A Review on Role of Nanoparticles in Targeted Drug Delivery Systems

Nanoparticles used in drug delivery range from 10 to 1000 nm in size with at least one dimension being below 100 nm in size. The small sizes of nanoparticles as well as their surface chemistry are known to offer pharmaceutically beneficial attributes but may also contribute to their toxic effects as discussed earlier. Smaller nanoparticles enter cells more effectively when compared with larger molecules, but the administration of nanoparticles with a reduced clearance may result in some of the particles being retained within the body. In the case of a more active or cytotoxic nanoparticle being retained rather than a bulk of the drug being eliminated during the first pass effect, this may result in harmful effects on the targeted site due to unwanted retention^.[1] Systemic administration of cytotoxic drugs may cause the drugs to exert their cytotoxicity on tissues during the first pass before they reach the intended tissues. Overall, 70% of globally synthesised drugs have poor aqueous solubility and hence poor pharmacokinetic properties in vivo. As a solution to this, nanoparticle drug delivery systems (DSSs) have been developed to achieve targeted and more efficient delivery of the therapeutic substance, which would prevent damage to surrounding organs from the effect of administered drugs that will otherwise arise if the drugs were in the free form. Over the past few decades, research efforts into DSSs have advanced significantly with various DSSs already being investigated and developed for the treatment of diseases, such as cancer and neurodegenerative diseases^.[2]

Nanoparticles offer better advantages over other carrier systems.  A major  advantage of nanoparticles which makes them  an  efficient delivery  system  is  their  submicron  size  which  makes  extravasations possible and occlusion of terminal blood vessels. In addition, high density of therapeutic agent can often be encapsulated, dispersed or dissolved in these nanoparticles, which in turn depends on the preparation process to yield different properties and release characteristics of the entrapped agent^.[3] Though liposomes have been used as potential carriers with properties including protecting drugs from degradation, targeting to  site  of  action  and  reduction  in  toxicity  or  side effect.  Despite of  this  versatility,  some  technical limitations  including  poor reproducibility  and  stability  have  been reported.  Moreover drug delivery systems designed as liposomes cannot be used for controlled release of drug because of leakage of drug entrapped inside liposomes. On the other hand, polymeric nanoparticles offer some specific advantages of increasing the stability of drugs/proteins and possess useful controlled release properties16. Other features of nanoparticles include low number of  excipients  used  in  their  formulations, simple procedure for preparation, high physical stability, and the possibility of sustained drug release that may be suitable in the treatment of chronic diseases^.[4] By varying the polymer composition of the particle and morphology, one  can  effectively tune in a variety of controlled release  characteristics , allowing  moderate  constant doses over prolonged periods of time. Liversidge and Cundy reported that availability of drug molecule entrapped in nanoparticle was 77% higher than  a  similar  formulation  consisting  of  microspheres17. Further,  the  nanoparticle  system  was  used  for  various  routes  for  administration including  oral, nasal, parenteral, ophthalmic application18. Oral delivery of small drugs molecules can also be achieved which otherwise would  not be  available as  injectable such  as anticancer  agents19.  Also, the  nanoparticles are good candidates to be shown as adjuvant for vaccines and advantageous features of nanoparticles include increased  interaction  of  drug  molecules  with  epithelial  cells  can  be  achieved  leading  to  maximal absorption of the drug molecule.

Nanomedicine and nano delivery systems are a relatively new but rapidly developing science where materials in the nanoscale range are employed to serve as means of diagnostic tools or to deliver therapeutic agents to specific targeted sites in a controlled manner. Nanotechnology offers multiple benefits in treating chronic human diseases by site-specific, and target-oriented delivery of precise medicines. Recently, there are a number of outstanding applications of the nanomedicine (chemotherapeutic agents, biological agents, immunotherapeutic agents etc.) in the treatment of various diseases^.[5] The current review, presents an updated summary of recent advances in the field of nanomedicines and nano based drug delivery systems through comprehensive scrutiny of the discovery and application of nanomaterials in improving both the efficacy of novel and old drugs (e.g., natural products) and selective diagnosis through disease marker molecules. The opportunities and challenges of nanomedicines in drug delivery from synthetic/natural sources to their clinical applications are also discussed. In addition, we have included information regarding the trends and perspectives in nanomedicine area. In the past few years, the successful development of nanotechnology, especially the emergence of new nanomaterials, has provided new ideas and potential methods for diagnosing and treating many major diseases^.[6] Because of their unique physicochemical and biological properties, nanomaterials are widely used in drug delivery systems (DDS). Compared to conventional DDS, nano-DDS can effectively enhance the therapeutic efficacy by improving the pharmacokinetic and pharmacodynamic properties of encapsulated drugs, including drug stability, and achieving targeted drug delivery and controlled drug release due to their special characteristics of size, shape, and material ^.[7]

Nanoparticles are crucial in targeted drug delivery systems because they act as carriers to deliver drugs specifically to diseased cells, which increases efficacy and reduces side effects on healthy tissue. They can be engineered to overcome biological barriers like the blood-brain barrier, improve drug stability and solubility, and control drug release over time. This precision is achieved through passive mechanisms like the enhanced permeability and retention (EPR) effect, active targeting using surface ligands that bind to specific cells, and stimuli-responsive systems that release the drug in response to a trigger^.[8]

a) Active Targeting:   The nanoparticle  carrier  or  therapeutic drug in active targeting attach and bind  itself  to  the specific tissue or  cell.  In the active targeting, the targeted molecules bind their-self to the drug delivery system to be reached directly to targeted site i.e., tumor tissue, intracellular organ, cancer cell or specific molecule in it. The carrier drugs through this system attach to the surface of tissue specific antigen, carbohydrate and receptor to treat tumor.

 b) Passive Targeting:  Passive targeting, together with the drugs carriers inactively reach the specific target site. The mechanism in which the vessels leak the drug and gather in the cell by increasing the retention and permeability (Muhamad et al., 2018) when the tumor size increases up to 2mm3 the absorption ability of the cell becomes weakened and start angiogenesis to fight with the  problem.  Due  to  this,abnormalities  in  the  basement  membrane  lead  to  leaking  of  vessels  of  the  pore  size  100 to1200nm^.[9] 

Figure no :1 Nanotechnology based targated drug delivery system

How nanoparticles enhance targeted drug delivery:

Targeting diseased cells: Nanoparticles can be designed to navigate the body and deliver drugs specifically to a target site, such as a tumor.

Overcoming biological barriers: Their small size allows them to cross difficult barriers like the blood-brain barrier (BBB) to treat conditions like brain tumors.

Improving drug properties: They can improve the solubility, stability, and bioavailability of a drug, ensuring it remains effective until it reaches its target.

Controlled drug release: Nanoparticles can be engineered to release their drug cargo in a controlled manner over an extended period, leading to sustained therapeutic effects^.[10]

Minimizing side effects: By targeting the drug to the site of action, nanoparticles minimize exposure to healthy cells, which significantly reduces systemic toxicity and side effects.

Nanoparticles The nano-fluid was first discovered by Choi. These are manipulated colloids comprising the base fluid and nanoparticles. These may be organic fluid, oil and other lubricants, water etc. As the name indicates the nanoparticle are so small i.e., less than 100nm.[11] The main constituent of nanoparticles are oxides, metals and carbon nanotube .Nano particle-Based Targeted Drug Delivery The nanoparticle drug delivery system gained attention in multiple filed due to its characteristics. Its small size and ability to penetrate different barriers, elevate the limit of drug in target cells/tissues. They are designed as controlled drug release system i.e., they control the property of particles by lowering their side-effects and increasing their efficiency. The nanoparticle is synthesized from biodegradable materials which are safe for the body use. Coating of the drugs in nanoparticles carriers guard them from environmental damage i.e., pH, Temp etc. They are shaped to ignore the immune system clearance and increase the drugs circulation time. Targeted and controlled release of the nanoparticle lower the effect of drugs on non-targeted tissues^.[12]

Nanotechnology and their use The technology or science permitting to regulate, study, manipulate and build the devices and structures of nanometer size. The Nanoparticle’s small size, customized coating, well developed solubility and many more functions assist them in creating innovative biomedical application. Through nanotechnology we can develop new tools that helps to diagnose, target and treat many notorious disease like neurodegenerative disease, cancer and tumor, develop single dose vaccine, and oral delivery of therapeutic protein ^.[13]

Physiochemical Properties of Nanoparticles in Medicine:

Nanoparticles have various properties that facilitate enhanced pharmacologic behaviour when compared with larger molecules. As such, significant efforts are being made in research modifying the nanoparticle size, shape, surface area, and surface chemistry to maximise their benefits for medical purposes.

Different nanoparticles such as gold nanos hells, liposomes, and micelles are synthesised in various ways, and the sizes and shapes of these nanoparticles can be controlled during the synthesis process based on the intended functionality. Nanoparticles can agglomerate into larger-sized particles during synthesis, which may enhance or indeed suppress the nanoparticle cytotoxicity depending on composition.

The surface chemistry of nanoparticles can be modified by adding reactive groups or molecules such as antibodies to surfaces in targeted drug delivery systems^.[14]

(Figure no :2 Types of nanoparticals)

CLASSIFICATION:

NPs On the base of size, structure and chemical properties nanoparticles are divided into different categories which are as follow

Organic NPs The organic nanoparticle are alternative to metallic nanoparticle because of their biocompatible nature, they are use as imaging agent because of their ability to deliver drug to target site, e.g. in cancer cell they deliver drug to tumor cell and disease site Moreover, with the passage of time the use of organic nanoparticle in medical field increased worries about the potential accumulation inside the body. The accumulation leads to unintentional concern and adverse reactions

A] In-Organic nanoparticles: Inorganic nanoparticles coated with biological membranes are promising in personalized medicine, integrating synthetic and bionic nanocarriers for disease treatment. These nanoparticles have been widely used in tumor treatment, toxin removal, and antibacterial applications, achieving excellent results compared to traditional drugs.

B] Carbon-based nanoparticles: The two major groups, carbon nanotube and fullerenes represent carbon-base nanoparticles. Fullerenes are made up of allotropic carbon. Due to their properties like electrical conductivity, electron affinity, high strength, versatile nature and structure they gain commercial importance . Carbon nanotube have tubular elongated structure having diameter 1-2 nm . It resembles graphite structurally.

C] Metal nanoparticles: The metal nanoparticles are synthesized from the precursors of metals. The nanoparticles of noble and alkali metals such as copper, gold, silver, have a large band of absorption in the visible portion of electromagnetic solar spectrum . Gold nanoparticle is use in SEM i.e., to obtain high resolution image.

D] Ceramics nanoparticles: They are non-metallic inorganic solid form through heat and successive cooling. In atmosphere they can be present in different forms i.e., porous, dense and hollow form. Due to their application in various field of research they attract greater attention of researchers Semiconductor nanoparticles They have characteristics between nonmetal and metal and because of this they have great importance . Semiconductor have bad gap and band proper therefore they are rarely effective in water splitting application^.[15]

E) Lipid nanoparticle: Nanoliposomes are lipid vesicles, spherical in shape, having a membrane bilayer that is made up of lipid molecules which are amphiphilic in nature. These nanoliposomes can be synthetic or natural. The most distinguishing feature of nanoliposomes is that it does not require any modification to carry either hydrophilic or hydrophobic drugs.

F) Polymeric nanoparticles: Polymeric nanoparticles are colloidal nanoparticles containing the therapeutic agent either encapsulated or adsorbed on the surface of the nanoparticle . These particles have the advantage of better circulation within the fine blood capillaries without getting agglomerated, thus, preventing blockage,

G) Gold nanoparticles: The application of gold nanoparticles in the medical field is not new but it is used for the treatment of diseases from centuries ago.

H) Dendrimer: Dendrimers are macromolecules having an ordered and highly branched structure having a core, branches coming out from core, and functional groups attached on it . The branched structure provides high ratio of surface area to size^[16]

EVALUTION:

1) Particle size analysis: The particle sizes of the nanoparticles were evaluated by scanning electron microscope were ranging from 350 nm to 600 nm, particle size varies depending on the polymer load.

2) Scanning Electron Microscopy (SEM) studies: The particle shape and surface morphology of nanoparticles were examined by scanning electron microscopy. Lyophilised and completely moisture free samples were consigned on aluminium stubs using adhesive tapes and coated with gold using sputter coater and observed for morphology at an acceleration voltage of 20 kV.

3) Differential scanning Calorimetry (DSC) studies: The physical status of the native drug inside the nanoparticles was ascertained by the DSC analysis (DSC-60, Shimadzu, Japan). Approximately, weighed 2 mg of native drug, polymer and nanoparticles were placed separately into the different sealed standard aluminium pan and were scanned between 25°C and 300°C with heating rate of 10°C/min under nitrogen atmosphere. An empty aluminium pan served as reference.

4) Atomic Force Microscopy (AFM) studies: Atomic Force Microscopy (AFM) studies were carried out to characterize the surface morphology of prepared drug loaded nanoparticles. The nanoparticle suspension was prepared with milli-Q water and dried overnight in air on a clean glass surface and observation was performed with AFM (JPK Nano Wizard II, JPK instrument, Berlin, Germany) with silicon probes with pyramidal cantilever having force constant of 0.2 N/m.

5) To avoid damage of the sample surface, all measurements were conducted in intermittent contact mode and the tip to sample distance was kept constant using the amplitude feedback function in attractive forces regimen. The scan speed of 2 Hz and 312 kHz resonant frequency was used for displaying amplitude, signal of the cantilever in the trace direction and to obtained images .

6) Determination of percentage of drug entrapment efficiency: Prepared nanoparticle suspensions were centrifuged at 2000 rpm for 30 min. The supernatant was collected and the particles were washed with water and then subjected to another cycle of centrifugation^.[17]

ROLE OF NANOPARTICALS

• Conveying medication in small particles builds the surface region of the medication, assisting it with separating quicker in the body.
• Drug conveyance frameworks are planned in unambiguous ways to move prescriptions to designated regions in the body.
• Prescriptions can go through boundaries in the body, like epithelial and endothelial obstructions, to arrive at their planned objective.
• Blend treatment includes utilizing two unique methods or prescriptions together to accomplish a more viable result in treating a condition^.[18]

(Figure no :3 Nanoparticals in damaged lining)

APPLICATION:-

1. Targeted Drug Delivery: - Nanoparticles can encapsulate drugs, delivering them directly to tumor cells, reducing side effects.
2. Biosensors:- Modified nanoparticles can detect specific molecules, aiding in diagnostics and research.
3. Tissue Engineering:- Nanomaterials are used to create implants and scaffolds for tissue repair.
4. Antimicrobial Applications:- Silver nanoparticles are used in various products for their antibacterial properties.
5. These systems in general can be used to provide targeted (cellular or tissue) delivery of drugs, improve bioavailability, sustain release of drugs or solubilize drugs for systemic delivery. This process can be adapted to protect therapeutic agents against enzymatic degradation
6. Thus, the advantages of using nanoparticles for drug delivery are a result of two main basic properties: small size and use of biodegradable materials. Nanoparticles, because of their small size, can extravasate through the endothelium in inflammatory sites, epithelium
7. In general, the nano size of these particles allows for efficient uptake by a variety of cell types and selective drug accumulation at target sites. Many studies have demonstrated that nanoparticles have a number of advantages over microparticles (>1 μm) as a drug delivery system Nanoparticles have another advantage over larger microparticles because they are better suited for intravenous delivery.
8. The smallest capillaries in the body are 5–6 μm in diameter. The size of particles being distributed into the bloodstream must be significantly smaller than 5 μm, without forming aggregates, to ensure that the particles do not cause an embolism. ^[19]

STRATERGIES  FOR TARGATED DRUG DELIVERY  USING NANOPARTICALS

a) Ligand-based Targeting  : Numerous nanoparticle-based drug delivery and drug targeting systems have been developed or are currently under development. Their  use  aims  to minimize drug degradation, prevent  side effects, and increase drug bioavailability. These systems use ligands, which recognize and bind to target antigens by specific cells  or tissue components. Ideal ligands for targeted  delivery  have  high  avidity,  specificity,  internalization  of  polymeric  particles,  compatibility  with  chemical modification, and  sufficient  quantity. Low  ligand  density is  necessary  for effective  interaction  with the  receptor. 

b) Antibody-based Targeting  : Immunotherapy  has  been  enhanced  by  the  discovery  of  antibodies' structure  and  hybridoma technology, enabling targeting  tumors  both  in  vitro  and  in  vivo.  Modern  antibody  technology  involves  designing  and  preparing  fragments against various tumor antigens.  Cancer  cells  overexpress  known protein biomarkers or tumor-associated  antigens  (TAA), and  these  TTA's  provides  insights  for  antibody-mediated  targeting.  Antibody-coupled  nanocarriers  are attractive  drug targeting systems  due  to their  specificity and  stability. 

c) Magnetic Targeting :  Due to magnetic field and the moment of network units these nanoparticle are activated and when the magnetic field is absent they act as an inactive particles. The magnetism and nanotechnology combination seek attention for many years due to their  wide  use  in different field  i.e.  catalysts,  magnetic fluids, magnetic  resonance,  water treatment, biomedicine, magnetic resonance imaging, biotechnology .

d) pH-responsive Targeting  : Due  to  the intracellular  and extracellular stimuli of  the  pH responsive  nanoparticles  against  tumor  increase  the glycolysis  which  in turn increases  the  production  of lactic  acid  through  which  tumor gain  energy .  The  external  pH  of tumor  is  between  6.5  to 7  which is  slightly  acidic  while the  internal pH is  slightly  higher than  the other body fluids and tissues.  Meanwhile some internal parts of the cells are more acidic such as lysosomes have pH 4.5 to 5 and endosomes have pH 5 to 6.5. ^[20]

(Figure no:4 role of nanoparticals in targated system)