ROAD MAP TO NANOMEDICINES
2004 was the year when the Nanotechnology Alliance was launched by the National Cancer institute for cancer. Besides this other many initiatives were promoted globally for the advancement in treatment, diagnosis and further prevention in future all due to this Nano science and nanotechnology. This step had encourages the scientists to form teams with others and learn from each other. This article is a brief explanation of all the Nano medicines interactions taking place in our human body.
INTRODUCTION
PAOLO DECUZZI
Nanomedicine is one application of nanotechnology. Ranging from medical applications of nanomaterials and various other biological devices. All the biosensors and the nanoelectronics are included in it. The advancement of these nanomedicines in the treatment and management of various disease is driven by many principles in other science fields. This includes various blades of different sizes and purposes, materials, geometries, and moieties.
This article focuses on the ongoing usage of all the nanomedicines. Initially it is discussed about the vision of the Paolo Decuzzi and all his colleagues on the shape, surface properties, size, and other features. Which all result in the increase in the efficiency of the drug delivery system. Decuzzi and team gave a conceptual framework of all the understanding on the significance of size, shape, surface, and other features.
KENETH HOWARD
The further enhancement in the field of nanomedicines was done by Kenneth Howard. They are designing new directions of carriers. Further moving towards the development in various diseases by the contributions of Daniel Rosenblum and Dan Peer on the treatment of cancer nanomedicines and future outlook of cancer and how to prevent it from spreading ahead. (Decuzzi, 2020)
MODULATING SIZE, SHAPE, SURFACE PROPERTIES, AND MECHANICAL STIFFNESS TO BOOST EFFICIENCY OF DRUG DELIVERY SYSTEM
STATUS
In the past 5 decades powerful and stronger molecules have been developed globally which have reduced the rate to cancer and its cause. However, their actual strength is imparted by the limited solubility in water, greater toxicity, and lack of specificity.
These shortcomings can be overcomes by using nanomedicines. By exploiting the EPR and it is because which can collectively affect the tumor with the poor chemotherapeutic drainage. The main property of all these nanomedicines is controlling drug release from limited diffusion to stimulus triggered. :
CHALLANGES
The clinical research on nanomedicines is faced by various challenges which include accumulation at biological targets, advancements of patient-specific interventions, scaling up production. Injected small nanoparticles can reach up to intra tumor impurities. Moreover, some of the nanoparticles have accumulation more than 20%. Some clinical impact had brought the concentration level down up to 10%. These types of scenarios may even occur with same patient upon various testing and checkups.
ADVANCEMENTS
Combining all the geometry (shapes and sizes) and all the attributes (surface and stiffness) of all the nanomedicines can overcome all the challenges. Non-Spherical particles which are mostly cylindrical in nature showed efficiency adhere to the diseased vasculature because of the greater level of area, interactions in the given area due to the multiple engagements of the ligand-receptor bonding and continuous combinations of various ligands to improve all the molecular recognition.
CONCLUSION
By combining imaging and therapy we can use the platform of modular manufacturing in the development of the effective scaling up techniques which are all a key success in the nanomedicines and full integration into clinical practice. This manufacturing process enables the realization of all the different nanomedicines with various attributes. The size range is kept few hundreds to nanometers, shape factors is also included where shape can be either cylindrical or spherical, or cubical.
The mechanical stiffness is also ranged from 1kPa to 10 KPa. Apart form all this the radionuclide imaging can also help towards personalized interventions via different satisfactions and identifications of the nanomedicines upon the efficiency of all the nanomedicines. The platform of artificial intelligence is also widely used in the algorithm formation of the parameters and to boost performance.
NANOMEDICINES FOR CANCER THERAPY
Cancer is basically the uncontrolled growth of the abnormal cells generally anywhere in the body. Cancer is also known as a group of diseases invading abnormal growth of cells with the potential to usually invade or spread to other body parts. Cancer is a multifactorial disease because many factors are responsible for causing cancer. Cancer cells may or may not invade other tissues or organs so on these basis they are divided into malignant and benign tumors
. In ancient times conventional chemotherapies were used to treat cancer but they have certain limitations. These basically are poor solubility of water of chemotherapeutic drugs including Doxetaxel, Paclitaxel and cis-platin , non-specific biodistribution , multidrug tumor resistance and therapeutic indices that are usually low. In order to treat these limitations nanotechnology is being used. Nanocarriers usually enable large therapeutic molecules including mRNA, RNAi and CRISPR, in order to improve their bioavailability and solubility, to alter biodistribution and facilitate entry in the particular target cell.
For cancer therapy NC-based delivery systems are used to show enhanced permeability and retention (EPR) effect, allow NCs to accumulate in the tumor or is known as passive targeting and solid tumors unique characteristics including defective lymphatic drainage and leaky vasculature [3]. NCs can be decorated by monoclonal antibodies, folate and peptides that are targeting moieties in order to improve tumor retention and cellular entry and to achieve usually active cellular targeting [38’39].
NCs that serve as an active target must reach firstly to target and thus avidity and affinity is increased. So our basic requirement is efficient passive targeting in order to target solid tumors systemically or usually its microenvironment. Even in high-EPR xenografted type tumors systemically administered NCs accumulation is of small percentage. Mostly NCs alter toxicological profile, pharmacokinetics or drug solubility. NCs usally alter the solubility of drugs¸ pharmacokinetics and toxicological profile.
NANOMEDICINES
Nanomedicines that are being used in chemotherapy are Myocet, Doxil, ThermoDox, Oncaspar and Polyglumex.
1) Myocet:- Its active ingredient is liposome encapsulated Doxorubicin. It is manufactured by Elan pharmaceuticals. Its use is in breast cancer therapy.
2) Doxil:- Its active ingredient is Pegylated doxorubicin. It is manufactured by Orthobiotech and is use to treat breast and ovarian cancer.
3) ThermoDox:- Doxorubicin is its active ingredient. It is manufactured by celsion corporation. It is used in hepatocellular carcinoma therapy.
4) Oncaspar:- PEG asparaginase is its active ingredient. Manufactured by Enzon and is used to treat acute lymphocytic leukemia.
5) Polyglumex:- It is mainly used to treat lung carcinoma.
NANOPARTICLES
Nanoparticles that are being produced to treat cancer are
1) Metal nanoparticles: Mostly silver and gold NPs are used to treat different types of cancers. PEGylated silver and gold NPs are usually used. They have unique optical properties, appropriate size scale and facile surface chemistry. Silver based nanostructured materials are usually used as bioimaging labels for human lung cancer H1299 cells. Antitumor ability of silver and gold NPs depend on concentration, nanoparticle size and IR dose. Gold NPs general working principle is to absorb incident photons and convert them into heat in order to destroy cancer cells. Metal oxide and magnetite are also used in nanomedicines.
2) SPIONs: Super paramagnetic iron oxide nanoparticles are used for inducing magnetic field and responsive functionality of drug delivery systems.
3) Mesoporous silicates: Studied for drug delivery and especially for cancer treatment alone or combined with organic or inorganic polymers.
STRATEGIES
Basic strategies to deliver nanoparticles into tumor are
1: Topical application for skin tumors.
2: Direct injection
Intraoperative application for accessible deep tumors or Intra vascular injections for inaccessible tumors.
CURRENT AND FUTURE CHALLENGES
There are many challenges that we are recently facing and in future we have to face, these usually are;
Limiting factors basically are permeability and NCs extravasation which usually display both temporal and spatial heterogeneity inside a tumor, thus additional complexity is added to control NC extravasation. NC extravasation is also affected byphysicochemical properties e.g; shape and size. Particle size reduction reduces diffusional hindrance, thus penetration into intestinal matrices is improved .Due to Lack of imaging techniques and quantitative tools for accumulation of NC and penetration into patients.
RECENT ADVANCES
Many recent advances have been made in order to treat cancer by using nanoparticles and nanotechonology these basically are;
1) Heat-based vasodilation
2) Cell-mediated nanocarriers delivery
3) Development of quantitative techniques.
We can improve the tumor accumulation rate by EPR augmention using usually angiotensin induced hypertension, or another solution is to use heat-based vasodilation. Application of active cellular targeting can also improve accumulation of tumor and retention in tumor so drug’s effective dose is increased. Cell-mediated NC delivery can also be utilized bypassing EPR.
This usually exploits some cell type ability to migrate to the tumor site e.g; leukocytes. For targeting tumor in low-EPR tumors or usually in metastatic tumor location that can’t be reached by certain free NCs. But it is limited to the therapeutics having low toxicity level to normal carrier cells. For therapeutics application certain body compartments can be locally accessed locally e.g; bladder, lungs, eye, peritoneum and brain. So, in these areas local delivery is effective and can increase significantly effective dose at the site of the disease thus it reduces systemic toxicity. Development of more accurate, effective and accurate quantitative techniques can show some advantages also. Cu-labeled HER 2- targeted liposomes and CT/PET was utilized by Lee et al in order to quantify accumulation of drug in 19 of the patients with particular type of breast cancer usually HER 2-positive metastatic breast cancer. The patients that were having high deposition of Cu-liposomal lesions were basically associated with usually more of those treatments that were favorable
.
NANOMEDICINES FOR DIABETES
Diabetes is usually a metabolic disorder characterized by abnormally elevated blood glucose level. There are basically two types of diabetes; Type 1 Diabetes and Type 2 Diabetes. Stage 1 of diabetes is DCBD insulin resistance, stage 2 is known as DCBD pre diabetes, stage 3 is called DCBD type 2 diabetes and stage 4 is DCBD vascular complications e.g nephropathy, retinopathy and neuropathy. Type 1 diabetes usually occur when your immune system attack and kill beta cells of pancreases that produce insulin. Type 2 diabetes generally caused by genetic and environmental factors these cause insulin resistance.
NANOPARTICLES NPs that are used to that diabetes are
1) Polymeric biodegradable nanoparticles
– N-iopropylacryl amide
– Polymethacrylic acid
– Poly isobutylcyanoacrylate
– Poly caprolactone
These are used for oral insulin administration.
2) Polymeric micelles
3) Ceramic nanoparticles
4) Liposomes
5) Dendrimer
NANOMEDICINES FOR ATHEROSCLEROSIS
Atherosclerosis is the build-up of a waxy plague on inside of blood vessels, thus plague deposits can eventually block the flow of the blood. We can also say that it is a low grade inflammatory disease of arteries.
NANOPARTICLES
1) Flash nanoprecipitation:
It is usually a simple scalable and the most common process that is being utilized for the production of polymer-based particles. It is also used as nanocarrier of atherosclerosis design.
2) Inorganic nanoparticles:
– Metal nanoparticles:
These are considered attractive carriers for the delivery of particular gene because of their low cytotoxicity and bioinert properties.
Au/ Ag nanospheres: These spheres have 5, 10, 20, 50nm target. They also have VCAM-1 targeting peptide.
Cyclodextrin NPs coated with phospholipids: Their size usually is approximately 100nm and they target phagocytosis.
– Oxidation-sensitive chitosan oligosaccharides nanoparticles coated/ not coated in macrophage membrane.
DIAGNOSIS
Early and accurate diagnosis is necessary in order to cure atherosclerosis.
– Early diagnosis: Early diagnosis is basically necessary to initiate specific type of care and to reduce clinical consequences. This also may lead to improve the quality of life of the patient that is suffering from atherosclerosis. \
– Accurate diagnosis: Usually it is critical, because the patient that has been discharged inappropriately from the hospital having acute coronary syndrome (ACS), having upto 26% potentially lethal and fatal complications.
NANOANTHERO PROJECT
In nanoanthero project certain nanoparticles have being used in order to check their efficacy in the treatment of atherosclerosis.
TECH-FUCOIDAN:
First drug was Tech-fucoidan, its aim was basically to provide safety and itr also provide SPECT imaging. It was tested on about 10 patients. Its first result was that it show favorable biodistribution. Its second result show about its safety profile and its third or final result show that it was observed under SPECT imaging.
PREDNISOLONE PEG-LIPOSOMES:
Its aim was the treatment of atherosclerosis plaque. Number of the patients on which it was tested were 57. Its first result was that it show improvement in pharmacokinetic profile. Its second result was that it can recognize the location of plaque. Its final result was that it show no reduction in inflammation or permeability of aterial walls.
CER-001: This drug aim was that it can effectively target atherosclerotic plaque. 8 patients were injected this drug. First result it show was it aids in increasing plasma apoA-I levels and efflux capacity of plasma cholesterol. Second result it show was the location of that plaque. Final result was that no adverse event was observed on change in heart rate or blood pressure was observed.
SILICA-GOLD NANOPARTICLES: Its basic aim was safety and the treatment of atherosclerotic plaque. 180 patients were given their dose. Its first result was the reduction or lowering of total atheroma volume. Its second result was that it can lower the risk of deaths that were caused by cardiovascular mal functioning. Final result was that this drug show safety profile clearance
CHALLENGES IN THE CLINICAL TRANSLATION OF NANOMEDICINES
It is an expensive and time consuming process if we talk about the clinical translation of NNMs. Conventional formulation technology containing free drug dispersed in a base (e.g., tablets, capsules and injections)are far more simple in comparison to NNM technology. Key issues related to the clinical development of NNMs include biological challenges, large-scale manufacturing .Other than the therapeutic efficascy , significant hurdles are being imposed by these factors.
BIOLOGICAL CHALLENGES
Traditionally, formulation-driven approach is being used for NNM development, in which by considering the physicochemical perspective, the characterization and engineering of noval delivery systems are being done . The limitation of NNMs in the clinical translation is only with a pathological application when attempting to align the NNM.
The relationship of biology and technology is understood by Understanding the nanomedicines accumulation influence on disease pathophysiology, distribution retention and efficacy and the relation between the drug and the delivery system properties and considering the difference between in vivo behavior of animal and humans should be considered for successful clinical approval of NNMS. Hence, disease-driven approach which exploit the pathophysiology of disease, is being applied for designing and developing NNMs, to improve its clinical translation .
Disease heterogeneity and pathophysiology of disease are two things which are linked together and their connection must be considered for the development of NNMs and while considering the biological barriers which are properly overcome for proper targeting to disease tissue, physiochemical characteristics of NNMs gained much importance. The problem arises regarding the link between patient biology and NNMs behavior and heterogeneity of disease is least efforts of research being dedicated to these arease for understanding them carefully—ands thses seeminglky the major reasons of clinical translation failure of NNMs. The pharmaceutical industry investment is also being effected by These biological challenges in case of nanomedicines.
The preclinical data should completely checked the efficacy, safety, biodistribution and pharmacokinetics in disease modal can reduce the investment risks of pharmaceutical industry. Results should be reproduced by evaluating of NNMs in multiple preclinical animal models. Useful data is being obtained by animal modal having narrow spectrum of clinical disease for the suitability of treating a specific patients-sub-group. Different routes of administration is based on the anatomy of humans compared to animal species should be taken into account. Biasness can be reduced in conducting Preclinical studies of NNMs by appropriate randomization and blinding and be evaluated against proper controls. Clinical application and translation difficulties arise because of not having these topics in already published studies.
LARGE-SCALE MANUFACTURING
The structural and physiochemical complexity regarding formulation of NNMs is also a major contributing factor in the slow pace of NNMs in clinical translation. Clinical translation potential is limited as large scale pharmaceutical manufacturing is quite problematic because the process of synthesis is complex and laborious one. Quality and cost are the centered point regarding the manufacturing of development of pharmaceutical.
Formulation stability and manufacturing process comes under the umbrella of quality and related issues are complexity regarding scale, quality control may be poor at some stages, purification might be incomplete, cost of manufacturing or materials may be high, production yield is low, batch to batch stability of final product is insufficient, unavailability of laboratory expertise or infrastructure.
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