**4. Applications of Nanoscale drug delivery systems**

#### **4.1. Nanotechnology for brain drug delivery**

The blood brain barrier (BBB) is a structure formed by a complex system of endothelial cells, astroglia, pericytes, and perivascular mast cells, preventing the passage of most circulating cells and molecules [42]. The tightness of the BBB is attributed mainly to the vascular layer of brain capillary endothelial cells which are interconnected side-by-side by tight and adherens junctions. Among the different nanodevices, nanosize drug delivery systems between 1 and 100 nm work as a whole unit in terms of transport to cross BBB [43]. Nanosize brain drug delivery systems may promote the targeting ability of drug in brain and at the same time enhance the permeability of molecules through BBB. However crossing of BBB by the nano drug carriers will depend completely on the physicochemical and biomimetic features and does not depend on the chemical structure of drug, inside the nanoparticles [44]. Nanosize drug carriers which do not cross BBB generally can be made "stealth" coated with some polymeric materials or other chemicals to avoid the reticuloendothelial system, to display long circulation time and stability in blood, and may be functionalized to successfully cross the BBB and target brain [45].

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

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.

The blood brain barrier (BBB) is a structure formed by a complex system of endothelial cells, astroglia, pericytes, and perivascular mast cells, preventing the passage of most circulating cells and molecules [42]. The tightness of the BBB is attributed mainly to the vascular layer of brain capillary endothelial cells which are interconnected side-by-side by tight and adherens junctions. Among the different nanodevices, nanosize drug delivery systems between 1 and 100 nm work as a whole unit in terms of transport to cross BBB [43]. Nanosize brain drug delivery systems may promote the targeting ability of drug in brain and at the same time enhance the permeability of molecules through BBB. However crossing of BBB by the nano drug carriers will depend completely on the physicochemical and biomimetic features and does not depend on the chemical structure of drug, inside the nanoparticles [44]. Nanosize drug carriers which do not cross BBB generally can be made "stealth" coated with some polymeric materials or other chemicals to avoid the reticuloendothelial system, to display long circulation time and stability in blood, and may be functionalized to successfully cross the BBB

**4. Applications of Nanoscale drug delivery systems**

**4.1. Nanotechnology for brain drug delivery**

532 Application of Nanotechnology in Drug Delivery

and target brain [45].

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 barrier in the eye.

#### **4.3. Nanoparticle loaded contact lenses**

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 lens matrix [50].

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

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 within the vitreous humor [53]. Anionic nanoparticles were found to diffuse through the vitreous humor and could even penetrate the retinal layers to be taken up by Muller Cells [54]. Vitreous humor is regarded as the barrier for non-viral ocular gene therapy because of the strong interaction of conventional cationic nature of non-viral gene vectors with the anionic vitreous humor [53]. The cationic PEI nanoparticles aggregated within vitreous humor and were prevented from distributing to the retina by the vitreal barrier. In contrast, cationic glycol chitosan (GC) nanoparticles and GC/PEI blended nanoparticles could penetrate the vitreal barrier and even reach at the inner limiting membrane because of the existence of glycol groups on nanoparticles [55].

was located within the polyanionic core [62] for drug targeting and detection. Similarly, many efforts are on for cancer cell targeting specifically with drug nanocarriers.. Thus the drug

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**Figure 3.** Schematic diagram of nanoparticle permeation and retention effect in normal and tumour tissues. Normal tissue vasculatures are lined by tight endothelial cells, hereby preventing nanoparticulate drug delivery system from escaping, whereas tumor tissue vasculatures are leaky and hyperpermeable allowing preferential accumulation of

Transfer of genetic material in nanocarriers may be an approach for the treatment of various genetic disorders such as diabetes mellitus, cystic fibrosis, alpha 1 antitrypsin deficiency and may more. A number of systemic diseases are caused by lack of enzymes factors that are due to missing or defective genes [63]. Previously gene therapy which was used to treat genetic disorders nowadays being contemplated as carrier systems which could be implanted for combating diseases other than genetic disorder like malignant form of cancer, heart diseases and nervous diseases [64]. Nanoliposomes can be used to deliver genetic materials into cells. Nanoliposomes incorporated with PEG and galactose target liver cells effectively due to their rapid uptake by liver Kupffer cells. Gene therapy may be tried with liposomal nanocarriers for liver disorders such as Wilson's and hereditary hemochromatosis. Cationic nanoliposomes have been considered as potential non-viral human gene delivery system [65]. Another effective method for administering nanoliposomes is by using ligand receptor complex using EGF-EGFR system for targeting purpose by nanoliposomes where EGF is a small protein which

nanoparticles or nanoliposomes in the tumor interstial space by passive targeting

**4.6. Gene delivery**

nanocarriers are of great hope for future cancer therapy.

#### **4.5. Nanoparticles in cancer**

Cancer cells are more vulnerable than normal cells to the effect of chemotherapeutic agents and the most of the anticancer drugs can cause injury to the normal cells. Optimum dose and frequency are both important factors in the persistence of cancer cells during cancer chemo‐ therapy [56]. Now attempts are focused on efforts to kill cancer cells by more specific targeting while sparing the normal cells.

Nanoparticulate delivery systems in cancer therapies provide better penetration of therapeutic and diagnostic substances within the cancerous tissue in comparison to conventional cancer therapies [57]. Nanoparticles are constructed to take advantages of fundamental cancer morphology and modes of development such as rapid proliferation of cells, antigen expres‐ sion, and leaky tumor vasculature. Nanoparticulate drug delivery systems are being devel‐ oped to deliver smaller doses of chemotherapeutic agents in an effective form and control drug distribution within the body [58]. Nanocarriers can offer many advantages over free drugs in cancer chemotherapy such as they protect the drug from premature degradation, prevent drugs from prematurely interacting with the biological environment, enhance absorption of the drugs into a selected tissue (solid tumour), control the pharmacokinetic and drug tissue distribution profile and improve intracellular penetration [59].

Nanoparticulate delivery systems utilize specific targeting agents for cancer cells minimizing the uptake of the anticancer agent by normal cells and enhance the entry and retention of the agent in tumor cells (Figure 3) [60]. Nanocarriers may actively bind to the specific cancer cells by attaching targeting agents with the help of ligand molecules to the surface of the nanocar‐ riers that bind to specific receptor antigens on the cell surface. Nanocarriers will recognize and bind to target cells through ligand receptor interactions. It is even possible to increase the drug targeting efficacy with the help of antibodies by conjugating a therapeutic agent directly to it for targeted delivery [61].

Like receptor targeting, targeting of angiogenic factors also takes advantage of properties unique to cancer cells. Anti-angiogenic treatment is the use of drugs or other substances to stop tumors from developing new blood vessels. In a study nanoparticles were formulated comprising a water-based core of Vickers microhardness sodium alginate, cellulose sulphate, and anti-angiogenic factors such as thrombospondin (TSP)-1 or TSP-517, crosslinked with dextran polyaldehyde with calcium chloride or conjugated to heparin sulphate with sodium chloride. In addition bioluminescent agent, luciferase, or contrast agent, polymeric gadolinium was located within the polyanionic core [62] for drug targeting and detection. Similarly, many efforts are on for cancer cell targeting specifically with drug nanocarriers.. Thus the drug nanocarriers are of great hope for future cancer therapy.

**Figure 3.** Schematic diagram of nanoparticle permeation and retention effect in normal and tumour tissues. Normal tissue vasculatures are lined by tight endothelial cells, hereby preventing nanoparticulate drug delivery system from escaping, whereas tumor tissue vasculatures are leaky and hyperpermeable allowing preferential accumulation of nanoparticles or nanoliposomes in the tumor interstial space by passive targeting

#### **4.6. Gene delivery**

within the vitreous humor [53]. Anionic nanoparticles were found to diffuse through the vitreous humor and could even penetrate the retinal layers to be taken up by Muller Cells [54]. Vitreous humor is regarded as the barrier for non-viral ocular gene therapy because of the strong interaction of conventional cationic nature of non-viral gene vectors with the anionic vitreous humor [53]. The cationic PEI nanoparticles aggregated within vitreous humor and were prevented from distributing to the retina by the vitreal barrier. In contrast, cationic glycol chitosan (GC) nanoparticles and GC/PEI blended nanoparticles could penetrate the vitreal barrier and even reach at the inner limiting membrane because of the existence of glycol groups

Cancer cells are more vulnerable than normal cells to the effect of chemotherapeutic agents and the most of the anticancer drugs can cause injury to the normal cells. Optimum dose and frequency are both important factors in the persistence of cancer cells during cancer chemo‐ therapy [56]. Now attempts are focused on efforts to kill cancer cells by more specific targeting

Nanoparticulate delivery systems in cancer therapies provide better penetration of therapeutic and diagnostic substances within the cancerous tissue in comparison to conventional cancer therapies [57]. Nanoparticles are constructed to take advantages of fundamental cancer morphology and modes of development such as rapid proliferation of cells, antigen expres‐ sion, and leaky tumor vasculature. Nanoparticulate drug delivery systems are being devel‐ oped to deliver smaller doses of chemotherapeutic agents in an effective form and control drug distribution within the body [58]. Nanocarriers can offer many advantages over free drugs in cancer chemotherapy such as they protect the drug from premature degradation, prevent drugs from prematurely interacting with the biological environment, enhance absorption of the drugs into a selected tissue (solid tumour), control the pharmacokinetic and drug tissue

Nanoparticulate delivery systems utilize specific targeting agents for cancer cells minimizing the uptake of the anticancer agent by normal cells and enhance the entry and retention of the agent in tumor cells (Figure 3) [60]. Nanocarriers may actively bind to the specific cancer cells by attaching targeting agents with the help of ligand molecules to the surface of the nanocar‐ riers that bind to specific receptor antigens on the cell surface. Nanocarriers will recognize and bind to target cells through ligand receptor interactions. It is even possible to increase the drug targeting efficacy with the help of antibodies by conjugating a therapeutic agent directly to it

Like receptor targeting, targeting of angiogenic factors also takes advantage of properties unique to cancer cells. Anti-angiogenic treatment is the use of drugs or other substances to stop tumors from developing new blood vessels. In a study nanoparticles were formulated comprising a water-based core of Vickers microhardness sodium alginate, cellulose sulphate, and anti-angiogenic factors such as thrombospondin (TSP)-1 or TSP-517, crosslinked with dextran polyaldehyde with calcium chloride or conjugated to heparin sulphate with sodium chloride. In addition bioluminescent agent, luciferase, or contrast agent, polymeric gadolinium

distribution profile and improve intracellular penetration [59].

on nanoparticles [55].

**4.5. Nanoparticles in cancer**

534 Application of Nanotechnology in Drug Delivery

while sparing the normal cells.

for targeted delivery [61].

Transfer of genetic material in nanocarriers may be an approach for the treatment of various genetic disorders such as diabetes mellitus, cystic fibrosis, alpha 1 antitrypsin deficiency and may more. A number of systemic diseases are caused by lack of enzymes factors that are due to missing or defective genes [63]. Previously gene therapy which was used to treat genetic disorders nowadays being contemplated as carrier systems which could be implanted for combating diseases other than genetic disorder like malignant form of cancer, heart diseases and nervous diseases [64]. Nanoliposomes can be used to deliver genetic materials into cells. Nanoliposomes incorporated with PEG and galactose target liver cells effectively due to their rapid uptake by liver Kupffer cells. Gene therapy may be tried with liposomal nanocarriers for liver disorders such as Wilson's and hereditary hemochromatosis. Cationic nanoliposomes have been considered as potential non-viral human gene delivery system [65]. Another effective method for administering nanoliposomes is by using ligand receptor complex using EGF-EGFR system for targeting purpose by nanoliposomes where EGF is a small protein which binds with receptor EGFR. Also mixing cationic lipids with plasmid DNA leads to the formation of lipoplexes where the process is driven by electrostatic interactions [66]. The negatively charged genetic material (e.g. plasmid) is not encapsulated in nanoliposomes but complexed with cationic lipids by electrostatic interactions. Plasmid liposome complexes can enter the disease cells by infusion with the plasma or endosome membrane. Allovectin-7 (gene transfer product) is composed of a plasmid containing the gene for the major histocompatibility complex antigene HLA-B7 with B2 microglobulin formulated with the cytofectin [67]. The nature of a composed lipid decides the unloading of the gene from nanoliposomes which enables control over the mode of release, doping of nanoliposomes with neutral lipids such as 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) which helps in endosomal mem‐ brane fusion by recognizing and destabilizing the phospholipids in a flip flop manner which paves way for the liposomes to integrate in the membrane with the dissociation of nucleic acid into the cytoplasm [64].

(VLPs) constructed from the virus are used to deliver therapeutic genes to human fetal glial cells. Another technique Cell-docking involves attachment of antibodies to the surface of brain natriuretic peptide (BNPs). Coupling reaction between murine polyoma-virus and antitumor antibody B3 yielded polyoma VLPs with 30 to 40 antibody fragments bound to the surface, allowing the modified VLPs to bind to the breast carcinoma cells with high efficiencies [72].

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Advancement of nanosize drug delivery systems establishes a new paradigm in pharmaceut‐ ical field. Convergence of science and engineering leads a new era of hope where medicines will act with increase efficacy, high bioavailability and less toxicity. Several nanoscale drug delivery systems are currently in clinical trials and few of them are already commercially available. Examples of such products are Abeicet (for fungal infection), Doxil (antineoplastic), Abraxane (metastatic breast cancer), Emend (antiemetic) etc. Despite the impressive progress in the field, very few nanoformulations have been approved by US-FDA (United States Food and Drug Administration) and even reached market in recent years. Although nanocarriers have lots of advantages because of the unique properties they have, there are many clinical, toxicological and regulatory aspects which are the matters of concern too. The biocompatibility of nanomaterials is of atmost importance because of the effect of the nanomaterials in the body ranging from cytotoxicity to hypersensitivity [8]. With the advancement of nanotechnology, the biological phenomenon such as host response to a specific nanomaterial should also be clinically transparent [9]. Therefore it is quite essential to introduce cost effective, better and safer nanobiomaterials which will provide efficient drug loading and controlled drug release of some challenging drug moieties for which there is no other suitable delivery available yet. Nanoliposomes are well developed and presently possess the highest amount of clinical trials among other nanomaterials with some formulations currently in the market. This may be due to the fact that other materials have not been investigated for the same duration and are relatively newer in comparison. However polymer based nanomaterial, carbon nanotubes, gold nanoparticles etc. should not be overlooked because of less number of clinical trials [7]. Genexol-PM is an example which was undergone recent clinical trial. This is an amphiphilic diblock co-polymer (PEG-D, L-Lactic acid) that delivers paclitaxel. Clinical trial currently is in phase IV using Genexol-PM for recurrent breast cancer and phase III for breast cancer. Fungal infections associated with acute leukemia and for central line fungal infections, amphotericin B containing nanoliposomes are in phase IV clinical trial. ThermoDox (Doxorubicin loaded nanoliposome) is currently in phase III trials for hepatocellular carcinoma. Similarly Caelyx, a doxorubicin HCl loaded nanoliposome that is pegylated, is currently in phase IV trials for

**9. A glimpse to future of nanosize drug delivery systems**

ovarian neoplasms [7]. Some recent clinical trials are shown in Table 1.

Ligand or antibody conjugated nanoformulation, bifunctional and multifunctional nanopar‐ ticles are the newer research approaches through which detection and treatment of cancerous cells can be achieved. Nanomachines are also largely in the research-and-development phase, but some primitive molecular machines have been tested. An example is nanorobot which is

Viral system based gene carrier had the ability to overcome the biological barriers in the body and then access to the host nucleus replicative machinery which resulted in the exploitations of the system for drug delivery using nanotechnology [64]. The develop‐ ment of a non-viral method for *in vivo* gene transfer was designed where the vector was packed into compact nanoparticles by successive additions of oppositely charged polyelec‐ trolytes including an incorporation of ligands into the DNA-polyelectrolyte shells which were mixed with Pluronic F127 gel serving as a biodegradable adhesive to keep shells in contact with the targeted vessel [68].

A novel method of gene delivery is with viruses such as adeno associated virus (AAV) which have their virulent genes removed with lentiviruses, clearly showing their efficiency [64].
