[0:18]Hello everyone. I welcome you all to the 17th lecture of this course. The 17th lecture is on nanopharmacology and drug targeting. So, in this lecture, we are going to learn what is nanopharmacology and various nanopharmacological targets and also, how to target the drug to a particular organs. So, this nanopharmacology is a new branch of pharmacology and it's gradually emerging with the application of nanoscience and nanotechnology in the field of nanomedicine. So, let us see the definition of nanopharmacology. So, it is a drug design and drug delivery to selected targets to improve pharmacodynamics and kinetic profiles toward safer and effective treatment is known as nanopharmacology. Okay. And let us see the definition between the pharmacokinetics and pharmacodynamics. So, the pharmacokinetics is simply defined as what the body does to the drug, as opposed to pharmacodynamics, which may be defined as what the drug does to the body. Okay. So, based on the pharmacokinetics and pharmacodynamics, the efficiency of drug get varied. So let us see how the nanopharmacology can be categorized. The first one is defining the targets. The next one is development of drugs and carrier system. And the third one is studying the target-drug interaction. And fourth one is monitoring the target-drug interaction outcomes. So let us see these in detail one by one. The first one is defining the targets. So, when you make a drug, it should exactly match with your binding site that is the receptor site. So, if it is not binding effectively, then the therapeutic efficiency will be less. For example, so if your receptor is like this, so the drug should go and exactly match with this. Okay. And this is your receptor or a binding site, and if your drug is like this, it cannot bind with the binding site. So the efficiency will be less if the target is not matching with the drug. The next one is development of drugs and carrier systems. So, we can make a biocompatible and biodegradable nano carrier, which can deliver the drug to the targeted location. For example, we can use that human serum albumin. So this is the HSA. It is a one of the highly compatible and biodegradable material, okay? And we can load with any kind of drug and also, we can target these HSA to the particular location. For example, if you want to target these nanoparticle to the cancer, we can add the cancer-specific antibodies so that it can go and bind only to the cancer cell and it can release the anticancer drug to the cancer cell. So next one is studying the target-drug interaction. So, in this, we will be learning pharmacokinetic interaction as well as pharmacodynamic interactions. So under the pharmacokinetic interaction, we will be studying the how the drug will be absorbed and what is the distribution and also the biotransformation and excretion of the particular drug. And in the pharmacodynamic interactions, we'll be studying how the drug will be interacting with the receptors and how is the sensitivity, whether it's binding only to the cancer cell or it is binding to the normal cell also. So, those things can be studied. And how the drug is transported. So, these things come under the pharmacodynamic interactions. And another important thing is studying the target-drug interaction. Usually, the binding sites of macromolecules are more hydrophobic in nature than the surface, and so this enhances the effect of an ionic interaction. For example, if you are having that target with a positive charge, and it would be nice if you have a drug with a negative charge. It can easily go and bind based on the ionic or electrostatic interactions. And as you know that most of your cells and nucleic acid, these have negatively charged, okay? So, when you have the drug with the positive charge, it can easily go and bind through the electrostatic interaction. So, if an ionic interaction is possible, it is likely to be the most important initial interaction as the drug enters the binding site. For example, you can see here, there is cationic and anionic nanoparticles can penetrate and accumulate in tumors, but only cationic particles diffuse fully throughout the tumor. So, you can see here, so this is anionic particles, and this is the cationic particles. And in the cationic particles, it is fully diffused throughout the tumor, and whereas anionic particles, it is not diffused properly when compared to the cationic particles. So, next important thing is quantitative systems pharmacology. So, that is QSP. So, in this, we will be studying the systematic as well as holistic understanding of the drug action. And this is divided into two categories, like vertical integration and horizontal integration. Okay. So, here, when you make a new drug, you will be purifying the compounds with the help of chemistry. And we'll be studying the effect of these purified compounds on the cells, and then you will study the effect of this drug on the organs. Then you will study the effect of this drug on the animals and patients and then the population. So, here, in vertical integration, you'll be studying the interaction of drug with this group. Okay. And in the horizontal integration, so you'll be studying the interaction of drug with the target and how the it will be interacting with the cellular networks and also, what is the molecular mechanism of the particular drug. So, everything will be studied under the horizontal integration. And the next one is monitoring the target-drug interaction outcomes. Okay? So, when you give the drug, we have to check whether there is any loss of therapeutic effect and what is the toxicity of the particular drug. And whether any unexpected increase in the pharmacological activity. And for example, it may give some beneficial effects. For example, it can give additive or sometime it may give antagonism effect. And next thing is you have to study the chemical as well as physical interaction. For example, you have to study whether your drug is compatible in a fluid or syringes mixture. So let us see what is the drawback of conventional therapy. So, in the conventional therapy, so you'll be using the particular concentration of drug. And that particular drug of drug will be taken at specified intervals of time with the result that there is considerable fluctuation in drug concentration level as indicated in the figure. You can see here, so the concentration of drug is going high and low. So, for an ideal dosage, you have to take the concentration, which is nearly matching with the minimum effective concentration that is MEC, okay? And it should be maintained at a constant level throughout the treatment period. So then only the therapeutic efficiency of the drug can be increased. So let us see the various nanopharmacological targets. So, under this, we'll be studying about what is slow release nanopharmacology, and what is controlled release nanopharmacology, and also we'll be studying about the biobarrier penetration nanopharmacology. So first, we'll see what is slow release nanopharmacology. So, here, the slow release nanopharmacology studies the question on how to realize the slow release and the influence of slow release on the drug metabolisms and therapeutic effects. So, you can see here, this is a non-stabilized carrier. So, where the drug is releasing very rapidly. So, when the drug is released in more concentration, what will happen, like it will be removed by your reticuloendothelial system. That is RES, reticuloendothelial system. So, it will be removed by your liver as well as spleen. And in case of stabilized carrier, your drug will be released very slowly. Okay? And you can see here, it can slowly release the drug and it can stay in the bloodstream for more time. So before we study the controlled release nanopharmacology, let us see what is sustain release dosage form. Okay? So, here, the drug delivery system that are designed to achieve prolonged therapeutic effect by continuously releasing the drug over an extended period of time after administration of single dose. And the basic goal of the therapy is to achieve steady state blood level that is therapeutically effective and non-toxic for an extended period of time. So, the design of proper dosage regimen is an important element in accomplishing this goal. So, let us see the difference between the controlled release and sustained release. So, the controlled delivery is which delivers the drug at a predetermined rate for a specified period of time. And here, the controlled release is perfectly zero order release that is the drug release over time irrespective of concentration. And in case of sustained release, it is defined as the type of dosage form in which a portion that is initial dose of the drug will be released immediately, and in order to achieve the desired therapeutic effect more promptly.
[9:10]And the remaining drug, that is maintenance dose, that will be released slowly, and thereby achieving a therapeutic level which is prolonged and not maintained constant. Okay? So, this sustained release implies slow release of the drug over a period of time, and it may or may not be a controlled release. So, let us see the controlled release nanopharmacology. So, here, the controlled release nanopharmacology studies how to realize the smart release of the drugs according to the therapeutic needs in the cellular and tissue microenvironments. So, we can use a smart nano carrier. For example, we can make a smart nano carrier, which can release the insulin depends on the blood glucose level. If there is a more blood glucose level, it can release the insulin from the smart nano carrier system. So, next one is biobarrier penetration nanopharmacology. So, here, the biobarrier penetration nanopharmacology studies the capabilities of nanodrugs to passing through biobarriers. The two important biobarriers is blood-brain barrier, and other one is air-blood barrier. Okay? So, to realize the treatment of some diseases where the traditional drugs cannot reach because of their incapability to penetrate biobarriers. So, we can use the nano carriers, which can easily cross the blood-brain barrier and it can deliver the drug and which could be useful for various therapeutic applications. So, let us see what really happens when you take a drug. So, this is a patient group, and same diagnosis and same prescription, but you can see here, different kind of effects. So, to particular group, the drug may be toxic, but it is beneficial. To other group, the drug is toxic and not beneficial. And to the other group, the drug is not toxic and beneficial. So, we have to study the effect of the drug to different patient groups before we take it for commercial application. So, here the question is, can we predict the drug efficacy and toxicity? And can we reuse the old drugs or can we design the personalized medicine for the particular patient's need? So, what is the perfect drug? Okay? So, here, the all drugs have side effects, but new drugs aim to provide beneficial effects with minimal side effects. Okay? So, how it can be achieved? So, by identifying the new molecules or modifying the structure of the known molecules and testing these in the biological tissue or the whole body. So, if we make any drug, the first thing we have to do the ADME evaluation. Okay? So, what is ADME evaluation? So, ADME means, so, it is the abbreviation in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion and describes the disposition of a pharmaceutical compound within an organism. So, how the drug will be absorbed, how it is distributed in the body, and what is the metabolism, and how it will be excreted from the body. Okay? And these four criteria influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological of the compound as a drug. For ADME evaluation, we can use the multiorgan microdevice. Instead of using the animal model, okay? So, we can use this multiorgan microdevice. So, this multiorgan microdevice are the in vitro setup of animal cells to simulate the same physiological environment and study the effect of drug on different cells and organs. So, here, these systems are capable of simulating human metabolism. So, this is like a organ-on-a-chip or human-on-a-chip. So, this chip will mimic like your human metabolism. So, we can add the drug into this chip, and we can study the effect of the drug on the particular organ. So, you can see here, this is example of human-on-a-chip. So, we can make this kind of chip. We'll study how the drug will be excreted, okay? So, this is like a kidney on a chip. Next one is, we can also make a gut, okay? So, and we can study how the drug will be absorbed. And also, we can make the liver on the chip, and we can study the metabolism of drugs. And we can make a bone marrow on the chip, and that will tell you the what kind of immune response it will, the drug will induce, okay? So, here, the devices have the potential to predict the potential toxic side effects with higher accuracy before a drug enters the expensive and time-consuming phase of clinical trials. So, before we take the drug to the clinical trials, which is time-consuming and expensive, so, we can use this lab-on-a-chip or human-on-a-chip. And we can study the effect of this drug on this. Then we can take it further for the clinical trial and commercial applications. So, since the single organ devices are testing platforms for tissues that can later be combined with other tissues within multi-organ devices. And here, the multi-organ microdevices can be seen as the physical representation of physiologically based pharmacokinetic models in which the organs are represented by an actual compartment. Okay? So, and these devices could be a way for the development of individualized or personalized medicine. So, let us see the drug dispersion. So, here, the life-saving drugs are one of the important ingredients in the latest medicines, but its unusual and excess usage could cause death. So, the nanomedicine has the successful application for the reduction of extra drugs from the human body. And implantation of nanomedicine devices could disperse drugs or hormones as required in people with chronic imbalance or deficiency states. So, this nano medicine or nano carrier, it can act like a smart delivery system and according to the need of the patient, it can release the drug and it can save the person from the particular disease. So, let us see the difference between entrapment and encapsulation of drug. So, encapsulation of drug means it involves the surrounding the drug molecules with a solid polymer shell. Okay? So, this yellow color is a drug, and it is surrounded by a polymer. And entrapment means it involves the suspension of drug molecules within a polymer matrix. You can see here, this yellow is the drug, and this blue color is the polymer. So, the drug is entrapped between the polymer matrix. So, let us see the drug release by the diffusion. So, when the polymer absorbs water, it swells in size. Okay? And this swelling created voids throughout the interior polymer. And the smaller molecules can escape through the voids at a known rate controlled by molecular diffusion. Okay? So, when you put this nanoparticle into water, so it will swell, and it will release the drug slowly. And we can control the release of this drug by simple cross-linking reaction. So, based on the cross-linking, so, we can control the release of the drug. We can if you want more release of drug at initial stage, we can do it, or if you want to release the drug slowly, that also can be possible. And the major areas of development of nanomedicine is prevention and control and by using these nano materials, we can early detect the any disease. And also, we can use it for various diagnostic applications, and also we can make a multifunctional nanomaterials which can do the diagnostics as well as therapeutics simultaneously. So, let us see the summary of checkpoints for nanomedicine design and optimization, and candidate selection for preclinical development. Methodology usually used, theoretical, in vitro, in vivo is also shown. The first thing is, we'll be studying the safety of nano material in vitro and in vivo. And you will be studying the biodistribution in in vitro and in vivo. And we have to make sure that what is the drug and imaging agent carrying capacity. It can be theoretical, or it can be in vitro studies. And you will be studying the drug release rate in vitro, and we'll be studying the effect of this drug on the cells. Then you will study the effect of this drug on the animal model and human applications in a particular group. Okay? So, then it will be taking it for commercial application. So, that's why each and every drug it's taking at least 10 to 15 years to reach the market. So, let us see the impact of nano in medicines. Okay? So, let us see the comparison between the current strategies as well as nano strategies. So, if you want to screen a particular disease, by using the current methodology, there may be a chance for non-specific markers. And when you use the nano materials, it can go and bind only to the specific markers. And here, we can do limited number of test, but here, we can do the large number of test using this lab-on-a-chip. And in case of diagnosis, like macro scale site imaging, by using the current methodology, but here, we can use the whole body as well as it can be non-invasive. In current strategy, we have to go for invasive technology. Okay? And here, in case of treatment, we have to go for surgery or radiation, okay? And whole body pharmacokinetics. And here, we can reduce that surgery. It can be minimal invasive or we can make a drug which can deliver to the particular target, okay? So, the targeted delivery is possible. And again, for follow-up, we have to use the macro scale site imaging. And here, when you use the nano, we can use the non-invasive quantitative imaging, and we can also do the early diagnosis and early follow-up. So, let us see how we can target this drug to a particular organs. So under this, we are going to see how we are going to target this drug to the respiratory system, and how we can target the drug to the brain, and how we can target the drug to the eye, as well as the neoplastic diseases. So, let us see how we can target the drug to the respiratory system. The dosing to the complete respiratory system was possible previously by a specialized nebulizer. And dosing to the complete respiratory system has only been regarded as an option for a very narrow range of therapeutics. So, some of the disease, we have to deliver the drug to the respiratory system directly. Okay? So, in those cases, we can make an inhalable nanoparticles or microparticles so that can reach the respiratory system and it can deliver the drug. So, here the particle-loaded inhaled gas is heavier. If it is heavier, it can penetrate deeper in the lungs, and if it is lighter, it can penetrate less deep. Okay? For example, the deposition occurs deeper in the lungs when particle loaded with sulfox drug, okay? When compared to the heliox drug. So, we can make the nanoparticle formulations for vaccine delivery and gene therapy, and also for various other drug delivery applications. So, we can make the inhalable nanoparticles. So, let us see how we can deliver the drug to the respiratory system. So, using the nebulizer, we can deliver this inhalable nanoparticles to the person, and these can reach the lungs, and it can deliver the drugs. For example, it can be useful for lung cancer, or it can be useful for other lung related diseases. So, we can use for mycobacterium tuberculosis therapy. So, you can have the this lipid based carriers or polymeric nanocarriers and which can reach the lungs and it can kill the mycobacterium tuberculosis. And we can also have the protein and peptide based drugs to the respiratory system. So, that will decrease the irritation caused by the drug. And also, it will decrease the toxicity due to high initial doses of the drug. And also, it will alter the immunogenicity of the protein and improve the taste of the product. And also, it will improve the shelf life of the product. So, let us see how we can deliver the drug to the brain. So, the problems of drug delivery to the brain is like the relative impermeability of the blood-brain barrier results from tight junctions between capillary endothelial cells which are formed by cell adhesion molecules. And approximately 98% of the small molecules and nearly all large molecules, such as recombinant proteins or gene-based medicines do not cross the BBB. So, that is the major problem for delivering the drug to the brain. So, most of the drugs, it cannot cross the blood-brain barrier. So, this blood-brain barrier is formed by a network of endothelial cells and is impermeable to large molecular weight chemotherapeutic agents, that is, large proteins. So, but most of the diseases, we have to send the drug to the brain. For example, CNS disorder requiring large molecules for drug therapy is Alzheimer's disease, Parkinson's disease, okay? And other disorders, which need small drug molecules are like depression, schizophrenia, and chronic pain. So, these things need a small drug molecule. So, let us see how we can target the drug to the brain. And to bypass this blood-brain barrier and to deliver therapeutics into the brain, there are three different approaches are currently used. The first one is invasive approach. The next one is pharmacological approach, and third one is physiological approach. The first one is invasive approach. In the invasive approach, we have to inject the drug directly into the brain. So, let us see the pharmacological approach. So, in this pharmacological approach consists of modifying through medicinal chemistry, a molecule that is known to be active against a CNS target to enable it to penetrate the blood-brain barrier. And here, modification of drugs through a reduction in the relative number of polar groups increases the transfer of a drug across the blood-brain barrier. So, when you reduce the polar groups in the particular drug, it will increase the transfer of the drug across the blood-brain barrier. So, here, mostly the lipid carriers are used for transporting the drugs to the blood-brain barrier. So, here, in this pharmacological approach, like formulation of drugs which facilitate the brain delivery by increasing the drug solubility and stability in plasma. So, but the limitations are, the modifications necessary to cross the blood-brain barrier often result in loss of the desired CNS activity. And increasing the lipophilicity of a molecule to improve transport can also result in making it a substrate for the efflux pump P-glycoprotein, that is P-gp. Okay? So, when you modify the drug for crossing this blood-brain barrier, what happens is it may lose its therapeutic activity. Or it may be removed by the P-glycoprotein pump. So, let us see the physiological approach. So, physiological approach is recognized by the scientific community as the one with the most likely chance of success. So, here, the drug will be delivered to the brain region by transporter mediated delivery, receptor mediated transcytosis, and receptors at the blood-brain barrier. So, you can see here, these hydrophilic molecules can be crossed, the blood-brain barrier, using this transporters or specific carrier endocytosis, or it can use the paracellular pathway, that is the the gap junction between these two cells. Okay? And the lipophilic molecules can simply diffuse the blood-brain barrier. Let us see an example how this nano particles can be useful for imaging the brain tumor. So, this is a MRI photoacoustic Raman imaging, that is MPR, imaging technique to delineate the tumor. So, here these nanoparticles can be intravenously injected into mouse bearing the brain tumor. And these nanoparticles can circulate in the bloodstream, and it diffuse through the disrupted blood-brain barrier, and it will be retained by the tumor. And these MPRs are too large to cross the intact blood-brain barrier. So, it cannot be accumulated in the healthy brain. And you can see here, this MPR is made up of gold core and Raman active layer, followed by you are having this silica shell. And on the top, you are having this GD coating, that is the Gadolinium coating, which could be useful for MRI imaging. So, by using this nanoparticles, we can do the imaging at three levels, like pre-surgery MRI, and surgery. And also, we can also evaluate after post-surgery also. So, let us see how we can deliver the drug to the eye. So, in the ophthalmic preparation, so it can be applied topically to the cornea, or it can be instilled in the space between the eyeball and lower eyelid. Okay? So, we can use a solution, but problem is it dilutes with tear and wash away through the lacrimal apparatus. And also, we have to administer at frequent intervals. And we can use a suspension, and it needs a longer contact time, and it may cause irritation due to the particle size of the drug. And we can use the ointment, and again, it needs a longer contact time and greater storage stability. And it may produce a film over the eye, and it will cause blurring vision. And we can use the emulsion for drug delivery. And here, it can have the prolonged release of drug from the vehicle, but blurred vision, patient non-compliance, and oil entrapment are the drawbacks. And we can also use the gels, and this is comfortable, but and again, it's less blurred vision, but the drawbacks are matted eyelids, and no rate control on diffusion. So, we can have the nano carriers which can have the controlled delivery system. So, it will release the drug at a constant rate for a longer time. And it can have the enhanced corneal absorption. And also, drug without not serious side effects, and it can be tolerated by the patient. So, here the advantages are, it will increase the ocular residence, and that's it, it will improve the bioavailability. And also, it gives the possibility for providing a prolonged release, and thus a better efficacy. And also, there is a lower incidence of visual and systemic side effects. And it will increase the shelf life with respect to aqueous solution. And here, we don't have to use the preservatives. So, thus, reducing the risk of sensitivity reactions. So, other advantages are, it will reduce the systemic side effects, okay? And that will reduce the other adverse side effects. And we can reduce the number of dosage. So, that's better patient compliance. And also, the administration of an accurate dose in the eyes, which is fully retained at the administration site. So, that will improve the therapeutic efficiency. So, we can deliver the drug to the eye using this various carriers. We can use the liposomes or niosomes, okay? And we can also use the microparticles or nanoparticles. So, depends on the drug as well as depends on the disease, which you are going to target, we have to select the suitable carrier. So, let us see an example. So, here you can see the example of normal eye and eye with glaucoma, okay? So, we can use the lipid based nano carrier, which can deliver the drug to this. And again, uh, we can use this lipid carrier for preventing the scar tissue formation after glaucoma filtration eye surgery. So, we can prevent this formation of scar by using this sustained siRNA delivery against this SPARC. The SPARC is secreted protein, acidic, and rich in cysteine, that is SPARC protein expression is associated with tissue scarring and fibrosis. Okay? So, we can reduce this SPARC protein expression with the help of siRNA. So, let us see how we can use this multi-layered nanoparticles as non-viral vectors for siRNA delivery. So, we can have this kind of multi-layered nanoparticles, and which will carry this SPARC siRNA. So, this multi-layered self-assembly of siRNA nano carriers are customizable, simple, solvent-free systems. And this layer will be decomposed in cytoplasm, and it will facilitate the release of the siRNA for gene silencing. Okay? So, this will be useful for preventing the scar formation after the glaucoma surgery. So, let us see how we can target the drug to the neoplastic disease. Neoplastic means cancer. Okay? So, here the goal is to inject treatment far from tumor and have large accumulation in the tumor and minimal accumulation in the normal cells and organs. So, this targeted delivery to tumors and cancer, so, I already discussed in one of my previous lecture in detail. So, but briefly we see here how we can use this. So, here most of the failure in the cancer treatment is the tumor penetration. Okay? So, the tumor penetration is a key issue for the successful chemotherapy. And most of the cases, the drug cannot enter into the inside of the tumor location. So, due to which, what will happen, these the tumor will regrow. Okay? So, to overcome this, we can use the nanoparticles, and this nanoparticles can pass through interstitial spaces between necrotic and quiescent cells. And this tumor cells typically have larger interstitial spaces than healthy cells. Okay? So, the particles can collect in the center and bringing therapeutics to kill the tumor from inside out. So, you can see here this nanoparticle can enter and only bind to the tumor cells, and it can eradicate the tumor cells. And these nanoparticles, and to maximize their effectiveness, the microenvironment of the tumor must be quantified. And the nano carrier should be developed specifically to target the tumor so that it can reach the inner part of tumor, and it can completely eradicate the tumor, and it will prevent the reoccurrence of tumor. Okay? So, in this lecture, we have learned what is nanopharmacology, and also we have learned what are the various nanopharmacological targets, and how to target this drug to the particular organs. Okay? So, I'll end my lecture here. I thank you all for listening this lecture. I'll see you all in another interesting lecture.
