Dendrimers are emerging as potential non-viral vectors for efficiently delivering drugs and nucleic acids to the cancer cells. These polymers are highly branched, three-dimensional macromolecules with modifiable surface functionalities and available internal cavities that make them attractive as delivery systems for drug and gene delivery applications. Recent work has suggested that dendrimers may be a keystone in the future of therapeutics, Dendrimers can also be being applied to a variety of cancer therapies to improve their safety and efficacy.
Dendrimer Polymers techniques is a controlled release system which helps to s...rita martin
Dendrimers are considered as the Polymers of 21st century, which ease the process of drug discovery, as we know that current drug discovery techniques takes years of time in inventing new drugs, this new Dendrimers technique help drug discovery companies and pharmaceutical industries to speed up their drug discovery process and provide better results
Dendrimers is an advanced source of pharmaceutical dosage forms. It improves the ease of drug delivery and better patient compliance. This technique can be used as the prodrug. It can be better used in Anti-Cancer therapy for better results.
Dendrimer Polymers techniques is a controlled release system which helps to s...rita martin
Dendrimers are considered as the Polymers of 21st century, which ease the process of drug discovery, as we know that current drug discovery techniques takes years of time in inventing new drugs, this new Dendrimers technique help drug discovery companies and pharmaceutical industries to speed up their drug discovery process and provide better results
Dendrimers is an advanced source of pharmaceutical dosage forms. It improves the ease of drug delivery and better patient compliance. This technique can be used as the prodrug. It can be better used in Anti-Cancer therapy for better results.
1. DENDRIMERS By: S.R.Rashmi (B.Pharma)
Kalinga University, New Raipur
2.The word "dendrimer" originated from two Greek words,
dendron: meaning tree, meros- meaning part or segment.
3. Dendrimers possess three distinguished components, namely
(i) An initiator core.
(ii) Interior layers:- composed of repeating units, radically attached to the interior core(generations).
(iii) Exterior layers attached to the outermost interior generations (terminal functionality).
4. Need of Dendrimers:
Nano-particle drug-delivery systems are most popular one.
However reticuloendothelial system (RES) uptake, drug leakage, immunogenicity, haemolytic toxicity, cytotoxicity, restrict the use of these nanostructures.
These are overcome by surface engineering the dendrimes such as Polyester dendrimer, Glyco-dendrimers, PEGylated dendrimers etc.
The bioactive agents can be easily encapsulated into the interior of the dendrimers. or Chemically attached i.e. physically adsorbed on to the dendrimer surface.
5. Types of Dendrimers:
1)PAMAM Dendrimers2) PAMAMOS Dendrimers3) PPI Dendrimers4) TECTO Dendrimers5) MULTILINGUAL Dendrimers6) CHIRAL Dendrimers7) HYBRID Dendrimers linear polymers8)AMPHIPHILIC Dendrimers9) MICELLAR Dendrimers10) MULTIPLE ANTIGEN PEPTIDE Dendrimers11) FRECHET-TYPE Dendrimers
6. Methods of Synthesis:
Divergent method: Dendrimers starts from the central core and extends toward the surface i.e. diverging into space.
Two step process:Activation of functional surface groups,Addition of branching monomers units.
7. Convergent Method: Dendrimer starting from the end groups and progressing inwards.
When the growing wedges are enough large, attached to a suitable core to give a complete Dendrimer.
8.Combined Method: This approach allows the preparation of monomers for both convergent and divergent growth from a single starting material
9. Mechanism of drug Loading :
Simple encapsulation:-It directly encapsulates guest molecules into macromolecule interior.
Electrostatic interaction:-Surface functional groups enhances solubility of hydrophobic drugs by electrostatic interaction e.g. Ibuprofen, ketoprofen, indomethacin.
Covalent conjugation:-The drug is covalently bound to dendrimers & its cleavage occurs via chemical or enzymatic cleavage of hydrolytically labile bonds. It allows tissue targeting & controlled delivery as drug-dendrimer conjugate diffuse slower than the free.
10. Applications of Dendrimers:
Dendrimers in biomedical field, Anticancer drugs, Dendrimers in drug delivery, Transdermal drug delivery, Dendritic sensors, Dendrimers used for enhancing solubility, Dendrimers as magnetic resonance imaging contrast agents
11. Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER-2 positive breast cancer
12. When a cancer is HER2-positive, it means that the cancer cells make too much HER2 protein, which can cause tumors to grow more rapidly than with other forms of breast cancer.
Dendrimers may be defined as synthetic three-dimensional hyper branched, globular macromolecule, which is characterized by its highly branched 3D structure that provides a high degree of surface functionality.
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research...iosrphr_editor
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research paper publishing, where to publish research paper, journal publishing, how to publish research paper, Call for research paper, international journal, publishing a paper, call for paper 2012, journal of pharmacy, how to get a research paper published, publishing a paper, publishing of journal, research and review articles, Pharmacy journal, International Journal of Pharmacy, hard copy of journal, hard copy of certificates, online Submission, where to publish research paper, journal publishing, international journal, publishing a paper
Nano Drug Delivery Approaches and Importance of Quality by Design (QbD)SABYA SACHI DAS
Different Novel drug delivery systems, their benefits as well as drawbacks.
Different polymers used for preparation of these novel structures:Literature survey.
Targeted drug delivery approaches.
Literature based survey of different nanostructured approaches for drug formulation.
Techniques incvolved for optimization before formulation.
Utilities of quality by design (QbD) approach of optimization.
Nanoparticle Drug Delivery Systems for Cancer TreatmentAranca
The engineered nanoparticles are effectively used for cancer treatment due to their targeted drug delivery approach. Download the Aranca report on Technology and Patent Research for current research trends and developments.
The engineered nanoparticles are effectively used for cancer treatment due to their targeted drug delivery approach. Download the Aranca report on Technology and Patent Research for current research trends and developments.
1. DENDRIMERS By: S.R.Rashmi (B.Pharma)
Kalinga University, New Raipur
2.The word "dendrimer" originated from two Greek words,
dendron: meaning tree, meros- meaning part or segment.
3. Dendrimers possess three distinguished components, namely
(i) An initiator core.
(ii) Interior layers:- composed of repeating units, radically attached to the interior core(generations).
(iii) Exterior layers attached to the outermost interior generations (terminal functionality).
4. Need of Dendrimers:
Nano-particle drug-delivery systems are most popular one.
However reticuloendothelial system (RES) uptake, drug leakage, immunogenicity, haemolytic toxicity, cytotoxicity, restrict the use of these nanostructures.
These are overcome by surface engineering the dendrimes such as Polyester dendrimer, Glyco-dendrimers, PEGylated dendrimers etc.
The bioactive agents can be easily encapsulated into the interior of the dendrimers. or Chemically attached i.e. physically adsorbed on to the dendrimer surface.
5. Types of Dendrimers:
1)PAMAM Dendrimers2) PAMAMOS Dendrimers3) PPI Dendrimers4) TECTO Dendrimers5) MULTILINGUAL Dendrimers6) CHIRAL Dendrimers7) HYBRID Dendrimers linear polymers8)AMPHIPHILIC Dendrimers9) MICELLAR Dendrimers10) MULTIPLE ANTIGEN PEPTIDE Dendrimers11) FRECHET-TYPE Dendrimers
6. Methods of Synthesis:
Divergent method: Dendrimers starts from the central core and extends toward the surface i.e. diverging into space.
Two step process:Activation of functional surface groups,Addition of branching monomers units.
7. Convergent Method: Dendrimer starting from the end groups and progressing inwards.
When the growing wedges are enough large, attached to a suitable core to give a complete Dendrimer.
8.Combined Method: This approach allows the preparation of monomers for both convergent and divergent growth from a single starting material
9. Mechanism of drug Loading :
Simple encapsulation:-It directly encapsulates guest molecules into macromolecule interior.
Electrostatic interaction:-Surface functional groups enhances solubility of hydrophobic drugs by electrostatic interaction e.g. Ibuprofen, ketoprofen, indomethacin.
Covalent conjugation:-The drug is covalently bound to dendrimers & its cleavage occurs via chemical or enzymatic cleavage of hydrolytically labile bonds. It allows tissue targeting & controlled delivery as drug-dendrimer conjugate diffuse slower than the free.
10. Applications of Dendrimers:
Dendrimers in biomedical field, Anticancer drugs, Dendrimers in drug delivery, Transdermal drug delivery, Dendritic sensors, Dendrimers used for enhancing solubility, Dendrimers as magnetic resonance imaging contrast agents
11. Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER-2 positive breast cancer
12. When a cancer is HER2-positive, it means that the cancer cells make too much HER2 protein, which can cause tumors to grow more rapidly than with other forms of breast cancer.
Dendrimers may be defined as synthetic three-dimensional hyper branched, globular macromolecule, which is characterized by its highly branched 3D structure that provides a high degree of surface functionality.
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research...iosrphr_editor
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research paper publishing, where to publish research paper, journal publishing, how to publish research paper, Call for research paper, international journal, publishing a paper, call for paper 2012, journal of pharmacy, how to get a research paper published, publishing a paper, publishing of journal, research and review articles, Pharmacy journal, International Journal of Pharmacy, hard copy of journal, hard copy of certificates, online Submission, where to publish research paper, journal publishing, international journal, publishing a paper
Nano Drug Delivery Approaches and Importance of Quality by Design (QbD)SABYA SACHI DAS
Different Novel drug delivery systems, their benefits as well as drawbacks.
Different polymers used for preparation of these novel structures:Literature survey.
Targeted drug delivery approaches.
Literature based survey of different nanostructured approaches for drug formulation.
Techniques incvolved for optimization before formulation.
Utilities of quality by design (QbD) approach of optimization.
Nanoparticle Drug Delivery Systems for Cancer TreatmentAranca
The engineered nanoparticles are effectively used for cancer treatment due to their targeted drug delivery approach. Download the Aranca report on Technology and Patent Research for current research trends and developments.
The engineered nanoparticles are effectively used for cancer treatment due to their targeted drug delivery approach. Download the Aranca report on Technology and Patent Research for current research trends and developments.
TARGETED DRUG DELIVERY SYSTEM IN CANCER THERAPEUTICS: WITH SPECIAL FOCUS ON S...AnkushSharma400
Due to the mutations in the genes, cancer occurs and propagates to the other areas of the human body. The mutation in the tumor suppressor gene, as well as the oncogene, leads to the growth of a tumor. The RNA interference (RNAi) targets these genes by inducing gene silencing. Gene
silencing has been an attractive approach to stop the growth of cancer cells after the detection of RNA
interference (RNAi) in the animal cells.
The field of nanotechnology was first Discovered by Professor Richard P. Feynman in 1959 (Nobel laureate in physics, 1965) [2]. Nanotechnology is the science of the small; very small and it is used for the management of substance at a small scale. At this size, molecules and atoms work in a different way, and provide a variety of unpredicted and attractive uses .
MD. ABU JAR GIFARI
Ph.D. Student
Dept. of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences
Prince of Songkla University
Hat-Yai, Songkhla, Thailand 90110
Phone: +660969247553
Email: agifari50@gmail.com
INNOVATIVE MEDICINES, TECHNOLOGIES AND APPROACHES FOR IMPROVING PATIENTS' HE...Jing Zang
Despite remarkable scientific and technological achievements during the 20th century, the 21st century has already witnessed additional new and profound changes in all areas of medical science and research, including innovations and discoveries in biology, cellular biology, genomics and proteomics, pharmaceuticals, medical devices, and information technology. This review is an up-date on some of the existing therapies, drug delivery technologies, and approaches that aimed to improve patients’ health care and quality of their life.
Nanotechnology for Cancer therapy: Recent developmentsroshan telrandhe
This paper is an overview of advances and prospects in applications of nanotechnology for cancer treatment. Nanotechnology is an use for prevention, diagnosis, and treatment. nanotechnology offers a promise for the targeted delivery of drugs, genes and protein to tumer tissue and therefore alleviating the toxicity of anticancer agent in healthy tissues. Cancer is one of the leading causes of death worldwide. Nanotechnology is one of the most rapidly growing fields in the 21st centuryThese mainly include arrays of nanocantilevers, nanotubes and nanowires for multiplexing detection, multifunctional injectable nanovectors for therapeutics and diagnostics. This article review current nanotechnology platforms for anticancer drug delivery, including polymeric nanoparticles, liposomes, dendrimers, nanoshells, nuclear acid base nanoparticle [DNA, RNA interference (RNAi), and antisense oligonucleotide (ASO) ] The review increases awarnes of advantages in cancer therapy.
Gene therapy is now bringing a revolutionary treatment options to most of genetic related diseases including cancers, offering the theoretical advantage of the possibility of achieving the therapeutic goal by a single treatment.
Clustered regularly interspaced short palindromic repeat is a recent genome-editing approach have attracted significant attention among the researchers due to their potential to cure all genetic related diseases including cancer by editing the genome in a way based on RNA-guided nuclease
Gut decontamination, including whole-bowel irrigation, may be necessary for amatoxins.
Beyond the first postprandial hour, orogastric lavage is not recommended, because of its questionable efficacy.
Activated charcoal plays a much more important role in limiting absorption of most toxins and is indicated for all patients with amatoxin mushroom poisoning, regardless of the timing of presentation.
Muscarine poisoning
Most patients with poisoning due to mushrooms containing muscarine can be treated without medications.
If patients exhibit excessive bronchial secretions or other symptoms of cholinergic excess (bradycardia) that are of significant concern, atropine (small doses) infusion may decrease these symptoms.
Liver transplantation Indications for immediate OLT include the following:
Stage III hepatic encephalopathy
Serum bilirubin levels higher than 4.6 mg/dL
Prothrombin time (PT) prolongation unresponsive to FFP infusions (patients with a PT >100 s should be considered for transplantation)
Age younger than 12 years
Serum creatinine level higher than 1.4 mg/dL
Hemorrhage
Shock
Acidosis
Hypoglycemia
Oral form silymarin may be obtained.
Other recommended therapies for amatoxin poisoning include the following:
IV benzyl penicillin – Reduces the uptake of amatoxin by hepatocytes
Cimetidine - Inhibits CYP450 enzymes, presumably reducing metabolism of alpha-amanitin into hepatotoxic metabolites
N -acetylcysteine (NAC) - A thiol containing glutathione precursor with free radical binding capacity and antioxidant effects
Systemic toxicity and seizures results from reduced concentrations of GABA
overcome by the infusions of pyridoxine (vitamin B-6) if they do not respond to benzodiazepines.
Inhibit the transformation of folic acid to tetrahydrofolic acid.
Therefore, patients with severe gyromitrin toxicity should receive folinic acid, as an adjunctive therapy
management of complications of poisoning
Rhabdomyolysis is treated with aggressive IV fluid resuscitation
Methemoglobinemia is treated with IV methylene blue
Hemolysis is usually mild, necessitates the administration of large amounts of IV fluids only to prevent renal complications; blood transfusions are rarely required.
An insect that has an elongated body and a segmented, curved tail tipped with a venomous stinger.
A sting can be fatal to a person who is allergic to it.
The toxicity of scorpion venom varies by species. A given species' venom may contain many chemicals, some toxic to insects, others toxic to mammals.
Scorpion species with smaller and more slender claws generally have more toxic venom.
Scorpion stings are much more dangerous for infants and small children.
Nano spray drying technology for heat sensitive biopharmaceuticalsSawsan Monir
Numerous drying methods have been used for preparing dried protein powders, although that choosing a suitable drying technique remains a challenge. In this thesis, we will discuss spray drying as a drying method for improving the stability and bioavailability of therapeutic proteins. Spray drying is a simple, fast, continuous, and scalable drying technology that is well established in biotechnological and pharmaceutical industry as for excipient production, micro-encapsulation, or granulation also it plays a crucial role in the processing of pharmaceutical products such as pills, capsules, and tablets as it is used to convert drug-containing liquids into dried powdered forms. Nano spray drying is in particular used to improve drug formulation by encapsulating active ingredients in polymeric wall materials for protection and delivering the drugs to the right place and time in the body. The Nano spray dryer developed in the recent years extends the spectrum of produced powder particles to the submicron- and Nano scale with very narrow size distributions and sample quantities in the milligram scale at high product yields. This enables the economical use of expensive active pharmaceutical ingredients and pure drugs. Critical process parameters like atomization pressure and cap size, feed rate, feed pressure, inlet and outlet temperature, residence time inside drying chamber and drying gas flow rate are optimized based on the required pharmacokinetics. In an optimized drying procedure, the screening of formulations according to their protein properties is performed to prepare a stable protein formulation for various delivery systems, including pulmonary, nasal, and sustained-release applications as they produce particles with different sizes and morphologies.
Decision analysis
DEFINITION of 'Decision Analysis - DA'
A systematic, quantitative and visual approach to addressing and evaluating important choices confronted by businesses. Decision analysis utilizes a variety of tools to evaluate all relevant information to aid in the decision making process. A graphical representation of alternatives and possible solutions, as well as challenges and uncertainties, can be created on a decision tree or influence diagram.
Decision analysis (DA) has been applied to business problems in management, marketing, operations, accounting, and finance. In addition, it has had an impact on the fields of medicine, law, military science, environmental sciences, and public policy more generally.
Markov chain:
Markov models are useful when a decision problem involves risk that is continuous over time, when the timing of events is important, and when important events may happen more than once. Markov models assume that a patient is always in one of a finite number of discrete health states, called Markov states. The ability of the Markov model to represent repetitive events and the time dependence of both probabilities and utilities allows for more accurate representation of clinical settings that involve these issues.
Market segmentation:
It is the process of dividing a broad consumer or business market, normally consisting of existing and potential customers, into sub-groups of consumers (known as segments) based on some type of shared characteristics such as shared needs, common interests, similar lifestyles or even similar demographic profiles.
Pricing strategies:
Good pricing strategy helps you determine the price point at which you can maximize profits on sales of your products or services. When setting prices, a business owner needs to consider a wide range of factors including production and distribution costs, competitor offerings, positioning strategies and the business’ target customer base.
Consumer Adoption Process:
The Consumer Adoption Process is a 5 step mental process by which all the customers/ consumer go through while adopting a product from learning about a new product to becoming a happy loyal user of that product or to decline/reject the product completely. The process of a consumer of moving from a cognitive state toward the emotional state and finally reaching towards the behavioral or conative state is another way to explain Consumer Adoption Process.
Buyer decision making process:
The customer buying process (also called a buying decision process) describes the journey your customer goes through before they buy your product.
Monosomy 7
Monosomy 7 or partial deletion of the long arm of chromosome 7 (7q-) is a frequent cytogenetic finding in the bone marrow of patients with myelodysplasia (MDS) and acute myelogenous leukemia (AML).
Furthermore, monosomy 7 or 7q- is the most frequent abnormality of karyotype in cases of AML that occur after cytotoxic cancer therapy or occupational exposure to mutagens.
The age distribution of de novo cases shows peaks in the first and fifth decades. Monosomy 7 is found in about 5% of de novo and 40% of secondary cases of AML. These findings suggest that loss of certain genes at this region is an important event in the development of myelodysplasia
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
For Better Surat #ℂall #Girl Service ❤85270-49040❤ Surat #ℂall #Girls
Dendrimers for Target Drug Delivery In Treatment of Cancer
1. 1
Pharmaceutics and Pharmaceutical Technology Dept.
PharmaceuticsandPharmaceutical TechnologyDept.
PHT518-Novel Drug Delivery
[Dendrimers for Target Drug Delivery In
Treatment of Cancer]
Authors:
Std count ID no
(serial order)
Name Contribution Signature Grade
1. 20140307 Fatma Ahmed
2. 20140550 Eman Abdelhady
3. 20140993 Mariam Ibrahim
4. 20141130 Aya Mohamed
5. 20141568 Madonna Hanna
6. 20142302 Hagar Abdelfatah
7. 20142496 Alaa Ahmed
8. 20142629 Sawsan Mounir
9. 20142666 Nada Mahmoud
10. 20143146 Norhan Reda
Submitted to:
Date of submission:
Soft copy: Submitted Not Submitted
2. 2
Research Article Rubric Topic
Required no of pages: 6-10
Font: Times Roman, 14, line spacing 1.5 (no handwriting allowed in any part of this document)
Reference style:
Abdel-Mageed, H.; Afaf, S.; Dalia S.; Saleh, A. Development of novel delivery system for nanoencapsulation
of catalase: formulation, characterization, and in vivo evaluation using oxidative skin injury model, Artificial
Cells Nanomed. Biotech., 2018, 16, 1-10. DOI: 10.1080/21691401.2018.1425213
Internet websites not preferred.
Suggestedwebsites:
www.pubmed.com
www.Google scholar.com
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topic; title and author ofworks are appropriatelyreferenced;
paragraphs are well-organized tocreate a coherent, carefullydeveloped and supported argument; transitions
between ideas are logical and each ideabuilds on the preceding; thepoint ofeach paragraph is always clear.
Conclusion effectivelyrestates theargument with fresh language and meaningful insightthatleaves the
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approach.
3. 3
Dendrimers for Target Drug Delivery In Treatment of Cancer
ABSTRACT
Dendrimers are emerging as potential non-viral vectors for efficiently delivering drugs and
nucleic acids to the cancer cells. These polymers are highly branched, three-dimensional
macromolecules with modifiable surface functionalities and available internal cavities that make
them attractive as delivery systems for drug and gene delivery applications. Recent work has
suggested that dendrimers may be a keystone in the future of therapeutics, Dendrimers can also
be being applied to a variety of cancer therapies to improve their safety and efficacy.
INTRODUCTION:
he idea of targeted drugs is not new,
but the history back to 1906 when
Ehrlich first postulated the ‘magic
bullet’. Dendrimers are an ideal delivery
vehicle candidate for explicit study of the
effects of polymer size, charge, composition,
and architecture on biologically relevant
properties such as lipid bilayer interactions,
cytotoxicity, internalization, blood plasma
retention time, biodistribution, and tumor
uptake. Over the last several years, substantial
progress has been made towards the use of
dendrimers for therapeutic and diagnostic
purposes for the treatment of cancer.
Nanoparticle-assisted drug delivery provides
a platform to modify the basic properties of
drug molecules such as solubility, half-life,
biocompatibility and its release
characteristics.in this review article, we will
discuss the new application in nanomaterial
which has an effective role in treating a various
type of cancer.1
Dendrimers are three-dimensional, immensely
branched, well-organized nanoscopic
macromolecules , possess low polydispersity
index and have displayed an essential role in
the emerging field ofnanomedicine, consistof
three parts from the interior to the surface: a
central corewith two or more reactive groups,
repeated units covalently attached to the
central core and organized in a series of
radially homocentric layers called
“generations” and peripheral functional
groups existed on the surface which
predominantly determine the
T
4. 1
physicochemical properties of a dendrimer.1
Figure 1
Dendrimers can be loaded with anticancer
compounds and/or diagnostic probes by non-
covalent interactions (ionic, hydrophobic,
hydrogen-bond interactions), covalent
bindings and spacer-mediated conjugates.2
Error! Reference source not found. They
can be targeted to cancer cells, tumor tissues,
or abnormal vessels adjacent to the disease
focus based on the molecular “hooks”
conjugated on the surface of dendrimer
through active targeting and can be
accumulated in tumors via the enhanced
permeability and retention (EPR) effect of the
nanosized dendrimer through passive
targeting. Compared with traditional
nanomaterials and polymers, Today,
researchers are actively integrating dendrimers
and dendrimer-based therapeutics for
prevention, diagnosis, monitoring, and
treatment of cancer. The usefulness of
dendrimers in humans is limited due to the
toxic effect of dendrimers and the difficulty
and expense associated with dendrimer
synthesis. However: approval of dendrimer-
based nanomedicines by the Food and Drug
Administration (FDA), entry of them into the
market, and humans really benefit from these
nanotherapeutics. Figure 5
THE SYNTHESIS OF DENDRIMERS
Dendrimers can be synthesized by two major
approaches. In the divergent approach, the
synthesis starts from the core of the dendrimer
to which the arms are attached by adding
building blocks in an exhaustive and step-wise
manner. In the convergent approach, synthesis
starts from the exterior, beginning with the
FIGURE 2 STRUCTURE AND COMPOSITION OF DENDRIMER
FIGURE 1: THE DIFFERENT TYPES OF DRUG-
DENDRIMER INTERACTIONS PROPOSED FOR DRUG
DELIVERY.
5. 2
molecular structure that ultimately becomes
the outermost arm of the final dendrimer.3 Figure
3
DENDRIMERS FOR DRUG DELIVERY
AND TARGETING
A drug delivery system should be designed to
attain the site-specific delivery preferentially.
In recent years, improved pharmacokinetics,
biodistribution and controlled release of the
drug to the specific targeted site has been
achieved with polymer-based drug delivery.
Unlike traditional polymers, dendrimers have
received considerable attention in biological
FIGURE 5 FUNCTIONALIZATION OF DENDRIMER SURFACE WI TH VARIOUS TARGETING MOIETIES.
FIGURE 3 SCHEMATIC REPRESENTATION OF DENDRIMER SYNTHESIS
BY (A) DIVERGENT AND (B) CONVERGENT METHODOLOGIES
FIGURE 4 COMBINATION DRUG DELIVERY SYSTEMS BASED ON
DENDRIMERS: CONCURRENT DELIVERY OF WATER-SOLUBLE AND -
INSOLUBLE DRUGS BY ADSORPTION TO THE SURFACE (IONIC
INTERACTION), ENCAPSULATION WITHIN HYDROPHOBIC
MICROCAVITIES INSIDE BRANCHING CLEFTS OR DIRECT COVALENT
CONJUGATION TO THE SURFACE FUNCTIONAL GROUPS.
6. 3
applications due to their high water solubility,
biocompatibility, polyvalency and precise
molecular weight.4 These features make them
an ideal carrier for drug delivery and targeting
applications. For investigating dendrimers as
drug delivery vehicles, their bio-permeability
across the biological membranes should be
considered. A study by Kitchens et al.
reviewed the cationic polyamidoamine
(PAMAM) (G0-G4) dendrimers and evaluated
its permeability across Caco-2cellmonolayers
as a function of dendrimer generation,
concentration and incubation time, for oral
drug delivery. 4
DENDRIMERS IN THE TREATMENT OF
BONE CANCER: OSTEOSARCOMA
Osteosarcomais ahigh grademalignantand
the most common type of primary bone
tumor and the second-high cause of cancer-
related deaths in children and youngadults.
Despite the improvement in surgical
techniques andneoadjuvantchemotherapy,
there is a significant limitation for the
treatmentof osteosarcomawith the current
neoadjuvant chemotherapy which leads to
poor in five-year survival rate for patients
not responding to treatment or with
metastases. So, all that makes usin need for
new therapeutic regimens. One of them is
the TRAIL which refers to tumor necrosis
factor TNF related apoptosis-inducing
ligand it is also a member of the TNF
superfamily. TRAIL induces apoptosis then
death in a wide range of tumor cells but
with minimal toxicity toward normal cells
except for hepatocytes. It has been proved
effective in the inhibition of tumor growth
and osteolysis in case of osteosarcoma.
Howeverquick clearance of TRAILin vivo is
a weakness for successful osteosarcoma
therapy. Delivering a plasmid DNA which
encodesTRAIL (pTRAIL)into tumor cells is
a solution to overcome this weakness
because it allows continuous and stable
expression of TRAIL in cancer cells and
effective introduction of apoptosisof tumor
cells. But that made us in need for a vector
to deliver DNA into plasmid. 5
In gene therapy, the design of efficient and
low cytotoxic gene vector is the major
difficulty, Viral and non-viral vectors are
the two main vehiclesfor deliveryof foreign
DNA into host cells. Viral vectors have
better gene transfection efficacy, but they
are associated with safety problems, while
non-viralvectors includingdendrimersare
7. 4
safe alternatives compared to the viral.
Dendrimershavebeen widely used as gene
vectors due to its unique properties as the
multivalent effect of surface charges in
binding DNA & the high pH-buffering
capacity which facilitates endosomalescape
via the proton sponge effect. Modifications
are made for dendrimers in order to get
high transfection efficacy and minimal
cytotoxicity for example Triazine which is
capable of binding DNA through
complementaryhydrogenbonds,butdueto
relatively low solubility and transfection
efficacy, triazine were conjugated to
generation 5 polyamidoamine (G5)
(PAMAM) dendrimer to finally form G5-
DAT66/pTRAIL complex (DAT refers to
diamine triazine) which show good
solubility in water and efficient efficacy cell
death when delivering TRAIL genes into
osteosarcoma cell. It was also found that
this complex efficiently causes cell death
which suggests that it has an excellent
antitumor activity. 5
Another example is Curcumin (Cur) Figure 6,
which is a natural product that has been
reported to have therapeutic effects such as
anti-inflammatory, antioxidant, and anticancer
effects.
It should be noted that Cur can efficiently
inhibit several types of cancer, including
breast cancer, colon cancer and osteosarcoma.
Moreover, Cur has regulated transcription
factors, adhesion molecules, growth factors,
and apoptotic and autophagy-related proteins.
But the water insolubility, instability under
illumination, heat and alkaline conditions
obviously limits the further clinical application
of Cur in cancer therapy. 6
The encapsulation of curcumin into nano-
formulations such as dendrimers have been
reported to render Cur dispersible into aqueous
media and they have displayed prior drug
release behavior and enhanced stability.
FIGURE 6 MOLECULAR-STRUCTURES OF NAPROXEN AND CURCUMIN
8. 5
Naproxen (Nap) Figure 6, is a member of the
class of nonsteroidal anti-inflammatory drugs
(NSAIDs). Has been used for the treatment of
many inflammation-associated conditions but
were demonstrated to berelated to increases in
the risk of cardiovascular events and
gastrointestinal adverse effects. 6
Novel bone-targeting prodrugs containing
dendritic naproxen and poly (aspartic acid)
oligopeptide were synthesized in a convergent
approach and well characterized by NMR,
mass spectral (MS) and elemental analysis
techniques. The modified naproxen prodrugs
showed a high affinity to hydroxyapatite in
vitro and provided an effective entry for the
synthesis of a dendritic naproxen-poly
(aspartic acid) oligopeptide conjugates used
for bone targeting. 7
The peptide amphiphilic dendrimers
constituted by glutamic acid or aspartic acid
exhibited potent selectivity to bone tissues.
Therefore, the design and development of Nap
and oligo-aspartic acid conjugated dendrimers
is probable targeted carriers of osteosarcoma.
6
Amphiphilic dendrimers differ from
conventional dendrimers, as they provide
asymmetry and can impart significantly
different chemical and/ or physical properties
within a single molecule. The broken
symmetry offers new and efficient
characteristic properties to form complex self-
assembled materials that are presently
incredible for homogeneous or symmetrical
dendrimers. Amphiphilic dendrimers also tend
to form micelles that characterized by high
drug loading and smaller size, amongst other
types of micelles, which is responsible for
effective therapeutic efficacy and deep tumor
penetration respectively. 8
These Nap-conjugated Cur-loaded micelles
displayed apoptosis-inducing capacity
inhibition on MG-63 osteosarcoma cells. The
mechanistic studies suggested that
inflammation and apoptosis-related proteins
were involved in the activation mechanism of
Cur-loaded micelles. 6
Markedly, Nap-dendrimer micelles loaded
with curcumin (Cur-M-Nap) possessed both
nanoscale particle size and potent negative
zeta potential. In in vitro experiments, the
drug-free M-Nap did not inhibit MG-63 cell
proliferation and only slightly induced
apoptosis. On the other hand, Cur-M-Nap had
higher cytotoxicity than that of free curcumin
in the cell proliferation assays and induced
9. 6
more mitochondrial apoptosis. Cellular uptake
analysis showed that the encapsulation of the
micelles promoted the selective uptake of
curcumin by MG-63 cells. 6
DENDRIMERS IN THE TREATMENT OF
BRAIN CANCER: GLIOMA
Dendrimers are smart, nanoscale in size, three
dimensional, safe, efficacious and peculiar
engineered architecture polymeric
nanocarriers with a cationic/neutral surface
which facilitates membranous and biological
barrier interaction. Characteristic attributes of
dendrimers to target the neuroinflammatory
cells and neurons, penetrate endothelial cells
efficiently, and cargo neurotherapeutics,
antitumor agents and nucleic acid materials,
made them promising nano-vehicles for brain
targeting. 9
In recent decades, intra-tumoral brain targeting
based on dendrimers drug conjugates of
chemotherapeutic agents for glioma therapy
has gained fame and attention of researchers.
PAMAM dendrimers have been widely
characterized for BBB transmigration-based
neurological disorders therapy. The 4th
generation of PAMAM dendrimers (G4
dendrimers) could effectively enter the brain,
target microglia and neurons, and the neutral
surface prevents plasma protein binding. their
smaller size made them not protected to the
clearance by glomerular filtration and
shortened the half-life. Dendrimers with a
larger size such as G6 are protected from renal
clearance and hence, prolonged the half-life
and enhanced brain accumulation.9 Flow of
drug molecules from blood-brain to the CSF is
limited by the tightly packed endothelial cells.
However, in injury and inflammation in the
brain, this barrier becomes leaky and allows
the passage from blood to CSF and
parenchyma. Zhang et al. while keeping in
consideration of above hypothesis compared
G4 with G6 dendrimers in brain injury model.
G6 dendrimers were superior in CSF targeting
and accumulation than G4 dendrimers which
were based on neural cells and microglia
targeting of the injured brain. The larger size
of G6 dendrimers protected them from renal
filtration and increase transportation to the
CSF.9 Dendrimers could be effective drug
delivery vehicles for brain injury and
neuroinflammation therapy such as TBI,
ischemic brain stroke and in brain tumor.
Animal models of ischemic adult and neonate
strokes, ischemic optic neuropathy and brain
injury related to cardiac arrest have shown
accumulation of dendrimers in the injured
10. 7
brain. BBB disruption, microglia sensitization
and injury condition are the deciding factors
on the fate of the dendrimers entered to
microglia. In another research to deliver drug
molecules to the microglia and treat
neuroinflammation in brain injury condition.
The smart version of nanotechnology
engineered dendrimers able to transport of
gene, nucleic acid, and nucleotides to the
brain. 9
Second generation dendrimers as nonviral
vectors set a novel platform for antiviral
siRNA delivery to transfect the astrocytes in
HIV associated dementia (HAD).
Gliomais a primary tumor in theCNS which
is responsible for most of brain cancer
death Due to its invasive character to the
surrounding normal cells which makes it
impossible for surgical removal, but in turn
it may lead to tumor recurrence , all of that
made us in an urgent need for a new
effective and noninvasive therapeutic
delivery system , in order to deliver
cytotoxic drugs to the tumor cells without
affecting the normal cells .10Also, the
difficultyof the drugand genetic material to
penetrate the BBB is a major obstacle in
drugdelivery, allof thatmadethetreatment
of the nervous system more difficult and
complicated which mostly may lead to
treatment failure. So we consider PAMAM
dendrimers which is a class of
nanoparticles as a promising system for
gene delivery due to the presence of
primary surface amine which makes it able
to bind to a variety of negatively charged
agent like plasmid and several types of
ligands but in this Article the use of target
ligand to deliver therapeutic agent to
tumors by targeting specific receptors on
the surface of BBB and Glioma cells such as
lactoferrin which was found to be a specific
ligand for targeting of LRP which refer to
one member of the LDL receptor gene
family. exist on the surface of the Brain.
LRP, is a member of the LDL receptor gene
family which is much larger than LDL
receptor, it's role include permeability
control of the BBB , more recently a
modification was made by binding G4
PAMAM dendrimer withSRLpeptidewhich
refers to somastatin receptor ligand , was
found to be a LRP ligand , to be a SRL
modified PAMAM , it was found that SRL
peptide serves as an LRP ligand and
Because C6 glioma cells are able to
11. 8
overexpress LRP, this was used for drug
delivery targeting system to Gliomacells . 10
As reported, the covalent attachment of
poly (ethylene glycol) (PEG), is a nontoxic
and nonimmunogenichydrophilicpolymer,
to the exterior of dendrimerscould reduce
the toxicity, improve biocompatibility and
prolong circulation time of the dendrimer-
based drug delivery systems due to the
decrease of surface positive charges and
increase of the size and molecular weight
It is well known that the site-specific
deliveryofanticancer drugsremainsagreat
challenge because it is difficult to control
the drugsmainly accumulated in the tumor
site rather than permeating in the normal
tissues in vivo, which leads to the harmful
side-effects and even death of the patients.
Many targeting agents have been tried to
conjugate on the surface of the dendrimers
to explore the targeting effects Folic acid
(FA), a necessary vitamin for the
proliferation of cells, has been wildly
studied for drug targeting because the
receptors (FRs) of FA are overexpressed on
cancer cells and activated macrophages,
while it shows a limited distribution in
normal tissues. 10
The advantages of using FA as a ligand are
due to the high affinity of FA to FR was
maintained even after FA was conjugated
via the γ-carboxylgroup to other molecules
the deeper penetration effect than
antibodies because of its small size and low
molecular weight.
Here, wereporta PAMAMdendrimer-based
drug delivery carrier (G4–FA–PEG/DOX)
with PEG2000 partly linked to the exterior,
doxorubicin (DOX) encapsulated in the
interior and FA directly conjugated on the
periphery of the carrier for taking the
advantage of "cluster" effect.28 Our aim is
to endow the carrier with good
biocompatibility and enhanced endocytosis
through both the targeting of FA and
electrostatic interaction between the
residual positive charges of PAMAM and
negative cell membrane. DOX was an
effective and widely used anti-cancer drug,
which was also reported to treat gliomas.1
For comparison, temozolomide (TMZ), an
alkylatingagent which was able to cross the
blood-brain barrier (BBB) and commonly
used for the treatment of aggressive brain
tumor, was also encapsulated in the carrier
of G4–FA–PEG. 10
12. 9
The synthesized carrier showed increased
size after conjugation of FA and PEG chains.
In the in vitro test, G4–FA–PEG was
nontoxic at measured concentrations as we
expected, but G4–FA–PEG/DOX exhibited
stronger cytotoxicity to C6 cells when
comparedto freeDOX for thehigher cellular
uptake than free DOX. G4–FA–PEG/DOX
showed the enhanced ability to enter the C6
cells by an FR-mediated endocytosis
pathway. In addition, the cellular uptake
couldbe inhibited by the additionof freeFA,
indicating the targeting effect of FA in the
glioma tumor-specific delivery of drugs. 10
DENDRIMERS IN THE TREATMENT OF
BLOOD CANCER: MULTIPLE MYELOMA
Multiple myeloma (MM) is a hematological
malignancy affecting B lymphocytes localized
in the bone marrow, that remains incurable
with high relapse rates. The main limiting
factor for the effective use of chemotherapies
in MM is the serious side effects caused by
these drugs such as lack of targeting
capabilities, systemic toxicity, and side
effects, low therapeutic index, as well as poor
water solubility. Therefore, dendrimers aim to
minimize drug degradation upon
administration, prevent undesirable side
effects, and increase drug bioavailability in the
affected area.2
Poly-phosphorhydrazone (PPH) dendrimers
are built on a cyclo-tri (or -tetra) phosphazene
core (N3P3 or N4P4) and by reduplication of
two reactions, it forms phenoxymethyl-
methylhydrazone (PMMH) branches. Then the
surface of PPH dendrimers is decorated by a
given number of different types of anionic
amino-phosphonate groups.11,12 PPH
dendrimers have immuno-modulatory
properties toward the human immune system
that are very active with a number of terminal
functions of 8, 10 or 12, but become poorly
active with 6, 4 or2 terminal functions, and the
monomer is non-active at all. An increased
number of terminal functions to 16 or 30 has a
harmful effect. The second generation that
contains 24 terminal group also has this effect.
The analogue of the first generation with 6
PMMH branches,12 terminations, is called
ABP dendrimer, which is the most active
dendrimer. ABP dendrimer can stimulate the
human immune system and induces NK cells
multiplication. This effect relies on Cross-talk
between monocytes and NK cells as activation
13. 10
of monocytes occur by internalization of the
dendrimer or through secretion of soluble
mediators that inhibit NK cells proliferation
triggering anti-inflammatory effect, which is
important against several chronic
inflammatory diseases. In contrast, NK cells
must kill dendrimer activated monocytes
before proliferation especially when
monocytes are activated toward an anti-
inflammatory pathway. Error! Reference source not
found.11-13
Activated NK cells secrete cytotoxic
molecules such as perforin, granzyme-B, and
granulysin by exocytosis, and induce
apoptosis of myeloma cells. NK cells also
express the inhibitory killer cell
immunoglobulin-like receptors (KIRs),
NKG2A 14 and tumor necrosis factor (TNF)-
related apoptosis-inducing ligand receptor
(TRAILR)15, NK cells also recognize major
histocompatibility complex (MHC) class I
molecules presentin normal cells unlike tumor
cells that only upregulate the expression of
HLA-G and HLA-E for evasion of
immunologic surveillance but lack of self-
MHC class I molecules which describes the
hypothesis of “missing-self “; This effect
prevents the killing of healthy host cell.14,15
PPH dendrimer-copper complexes found to
be more toxic toward cancerous cells but less
toxic towards noncancerous cells than the free
dendrimer. The free dendrimer moderately
activates caspase-3, whereas the complex
FIGURE 7 TWO-DIMENSIONAL STRUCTURE OF THE ABP
DENDRIMER (C1-G1-ABONA-12). THE N3P3 CORE IS IN BLUE,
PMMH BRANCHES ARE IN BLACK, ABP SURFACE GROUPS ARE
IN RED.
FIGURE 8 CYTOSOLIC BAX IS THOUGHT TO BE A
MONOMER THAT IS ACTIVATED BY BH3-ONLY
PROTEINS TO INDUCE CELL DEATH.
14. 11
largely reduces the caspase-3 activity and
induces a noticeable translocation of BAX to
the mitochondria, resulting in a severe DNA
fragmentation inducing apoptosis of cancer
cells.1 BAX is a Pro-apoptotic protein that
regulates cellular homeostasis and apoptosis.
BAX is predominantly localized in the cytosol.
Upon cellular stress, cytosolic BAX is
activated and translocated to the mitochondria
to initiate mitochondrial permeation followed
by the release of Apoptosis Inducing Factor
(AIF) from the mitochondria that induce
caspase-independent pathway for
apoptosis.16,17 Figure 8
Bortezomib (BTZ) approved by the FDA for
the treatment of newly diagnosed and relapsed
MM as the first proteasome inhibitor. Which
inhibits pro-apoptotic protein degradation,
resulting in programmed cell death in
cancerous cells. The drawbacks of BTZ are
that it is only available only in injectable forms
and no oral formulation is available due to
hydrophobic nature of the drug that causes
poor solubility, efflux by P-glycoproteins (P-
gp) and drug resistance. Also, Intravenous
administration of BTZ sometimes causes
blood coagulation in capillaries causing
serious complications18 such as peripheral
neuropathy, thrombocytopenia and
cardiotoxicity, which affects the effective
dose.19
Additionally, BTZ has relatively short mean
elimination time in patients with advanced
myelomas and less penetration potencyagainst
tumors.18
The hydrophobic core of dendrimer
considered as a suitable condition to improve
FIGURE 9 STRUCTURE OF THE DIFFERENT GENERATIONS OF PPH DENDRIMER. AND AZA-BIS-
PHOSPHONATE (ABP) TERMINAL FUNCTION.
15. 2
solubility of hydrophobic moieties such as
BTZ. Solubility enhancement of BTZ is
concentration dependent as it increases
respectively with dendrimer concentration.18
And to avoid systemic toxicity of BTZ, pH-
responsive mechanism is obtained by reaction
of boronic acid group in BTZ with catechol-
functionalized generation 5 dendrimer then the
dendrimer surface is fully grafted with a
neutral shell (acetylated lysine, KAc) to reduce
cellular uptake and triggered release of
anticancer drugs by acidic vesicles in normal
cells (such as endosomes and lysosomes) and
BTZ-loaded G5-KAc-Cat complex is
obtained. This reaction is due to that tumors
exhibit a more acidic extracellular
microenvironment compared to normal
tissues. Because of the up-regulation of
aerobic glycolysis and reduction in oxidative
phosphorylation in tumors leading to high
levels of lactic acid secretion in the
microenvironment.19
DENDRIMERS IN THE TREATMENT OF
BREAST CANCER:
HER2 gene (human epidermal growth factor)
is the most gene that shares high levels in
breast cancerand around 20% ofhuman breast
cancer is positive HER2 type 2 which is more
aggressive and have high levels of HER2
receptor that stimulates breast cancer cell
growth. New techniques were developed to
overcome the failure of chemotherapy in
targeting breast cancer cells. 20,21
In this partof the article, we will Discuss a new
methodology for delivering trastuzumab(TZ)
which is a monoclonal antibody and approved
by FDA as a treatment of breast cancer and its
metastatic form.
Using TZ in targeting breast cancer is due to
specific binding to HER2 receptor by using it
as a tool for drug delivery. The presence of
NH2 and COOH on the surface of TZ make it
easier to conjugate with PAMAM Dendrimer.
Docetaxel(DTX) is semi-synthetic paclitaxel
analogue used for several types of cancer
including breast cancer. 20
A new study demonstrated that when we
loaded DTX into dendrimer, non-covalent
interactions occurred between them and TZ
conjugated to this complex using a MAL-
PEG-NHS cross-linker. 22
16. 3
The study showed that the drug release from
DTX alone is much faster than the Dend-DTX-
TZ SYSTEM as about 94% of the drug
released over 10 hours which is not
recommended in chemotherapy drug. on the
other hand the release has been decreased and
becomecontrolled release over 48 hours in the
conjugating system. 22
Fluorescein isothiocyanate (FITC)-labelled
dendrimers used to detect cellular uptake by
HER2-positive and HER2-negative cancer
cells. Free Dend-FITC and TZ-Dend-FITC
uptake was observed in both MDA-MB-453
(HER2-positive) and MDA-MB-231(HER2-
negative) cells, the results show that both
showed fluorescence after just 1 h.Figure 11
Fluorescence intensity was significantly
higher after treatment with TZ-Dend-FITC. A
higher uptake of TZ-Dend-FITC than Dend-
FITC clearly reveals significant internalization
of TZ-Dend in HER2-positive cells. 20
Magnetic hyperthermia of breast cancer cells
with dendrimer-coated iron-oxide
nanoparticles is Another application for
dendrimer in the treatment of breast cancer.
As dendrimers suitable have properties and
attractive characteristics of compared to the
other nanovectors including micelles and
liposomes, whose properties are difficult to
control, they considered as an attractive
suitable for biomedical applications.
FIGURE 10 IN VITRO RELEASE OF DOCETAXEL (DTX) FROM THREE DIFFERENT FORMULATIONS: TAXOTERE(DTX), DTX-
LOADED PAMAM DENDRIMERS (DEND-DTX), AND TRASTUZUMAB-CONJUGATED DEND-DTX (TZ-DEND-DTX)
FIGURE 11 DENDRIMER FORMULATIONS ALSO SHOWED TIME-DEPENDENT UPTAKE. AFTER 4 H OF
INCUBATION, UPTAKE INCREASED TO 34.2% AND 57.9% FOR DEND-FITC AND TZ-DEND-FITC,
RESPECTIVELY
17. 4
They are appropriate candidates for coating
iron-oxide nanoparticles which are applied in
magnetic hyperthermia. The novelty of them
was investigated by a study of fourth-
generation dendrimer-coated iron-oxide
nanoparticles (G4-IONPs) in magnetic
hyperthermia, and an alternating magnetic
field (AMF) is utilized to heat magnetic
nanoparticles (MNPs) such as iron-oxide
nanoparticles (IONPs), which increases the
tumor temperature by 3–7 °C and destruction
of cancer cells occur due to MNPs heating. 23
MTT (3-[4,5-dimethylthiazol-2yl]-2,5-
diphenyltetrazolium bromide) assay was used
to determine the cytotoxicity of G4-IONPs in
MCF7 and HDF1 cell lines at different
concentrations. The results clearly indicated
that G4-IONPs had no significant cytotoxicity
at concentrations of 500 µg/ml and lower. At
1000 and 1500 µg/ml, the viability ofboth cell
lines decreased significantly (for MCF7:63%
and 61%; for HDF1: 65% and 59%,
respectively).23 Figure 13
Cell internalization of G4-IONPs staining
assessed by Prussian blue illustrated a high
FIGURE 12 MCF7 CELLS INCUBATED A
WITH AND B WITHOUT (CONTROL)
G4-IONPS FOLLOWED BY PRUSSIAN
BLUE STAINING. C ICP-MS OF
DIFFERENT CONCENTRATIONS OF
G4-IONPS.
FIGURE 13 CYTOTOXICITY OF G4-IONPS IN
MCF7 AND HDF1 CELLS (*P < 0.05). THE
CYTOTOXIC EFFECT AT CONCENTRATIONS OF
1000 AND 1500 µG/ML IS SIGNIFICANT IN
BOTH CELL LINES.
18. 5
density of iron inside the incubation with
MCF7 cells after 2 hG4-IONPs. The iron
appeared as the blue precipitate in the
cytoplasm.23 Figure 12
Finally, all that is investigate the efficiency of
G4-IONPs in magnetic hyperthermia of breast
cancer cells. They are promising therapeutic
agents for magnetic hyperthermia of breast
cancer cells. 23
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