Chapter 12 Fundamentals of a targeted drug delivery system PDF

C H A P T E R 12 Fundamentals of a targeted drug delivery system Akash Chaurasiya1, Sonali Singh1, Kanan Panchal1, Rishi Paliwal2 and Akanksha Malaiya2 1 Translational Pharmaceu...

C H A P T E R 12 Fundamentals of a targeted drug delivery system Akash Chaurasiya1, Sonali Singh1, Kanan Panchal1, Rishi Paliwal2 and Akanksha Malaiya2 1 Translational Pharmaceutics Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Hyderabad, Telangana, India 2Nanomedicine and Bioengineering Research Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India Abbreviations TDDS Targeted drug delivery systems DDS Drug delivery systems NP Nanoparticle PNP Polymeric nanoparticles NLC Nanostructured lipid carriers SLN Solid lipid nanoparticles RES Reticuloendothelial system USFDA United States Food and Drug Administration EPR Enhanced permeability and retention 12.1 Introduction Delivering drugs in a precise and accurate manner and the technology associated with them have always been cumbersome and challenging in the pharmaceutical research field. The idea of targeted drug delivery was first introduced by Paul Ehrlich, who termed it “magic bullet.” It was conceptualized that the drug for the marked pharmacological action should be delivered at a specific site of action so as to minimize the undesirable toxicity and an optimal dose of the drug should be delivered, which cannot be achieved by using the traditional drug delivery systems (DDS). The most ideal condition is to deliver the drug directly to its target cell/tissue/organ in desired Molecular Pharmaceutics and Nano Drug Delivery DOI: https://doi.org/10.1016/B978-0-323-91924-1.00007-1 289 © 2024 Elsevier Inc. All rights reserved. 290 12. Fundamentals of a targeted drug delivery system FIGURE 12.1 Mechanism of Target drug release. Retain Evade Release Specific Site concentrations. There are several pharmaceutical formulations employing the use of tar- geted DDS (TDDS) to deliver an accurate dose of a drug to the specific site to achieve a desirable pharmacological action. The application of nanotechnology in DDS can improve drug solubility and distribution in various tissues and organs, obtain controlled or sustained release profiles, and promote the aggregation of drug molecules at a specific site of action. There are several chal- lenges while developing these targeted nano-sized DDS. After development, only a few enter the clinical trial, and a handful are approved. Also, the scale-up of such formulations is quite challenging. Despite these difficulties, there are several advantages of TDDS for better drug delivery, dose-effectiveness, and less toxic effects. The overall function and performance of TDDS depend on four key requirements, viz, retain, evade, target, and release (Fig. 12.1). The challenging part while developing these DDS is to retain their contents (encapsulated/associated material) during prepara- tion, processing, and final intended application. It should be able to evade the body’s defense to reach the disease area. TDDS, either passively or actively through specific methods, provide high accumulation of drug substances at a specific target site, while avoiding healthy tissues and organs. Ultimately, the drug from the system must be released at the desired site of action and give a desirable and effective pharmacological action. There are different DDS intended for various sites of action as well as for differ- ing therapeutic effects. The need for targeted drug delivery over conventional DDS is because of the unsatisfac- tory performance of the drug concerning its pharmacodynamic, pharmacokinetic, pharma- ceutical, and pharmacotherapeutic properties. Targeting drugs to a particular site of action through optimization of the DDS is not only important in enhancing the therapeutic effi- cacy but also in reducing toxicity and other side effects associated with the high doses and small therapeutic index. Thus, targeting is required to achieve solutions to these constraints and to overcome the innate disadvantages of conventional DDS. Although parenteral drug delivery is highly invasive, oral delivery cannot be preferred to deliver pH-sensitive drugs and biologics like proteins, peptides, and other enzymes. Supplying a high concentration of the medicine to the targeted site while bypassing the nontargeted area is the fundamental idea behind drug targeting. By reducing the side effects brought on by multiple site interactions, larger dosages, and nontarget concentra- tions, this approach helps to maximize the therapeutic effect of the medicines. Targeting also reduces drug interactions that are undesirable and affect the drug’s ability to reach the targeted areas in the body. Coordinated drug behavior, a targeted area, and a phar- maceutical carrier are key components of TDDS. The target is the particular organ, cell, or group of cells that the medicine will interact with when they are in a chronic or acute state. The carrier is a carefully designed system that is necessary for the efficient delivery of the loaded medicine to the desired area. A drug-targeting complex should ideally be bio- chemically inert, biocompatible, nonimmunogenic, biodegradable, and physically and Molecular Pharmaceutics and Nano Drug Delivery  12.3 Mechanism of drug targeting 291 chemically stable both in vivo and in vitro. It should also be relatively easy to prepare, have a predictable and regulated pattern of drug release, be easy to eliminate from the body, and have little to no drug leakage while in transit. 12.2 Approaches for drug delivery Drug delivery is a method to deliver the pharmaceutical dosage to the human body to achieve a certain desirable therapeutic effect. Various delivery system approaches are used to deliver the drug to the target site. By designing efficient dosage forms, one can deliver the drug to the human body and can minimize its toxic effects. Due to the versatility in the nature of the active molecules such as therapeutic enzymes, proteins, peptides, antibo- dies, and small molecules, optimization of these dosage forms is required. Innovative designs in drug delivery approaches improve the physical properties, therapeutic efficacy, and bioavailability of the drug molecule and reduce/mitigate the toxicity of these sub- stances. Table 12.1 describes different types of TDDS and their salient features. 12.3 Mechanism of drug targeting There are many strategies by which drug molecules can be targeted to a certain site so that the toxic and other side effects can be mitigated (Fig. 12.2). Drug targeting can be fur- ther categorized into three orders of targeting. The drug carrier system’s distribution to the target organ or tissue is constrained in first-order targeting. The second order is the selective targeting of a particular cell or cell type of a specific tissue or organ. Drugs that target macromolecules like DNA, proteins, and other intracellular components of the cell are designated under third-order targeting. 12.3.1 Passive targeting In the passive targeting method, the body’s natural reaction to the physicochemical properties of the drug or drug carrier system results in drug targeting. It relies on physio- logical body features such as the reticuloendothelial system (RES), monocyte macrophage system, and the enhanced permeation and retention (EPR) effect. In this method, nanocarriers are utilized to carry drugs and are designed meticulously to enter blood ves- sels at the disease area from the systemic circulation, creating the potential for large drug accumulation at the target site. The EPR effect, which causes sluggish lymphatic drainage, facilitates this procedure. 12.3.2 Active targeting Active targeting is based on imposing targeting properties to the drug intrinsically (drug designed to target a specific molecule) and/or extrinsically (drug designed with certain tar- geting features, physical targeting programmed released at a certain temperature or pH, Molecular Pharmaceutics and Nano Drug Delivery 292 12. Fundamentals of a targeted drug delivery system TABLE 12.1 Different types of targeted drug delivery system, their components, uses, and special properties. Types of TDDS Components used Uses Special properties References Liposomes Phospholipids Oral, topical and pulmonary Unstable, requires special dispersed in targeted drug delivery preparation and storage aqueous solution conditions Niosomes Cholesterol, charged Carrier for lipophilic and Stable, does not require substances, nonionic amphiphilic drugs special preparation and surfactants storage conditions Transferosomes Surfactants, alcohol, Transdermal delivery for deeper Ultraflexible and dye, penetration into epidermic layers deformable vesicles phosphatidylcholine in buffer solution Polymeric Polymer, drug, Controlled release, improved Facile synthesis, nanoparticles surfactant in vivo and in vitro drug biocompatible, nontoxic, stability, enhanced therapeutic nonimmunogenic, index and bioavailability biodegradable, inexpensive Solid lipid Lipid, surfactant, Encapsulated drug, vitamins, Nanosize, high drug nanoparticles aqueous phase xenobiotics loading, low toxicity and stability while production Albumin Albumin (protein), Drug delivery to different Biodegradability, nanoparticles drug, surfactant cancers biocompatibility, and favorable toxicological profiles Nanocrystals Lipid, polymer Used to absorb poorly water- Composed of 100% drug surfactant soluble drug quickly and no carrier material is used Nanoemulsions Oil phase, aqueous Used to deliver both hydrophilic Greater surface area phase, surfactant as well as lipophilic drug for provides greater diseases like cancer bioabsorption Dendrimers Drug, polymer Used to deliver or carry drug Higher branching and molecules, peptides and genes surface area, increased drug bioavailability and ligand-based approach). Delivering drug molecules, theragnostic agents, and genes at the desired site of action while avoiding healthy tissues will reduce side effects and toxicity and will increase therapeutic effectiveness. Comparing active targeting to passively tar- geted nanosystems, the amount of drug supplied to the target cell can be greatly increased. After aggregation in the tumor region, presumed active targeting can even boost the drug’s effectiveness. This is accomplished by functionalizing the surfaces of the nanocarriers with ligands in order for them to bind to the receptors that are overexpressed on the tumor cells to achieve targeting. It is a specific ligand receptor type interaction that happens following extravasation from the blood circulation. This strategy increases the nanocarriers’ Molecular Pharmaceutics and Nano Drug Delivery  12.4 Targeted drug delivery systems 293 FIGURE 12.2 Mechanism of drug 1st order targeting. 2nd order Type 3rd order 4th order Biological Mechanism Acve targeng Mode Physical Passive targeng Chemical Inverse targeng Site-specific Combinaon targeng Target Local Dual affinity to the surface of cancer cells and hence increases drug penetration. Receptors like transferrin receptor and nicotinic acetylcholine receptor are examples of classical targets that enable the drug to reach the tumor microenvironment [23,24]. 12.3.3 Inverse targeting Inverse targeting can be achieved by blockage or saturation of passive targets or by blocking RES using sugar polymer or lipid micromolecules. Delivery of a carrier molecule having therapeutic activity itself is known as dual targeting, which synergistically enhances the efficacy of the drug. In the case of double targeting, geographical and temporal methodologies, viz, the placement of information in precise locations and the controlled delivery of time, are merged. Combination targeting is a method of directly approaching a target with drug-equipped polymers, carriers, and homing devices with molecular specificity. 12.4 Targeted drug delivery systems Nanotechnology is a promising approach for drug delivery via different routes of administration. These are proven, reliable, and efficient systems for targeted drug delivery during many life-threatening diseases. The application of nanotechnology as magic bullets in the delivery of actives to the brain, cancers, ocular sites, topical, transdermal, and so forth provides a new domain to the existing therapeutic regimen [27,28]. Table 12.2 enlists various nanostructured carrier systems used through different routes of Molecular Pharmaceutics and Nano Drug Delivery 294 12. Fundamentals of a targeted drug delivery system TABLE 12.2 Application of nanocarriers in targeted drug delivery. Therapeutic Application: Carrier agent Disease Route Features/property References NLC Meropenem Soft tissue infection Topical Enhanced adhesion property, occlusion and sustained release Hyaluronic Methotrexate Breast cancer Systemic Sustained and prolonged acid NPs delivery—IV release, reduced toxicity Chitosan NPs Doxorubicin Breast cancer Intracellular Increased potency of delivery anticancer activity on MCF- cell lines Nanogel Diacerein Arthritis Topical Overcomes drawback of the oral route, highly efficient, sustained and targeted release Silver NPs Plectranthus Anti-oxidant activity Free radical scavenging barbatus activity NLC Zopiclone Insomnia Nasal Nose-to-brain delivery, faster and higher uptake NLC Docetaxel Glioblastoma Brain Sustained release, delivery improved brain targeting action and potent anticancer activity Chitosan NPs Tedizolid Methicillin-resistant Ocular 2.4-fold increase in trans Phosphate Staphylococcus aureus corneal flux and apparent related ocular and permeation, nonirritant orbital infection properties Micelles Posaconazole Ocular irritation and Ocular Effective and safe delivery antifungal activity delivery PAMAM Docetaxel Metastatic breast cancer Cancer Sustained and controlled dendrimers delivery delivery, also used in chemophotothermal therapy Nanoemulsion Methotrexate Local treatment for skin Topical Higher penetration, gel diseases optimum release and retention at the disease site Microemulsions Acemetacin Analgesic and Transdermal Higher penetration and antiinflammatory significant analgesic and antiinflammatory effect Liposomes Sumatriptan Migraine Nasal Nose-to-brain delivery, containing succinate sustained impact on drug in-Situ gel delivery, reduced toxicity Molecular Pharmaceutics and Nano Drug Delivery  12.4 Targeted drug delivery systems 295 FIGURE 12.3 Different types of nanocarriers used for targeted drug delivery. Source: Reprinted from Lôbo GC, Paiva KL, Silva AL, Simões MM, Radicchi MA, Báo SN. Nanocarriers used in drug delivery to enhance immune sys- tem in cancer therapy. Pharmaceutics. 2021 Jul 28;13(8):1167. https://www.mdpi.com/1999-4923/13/8/1167. Copyright r 2021, The Author(s). administration for diverse therapeutic applications. Besides the ones enlisted, nanocarriers such as transferosomes, ethosomes, magnetic nanoparticles, carbon nanotubes, magnetic nanoparticles, and so on are also employed for biomedical applications. Fig. 12.3 illus- trates various nanocarrier systems employed for the purpose of targeted drug delivery. However, nanocarriers injected by these routes need to fulfill some primary requisites of being biodegradable, biocompatible, nonimmunogenic, as well as physically stable in vivo which is essential for it to be safe and efficacious. These must be developed in a way suitable for scaling-up and large-scale production, which makes the product useful for a clinical setup [3,30]. The drug can be loaded into polymeric nanoparticles (PNPs), which range in size from 1 to 1000 nm and can be made of natural or synthetic polymers. The drug may also be adsorbed or chemically attached to the surface of the PNP. The central matrix is made up of a variety of biodegradable polymers, including poly(lactic acid) (PLA), poly(lactic-cogly- colic acid), poly(e-caprolactone) (PCL), chitosan, poly(alkyl cyanoacrylate), and poly (lysine). Typically, these are made from preformed polymers or by polymerizing mono- mers like alkyl cyanoacrylates and other similar substances. PNPs have drawn scientists to study drug compounds that target the brain [45,46]. Using biodegradable PNPs is one of the potential methods for delivering actives to the CNS, cancer, topical regions, and other Molecular Pharmaceutics and Nano Drug Delivery 296 12. Fundamentals of a targeted drug delivery system areas. These are additionally being used as possible DDS because of their potential use throughout gene therapy, peptide, and protein delivery, as well as drug targeting to spe- cific organs and tissues. In addition to recently created synthetic and semisynthetic poly- mers, natural polymers like chitosan, gelatin, sodium alginates, and others are still used in the development of novel DDS [45,46]. Advantages of PNPs Provide targeted and sustained drug delivery. Enhance the stability of any volatile pharmaceutical agents. Facile and economical large-scale fabrication by a multitude of methods. Significant improvement over traditional oral and intravenous methods of administration with respect to their efficiency and effectiveness. Ability to choose polymer and/or their combination to modify the release of drugs from PNPs to obtain a desirable pattern of drug release. Can be used for other activities related to drug delivery, such as tissue engineering. 12.4.1 Dendrimers Nanomaterials called dendrimers are useful for therapeutic and diagnostic reasons. They have a peculiar tree-like structure and exhibit a variety of appealing qualities. They are especially appropriate for biomedical uses due to their monodispersity and tunable characteristics. The readily available polyamidoamine (PAMAM) dendrimers’ properties, such as their surface charge or lipophilicity, could be simply tuned. The use of dendrimers is extensive in a variety of biological and diagnostic uses, including the delivery of drugs and genes, biosensing, the use of contrast agents, and so forth. 12.4.2 Liposomes Amphipathic phospholipids are organized into circular bilayers called liposomes. Three distinct liposomal systems have been recognized by the New York Academy of Science since 1997: multilamellar (100 nm 20 mm), small unilamellar (10 50 nm), and large unila- mellar (50 1000 nm) vesicles. The vesicles can contain various varieties of therapeutic molecules. The interior aqueous phase and lipid bilayer of liposomes, which are hydro- philic and hydrophobic substances, correspondingly [48,49]. 12.4.3 Solid lipid nanoparticles Solid lipid nanoparticles (SLNs), which are stabilized by different surfactants, are parti- cles composed of highly purified solid lipids such as triglycerides, complex glyceride mix- tures, or waxes. SLNs are made up of a solid hydrophobic lipid core that is comparatively rigid and solid at body and room temperatures. Physical stability, preserving incorporated drugs from deterioration, controlled drug release, and in vivo tolerability are the distin- guishing features of SLNs. The low loading capacity, which is reliant on the drug’s solubil- ity in the lipid and the structure and polymorphic state of the lipid matrix, drug expulsion after crystallization, and comparatively high water content of the dispersion are other Molecular Pharmaceutics and Nano Drug Delivery  12.5 Targeted drug delivery systems for the management of different disorders 297 drawbacks that have been noted. They are encircled by a phospholipid monolayer, which is further secured by the presence of significant amounts of surfactants. They are much less deleterious than polymer or ceramic nanoparticles due to their biodegradability. They can be produced with one of three hydrophobic core designs, a homogenous matrix, a drug-enriched shell, or a drug-enriched core, and have controllable pharmacokinetic characteristics. The shelf-life of SLN formulations is increased by the fact that they have been designed to be robust for a few years. Their tendency to be recognized by the RES still represents a significant limitation. 12.4.4 Nanostructured lipid carriers Solid and liquid lipids are combined to create nanostructured lipid carriers (NLCs), a unique nanostructure with greater payload, smaller particle size, and resistance to drug expulsion. This process also creates a special nanostructure that is used to deliver drugs. They are reasonably simple to formulate and produce, and they can accommodate both hydrophilic and lipophilic pharmaceuticals. NLCs are second-generation lipid-based nano- particles designed to overcome problems of entrapment efficiency and drug expulsion during storage encountered with SLNs. NLCs possess greater flexibility for achieving the required release profiles and remain in an amorphous state even after solidification. These carrier systems are biocompatible, biodegradable, and employed for quick absorp- tion [51,52]. 12.4.5 Polymeric micelles Polymeric micelles are formed by the spontaneous association of amphiphilic copoly- mers in an aqueous phase. This property thus becomes an innovative tool to overcome various problems such as low water solubility and poor drug permeability. The key fea- tures of micelles such as size (diameter not exceeding 100 nm), size distribution, drug loading, and kinetics of drug release are critical for effective drug delivery. The inter- action between the hydrophobic and electrostatically neutral components of the commonly used copolymers, such as PLA, PCL, poly(L-amino acid):poly(aspartic acid) (PAsp), and phospholipids:phosphatidylethanolamine, results in the attractive force that causes micelli- zation [55,56]. However, the compromised stability of the polymeric micelles compared to other lipidic and PNPs needs further developmental research. 12.5 Targeted drug delivery systems for the management of different disorders Targeted drug delivery is described as a drug carrier complex/conjugate that deli- vers the drug exclusively to the preselected target cells in a specific manner. Drug tar- geting is the delivery of a drug to receptors or organs or any other specific part of the body, to which one aims to deliver the drug exclusively. Over the years, there have been several medicines developed based on targeted nanotechnology that have been in clinical usage (Fig. 12.4). The drug’s therapeutic index, as measured by its Molecular Pharmaceutics and Nano Drug Delivery 298 12. Fundamentals of a targeted drug delivery system Polymeric PEGylated BIND-014 Systems Lyposomes Abraxane NanoTherm Phase I/II Vyxeos 1967 1980 2005 2012 2015 2017 Lipsomes Dendrimers Doxil Marqibo Kadcyla MM-310 Multiple ADC 1965 1978 1995 2012 2013 Anti-EPHAz Approvals Liposomes 2019 2016 FIGURE 12.4 Timeline of the development of carrier-mediated agents. Source: Reprinted from Piscatelli JA, Ban J, Lucas AT, Zamboni WC. Complex factors and challenges that affect the pharmacology, safety and efficacy of nanocar- rier drug delivery systems. Pharmaceutics. 2021;13(1):114. https://doi.org/10.3390/pharmaceutics13010114. (under the terms and conditions of the Creative Commons Attribution (CC BY) license). TABLE 12.3 Clinically approved nanotechnology-based product for targeted drug delivery application. Trade name Active drug/delivery system Application Invega Paliperidone palmitate/ Schizophrenia Sustenas nanocrystal Diprivans Propofol/lipid emulsion Anesthetic s Vyxeos Cytarabine and daeunorubicin/ Acute myeloid leukemia liposomes Doxils / Doxorubicin/liposomes Metastatic ovarian cancer and advanced Caelyxs Kaposi’s sarcoma Ambisomes Amphotericin B/liposomes Fungal infection s Onivyde Irinotecan/liposomes Pancreatic cancer s Marqibo Vincristine sulfate/liposomes Acute lymphoblastic leukemia s Abraxane Paclitaxel/nanosuspension Metastatic breast cancer, non-small-cell lung cancer, pancreatic adenocarcinoma pharmacological response and safety, relies upon the access and specific interaction of the drug with its corresponding receptor, while minimizing its interaction with nontar- get tissue. This targeted delivery would bypass the rest of the body, thus signifi- cantly reducing the overall toxicity while maintaining the therapeutic benefits of the drug. Table 12.3 enlists clinically approved nanotechnology based TDDS for the treat- ment of various diseases. Molecular Pharmaceutics and Nano Drug Delivery  12.5 Targeted drug delivery systems for the management of different disorders 299 12.5.1 Brain delivery Unlike other tissues, the blood brain barrier (BBB) shields the brain from injuries. The BBB acts as the primary barrier to the entry of potentially harmful endogenous and exoge- nous molecules from the bloodstream, but it also creates an important challenge for the treat- ment of brain tumors. The BBB is composed of astrocytes’ feet, pericytes, a basement membrane, and rigid junctions between endothelial cells. The blood cerebrospinal fluid barrier is the second barrier that hinders therapeutic drugs administered systemically from passing. Due to the BBB’s complexity and structure, delivering drugs, diagnostic tools, and immunomodulators into the CNS and enabling them to pass through is not an easy task. Bevacizumab (for brain cancer) and natalizumab (for multiple sclerosis) failed clinical trials in people with acute dementia because of their inability to cross BBB. Therefore, the US Food and Drug Administration did not authorize biologicals for CNS disorders until 2019. A third obstacle to the delivery of therapeutic agents is the blood tumor barrier within the tumor. The tight junctions of endothelial cells in the tumor are severely weakened, in contrast to nor- mal brain capillaries. Drug penetration from the circulation into the tumor is constrained by the high intratumoral interstitial pressure produced by the leaky tumor vasculature. Additionally, the presence of various tumor microvessel populations and spatial variation in the capillary functions in the tumor region led to fluctuations in infiltration. For instance, this might result in a heterogeneous distribution of drug molecules, which could potentially affect therapeutic outcomes. The BBB can be passed by passive diffusion for small molecules with a low molecular weight (less than 400 500 Da) and a high lipid partition coefficient. Consequently, it is crucial to obtain safe and efficient therapy through the delivery of pharma- ceutically active compounds to specific sites in order to treat neurodegenerative diseases. According to a published research, double emulsion solvent evaporation was used to create dopamine nanoparticles of borneol and lactoferrin for the treatment of Parkinson’s disease. When compared to free dopamine, polymer-encapsulated dopamine formulation demon- strated less toxicity in an in vitro cytotoxicity study on SH-SY5Y and 16HBE cells. In a related research, frovatriptan succinate polymeric NPs were developed for nasal delivery to the brain. Smooth NPs with a zeta potential of 235.17 6 0.07 mV and a particle size of 264.4 6 0.04 nm were produced using the double emulsification technique. An ex vivo diffusion investigation on goat nasal mucosa revealed that PNPs penetrated the mucosa about three times as quickly as pure drug solution. Fluorescence microscopy was used to show that PNPs were delivered to the brain in male Wistar rats after intranasal administration. 12.5.2 Cancer delivery Cancer presents an imminent danger to life and has a poor prognosis. It is a pathophysiolo- gically diverse disease that quickly progresses after onset into an uncontrollable stage. For the majority of cancers, multimodality strategies like chemotherapy, radiotherapy, and surgi- cal resection continue to be used as first-line treatment option. The two main types of chemo- therapy used to treat various cancers are cytotoxic and cytostatic agents. Direct tumor cell death, antiangiogenesis, prodifferentiation, disruption of growth factor pathways, and sup- pression of tumor invasion are all components of these drugs’ mechanisms. Conventional che- motherapy is the major strategy causing undesirable side effects to the healthy tissue due to Molecular Pharmaceutics and Nano Drug Delivery 300 12. Fundamentals of a targeted drug delivery system the nontargeting mechanism causing severe toxicity to normal cells. Additionally, because of their inherent properties like poor aqueous solubility, the requirement of high doses, inade- quacy to attain desirable drug concentration in tumor or cancer cells, nonspecific biodistribu- tion and development of multiple drug resistance make their use even more cumbersome. Unconventional therapies such as photodynamic therapy, gene therapy, hormone ther- apy, and immunotherapy are potential adjuvant treatments that have shown promise in clini- cal trials for eradicating cancer. The range of therapeutic agents including antibodies, genetic material, and photosensitizers, has been expanded by these additive treatments. Drug distribution is still a problem when treating cancer. In addition to complementing traditional chemotherapy and radiotherapy, the more recent methods of cancer treatment also avoid harming healthy tissues and preventing drug resistance. The use of nanotechnology for deliv- ering these chemotherapeutics and other pharmaceutical actives to various cancers helps to improve their pharmacokinetic properties and solubility, reduce in vivo metabolism, prolong plasma half-life, and so on. It also helps the drug to reach tumor tissue by passing through the discontinuous fenestrations in the endothelial layer and by evading circulation in the tumor microenvironment. In contrast to other normal tissue, which is surrounded by endothelial cells with tight junctions and functioning lymphatic drainage, they also primarily accumulate in the interstitial fluid of the tumor. These properties act as a magic bullet to reduce the toxicity to the normal tissue compared to conventional drug treatment and provide beneficial effects to the patients by enhancing the permeability and retention effect. In a research, an NLC gel of quercetin and resveratrol was produced with a particle size of 191 6 5.20 nm, a zeta potential of 210.00 6 0.30 mV, and an entrapment efficiency of 92.85% 6 0.25% to enhance their deposition in dermal and epidermal layers. NLC gel could be used as a potential carrier for the delivery of quercetin and resveratrol into the deeper layers of the skin as a result of a cytotoxicity research on human epidermoid carci- noma (A431) cell line by MTT assay. This would be a hopeful formulation for the treat- ment of skin cancer. 12.5.3 Ocular delivery The limitations of traditional ocular therapy are overcome by nanocarriers, which also offer novel utility with increased therapeutic efficacy. Various nanocarriers have currently been designed for use in ocular applications. These extend ocular residence duration as well. Nanocarriers’ surface charge and size are crucial for their fusion and retention at the target location. Zeta potential is used to determine surface charge. The cornea and conjunctiva in ophthal- mic delivery have a negative charge on their surfaces; as a result, the cationic NP is attracted to the anionic biomembrane through electrostatic interactions. This results in topical drug transport to the anterior segment of the eye and the retention of cationic NP on the negatively charged ocular tissues. The anionic NPs can diffuse into the retina, whereas the cationic NPs cause NPs to concentrate in different areas of the eye without doing so. These nanocarriers can transport therapeutics to the desired site despite ocular barriers, thanks to their nanosize and surface properties. There are currently a few nanostructured ophthalmic products on the market, including Cyclokats (a cationic nanoemulsion of cyclosporine A), Molecular Pharmaceutics and Nano Drug Delivery  12.6 Characterization of targeted drug delivery systems 301 Cequas (an ophthalmic nanomicellar solution of cyclosporine A), Visudynes (a liposomal injection of verteporfin), and Artelacs Rebalance (Vitamin B12 liposomal eye drops). Due to the fact that they are biodegradable, biocompatible, safe, and efficient, these products are used to alleviate dry eye syndrome. Latanoprost and thymoquinone liposomes were pre- pared through studies using the thin film hydration technique to treat glaucoma. When com- pared to the test formulations, in vivo studies revealed that the drug-loaded liposomes substantially reduced intraocular pressure by up to 84 hours. Another research devel- oped betaxolol hydrochloride-loaded montmorillonite-chitosan nanoparticles with mean par- ticle sizes of 460 nm and surface charges of 29 mV. This study showed that these chitosan NPs had a longer residence time and were more bioavailable on the corneal surface, suggest- ing that the current treatment method could be improved. 12.5.4 Transdermal delivery One of the most appealing and cutting-edge methods for distributing medications through the epidermis is transdermal drug delivery. Compared to traditional dosage forms for the treatment of different illnesses, the transdermal route of drug administration offers a number of benefits. The epidermis serves as a reservoir and has the capacity to continuously and slowly release the drug that has penetrated it. Due to the existence of numerous absorption sites, it also reduces toxins and local irritability. The present sce- nario demands a particular emphasis on the invention of safe medications with fewer side effects that support patient compliance, prevent hepatic first-pass metabolism, and so forth. However, due to the stratum corneum, which acts as an effective barrier to the pene- tration of drugs, and the highly organized structure of the skin, transdermal delivery is accompanied with some challenges. Fortunately, it has been established that the use of nanocarriers significantly increases the penetration of drugs (both hydrophilic and lipo- philic) through this barrier and offers the desired local or systemic effect. In light of this, a microneedle patch containing nanoparticles loaded with capsaicin for transdermal drug administration was created. The zeta potential of the 106.8 nm-sized nanoparticles was 250.8 mV. When compared to native capsaicin, the plasma bioavailabil- ity of the capsaicin-loaded nanoparticles was higher in C57NL/6 mice. The dynamic release of MNPs in vitro and ex vivo peaked at 3 minutes. In a different study, curcumin-loaded SLN microneedle patches were developed. The manufactured micronee- dles were also discovered to be nonirritating, demonstrating the improved efficacy of the novel formulations by reducing bradykinesia and increasing motor coordination and bal- ance ability. 12.6 Characterization of targeted drug delivery systems Characterizing the developed TDDS is a critical step, as it gives information about its physicochemical and functional properties. Different aspects of the DDS require to be characterized, which provides specific insights about the nature and behavior of the prod- uct. Also, the intended use such as the pattern of drug release, surface modification, and Molecular Pharmaceutics and Nano Drug Delivery