structure is minimised [27]. Due to classical polymerization dendrimers have a negligible degree of polydispersity. They are random in nature and produce molecules of various sizes. The size of dendrimers can be carefully controlled during the process of synthesis of dendrimers. Scientists are focusing on newer approaches for speeding up the synthesis process by preassembly of oligomeric branches which can be linked together to reduce the number of synthesis steps involved and

Dendrimers are popularly used for transfer of genetic materials in cancer therapy or other viral diseases in different organs because of their monodisperisity, high density of functional groups, well-defined shape and multivalency. In gene delivery polyamidoamines (PAMAM) dendrimer is widely used. Some other types of dendrimers are peptide dendrimers, glyco‐

dendrimers, polypropilimine dendrimers, Polyethyleneimine (PEI) dendrimers etc.

Nanoliposomes are expected to bring lots of change in drug delivery in near future.

*3.1.2. Dendrimers*

530 Application of Nanotechnology in Drug Delivery

crowding [25].

also increase the dendrimer yield [28].

Nanoshells (100-200 nm) may be used for drug carrier of both imaging and therapy. Nanoshells consist of nanoparticles with a core of silica and a coating of thin metallic shell [29]. They can be targeted to a tissue by using immunological methods. Nanoshells can also be embedded in a hydrogel polymer [30]. Nanoshells are currently being investigated for prevention of micrometastasis of tumors and also for the treatment of diabetes. Nanoshells are useful for diagnostic purposes in whole blood immunoassays [31].

#### **3.2. Fullerenes and nanotubes**

Fullerenes composed of carbon in the form of a hollow sphere or ellipsoid tube. These are also known as 'bucky balls' because of their resemblance to the geodesic dome design of Buck minster Fuller. Fullerenes are being investigated for drug transport of antiviral drugs, antibiotics and anticancer agents [32]. Fullerenes have the potential to stimulate host immune response and productions of fullerene specific antibodies. Soluble derivatives of fullerenes such as C60 have shown great utility as pharmaceutical agents.

Nanotubes are nanometer scale tube like structure and they are of different types like carbon nanotube, inorganic nanotube, DNA nanotube, membrane nanotube etc. [33]. Carbon nano‐ tubes can be made more soluble by incorporation of carboxylic or ammonium groups to their structures and can be used for the transport of peptides, nucleic acids and other drug mole‐ cules. The ability of nanotubes to transport DNA across cell membrane is used in studies involving gene therapy. DNA can be attached to the tips of nanotubes or can be incorporated within the tubes [34].

#### **3.3. Nanopores**

Nanopores (20 nm in diameter) consist of wafers with high density of pores which allow entry of oxygen, glucose and other chemicals such as insulin to pass through. Nanopores can be used as devices to protect transplanted tissues from the host immune system, at the same time, utilizing the benefit of transplantation [35]. β-Cells of pancreas can be enclosed within the nanopore device and implanted in the recipient's body. Nanopores can also be employed in DNA sequencing. Nanopores are also being developed with an ability to differentiate purines from pyrimidines [36].

#### **3.4. Quantum dots**

Quantum dots (QD) are tiny semiconductor nanocrystals type of particles generally no larger than 10 nanometers that can be made to fluoresce in different colours when stimulated by light. The biomolecule conjugation of the QD can be modulated to target various biomarkers [37]. They can be tagged with biomolecules and used as highly sensitive probes. QD can also be used for imaging of sentinel node in cancer patients for tumour staging and planning of therapy. This technology also outlines some early success in the detection and treatment of breast cancer [38]. QD may provide new insights into understanding the pathophysiology of cancer and real time imaging and screening of tumors.

Bioconjugated QD are collections of variable sizes of nanoparticles embedded in tiny beads made of polymer material. In a process called "multiplexing," they can be finely tuned to a myriad of luminescent colors that can tag a multitude of different protein biomarkers or genetic sequences in cells or tissues [39]. The new class of quantum dot conjugate contains an amphi‐ philic triblock copolymer layer for *in vivo* protection and multiple PEG molecules for improved biocompatibility and circulation, making it highly stable and able to produce bright signals. Another advantage is that quantum dot probes emitting at different wavelengths can be used together for imaging and tracking multiple tumor markers simultaneously, potentially increasing the specificity and sensitivity of cancer detection [40]. Recent progress in the surface chemistry of QD has expanded their use in biological applications, reduced their cytotoxicity and rendered quantum dots a powerful tool for the investigation of dinstinct cellular processes, like uptake, receptor trafficking and intracellular delivery. Another application of QD is for viral diagnosis. Rapid and sensitive diagnosis of Respiratory Syncytial Virus (RSV) is impor‐ tant for infection control and development of antiviral drugs. Antibody-conjugated nanopar‐ ticles rapidly and sensitively detect RSV and estimate relative levels of surface protein expression. A major development is the use of dual-colour QD or fluorescence energy transfer nanobeads that can be simultaneously excited with a single light source [41]. QD linked to biological molecules, such as antibodies, have shown promise as a new tool for detecting and quantifying a wide variety of cancer-associated molecules. In the field of nanomedicine, QD can make a worthy contribution to the development of new diagnostic and delivery systems as they offer unique optical properties for highly sensitive detection and they are well defined in size and shape and can be modified with various targeting principles.

**4.2. Nanosize drug carriers in ocular drug delivery**

barrier in the eye.

lens matrix [50].

**4.3. Nanoparticle loaded contact lenses**

**4.4. Biodistribution of nanoparticles in the retina**

Drug loaded nanoparticles with favourable biological properties include prolonging the residence time, decreasing toxicity and high ability of drug penetration into the deeper layers of the ocular structure and minimizing precorneal drug loss by the rapid tear fluid turnover [46]. Nanoparticles could target at cornea, retina and choroid by surficial applications and intravitreal injection. Nanocarrier based drug delivery is suitable in the case of the retina, as it has no lymph system, hence retinal neovascularisation and choroidal neovascularization have similar environments to that of solid tumors, and the EPR effect as available for solid nanoparticles in case of solid tumor may be also available for drug delivery targeted to eyes by nanoparticles [47]. Nanoparticles can deliver ocular drugs to the target sites for the treatment of various diseases such as glaucoma, corneal diseases, diabetic retinopathy etc. The uses of nanotechnology based drug delivery systems like nanosuspensions, SLNs and nanoliposomes have greater effect for ocular therapeutic efficacy [48]. Nanotechnology-based drug delivery is also very efficient in crossing membrane barriers, such as the blood retinal

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Contact lenses loaded with nanoparticles can be effective for topical administration of ophthalmic drugs. Drug loaded contact lenses can also provide continuous drug release because of slow diffusion of the drug molecules through the lens matrix. The soaked contact lenses also delivered drugs only for a period of few hours for some typical drugs [49]. The duration of drug delivery from contact lenses can be significantly increased if the drug is first entrapped in nanoformulations, such as nanoliposomes, nanoparticles, or microemulsions. Such drug nanocarriers can then be dispersed throughout the contact lens material. The entrapment of drug in nanocarriers also prevents the interaction of drug with the polymeri‐ zation mixture. This provides additional resistance to drug release, as the drug must first diffuse through the nanocarriers and penetrate the drug carrier surface to reach the contact

The ocular biodistribution of nanoparticles can provide insights into the bioavailability, cellular uptake, duration of drug action and toxicity. Factors such as particle size, composition, surface charge and mode of administration influence the biodistribution in the retinal struc‐ tures and also their drainage from the ocular tissues [51]. Larger particles (2 μm) were found to remain in vitreous cavity near the trabecular meshwork from which they are discharged out from the ocular tissue within 6 days, whereas the particles 200 nm were found evenly distrib‐ uted in the vitreous cavity, and the inner limiting membrane. The smaller particles ∼50 nm crossed the retinal barriers, and was detected in the retina even after 2 months post injection [52]. The surface chemistry can also affect nanoparticle distribution. Positively charged nanoparticles can adhere to the anionic vitreous network components and aggregate within the vitreous network. The surface chemistry can also affect nanoparticle distribution. Posively charged nanoparticles can adhere to the anionic vitreous network components and aggregate
