This document summarizes a presentation given by Dr. Alberto Gabizon on the clinical efficacy and safety of cancer nanomedicines. Dr. Gabizon discussed how pegylated liposomal doxorubicin (Doxil/Caelyx) provides improved pharmacokinetics and tumor delivery over free doxorubicin, resulting in superior efficacy with reduced cardiotoxicity in several cancer types. He also reviewed other liposomal formulations in clinical use and development, including targeted liposomes. Dr. Gabizon explained how prolonged circulation time allows liposomes to accumulate in tumors via the enhanced permeability and retention effect. Combining drugs within liposomes was also discussed as a way to provide synergistic anti-tumor effects with non-
This document summarizes the work of Dr. Horacio Cabral in the area of nanomedicine for cancer diagnosis and treatment. It discusses (1) how polymeric nanodevices can be engineered to selectively target cancer cells and reduce toxicity compared to traditional chemotherapy, (2) research using in vivo imaging to observe the behavior and distribution of nanodevices in tumors over time, and (3) ongoing clinical trials evaluating nanomedicine formulations to treat various cancer types. The overall aim is to develop theranostic nanomedicines that can both diagnose and treat cancer with higher precision and lower side effects.
Nanoparticles show promise for drug delivery applications in the pharmaceutical industry. They can increase drug solubility and bioavailability, target drug delivery, and potentially allow drugs to avoid generic competition through novel delivery methods. In particular, niosomes, nanocrystals, nanoclusters, micelles, and other nanoscale carriers are being investigated for controlled and targeted drug delivery using biocompatible polymers, lipids, and surfactants. These nanocarriers aim to improve drug therapies by more efficient transport and release of pharmaceutical compounds in the body.
Nanotechnology essentially restructures molecules to make materials lighter, stronger, more penetrating or absorbant, among many innovative qualities. In cancer research, it offers a unique opportunity to study and interact with normal and cancer cells in real time, at the molecular and cellular scales, and during the various stages of the cancer process. For cancer researchers, a special interest lies in ligand-targeted therapeutic nanoparticles (TNP), which are expected to selectively deliver drugs and especially cytotoxic agents specifically to tumor cells and enhance intracellular drug accumulation. Targeting can be achieved by various mechanisms. For example, nanoparticles with numerous targeting ligands can provide multi-valent binding to the surface of tumor cells with high receptor density (as opposed to low receptor density on normal cells) or nanoparticle agents can enhance permeability and retention (EPR) effect to exit blood vessels in the tumor, to target surface receptors on tumor cells, and to enter tumor cells by endocytosis before releasing their drug payloads.
In this presentation we shall look at nanotechnology in drug development with a focus on anticancers and the advantages of nanoparticles as therapeutic platform technology. Approved nanotech based drugs and their clinical trials will be discussed. Two specific clinical trial case studies will be focused on along at some length with a mention of some ongoing clinical trials of nanotherapeutics. We shall also take a look at the future direction of nanotechnology based therapeutics.
The document discusses nanotechnology and its applications in pharmaceuticals and cosmetics. It provides definitions and history of nanotechnology. It describes various nanostructures used for drug delivery such as liposomes, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, etc. It discusses how nanotechnology can help in targeted drug delivery, overcoming drug resistance and reducing toxicity. The document also discusses use of nanotechnology in cosmetics for delivery of active ingredients to deeper skin layers and for UV protection.
The document discusses nanotechnology and nanoparticles. It provides background on the history of nanotechnology, defining it as the study and control of matter at the nanoscale, between 1 to 100 nanometers. It discusses different types of nanoparticles used for drug delivery, including liposomes, solid nanoparticles, polymeric nanoparticles, nanocapsules, nanospheres, dendrimers, nanotubes, nanowires, and nanocrystals. The document also provides examples of biomedical applications of nanotechnology such as targeted drug delivery for cancer treatment.
Nanotechnology and its Application in Cancer TreatmentHasnat Tariq
Nanotechnology
Nanomaterials
Nanostructures
Nanoparticles
Unexpected Optical Properties of Nanoparticles
Synthesis of Nanoparticles
Nanotechnology in Cancer Treatment
Role of Sulfur NPs in Cancer Treatment
Human Tumour Cell Lines Used in Research
Ehrlich ascites carcinoma (EAC)
Sulfur Nanoparticles Preparation
MTT Assay
Sulphorhodamine-B (SRB) Assay
Median lethal dose (LD 50)
Experimental design
FT-IR Characterization of Sulfur Nanoparticles
SEM Characterization of Sulfur Nanoparticles
EDS Characterization of Sulfur Nanoparticles
XRD Characterization of Sulfur Nanoparticles
Chemical Studies on Sulfur Nanoparticles In Vitro
Biochemical investigations
Conclusion
Applications of Nanoparticles in cancer treatment
Nanoshells
Nano X-Ray therapy
Drug Delivery by Nanoparticles
This document discusses the use of nanotechnology for cancer treatment. It begins with background on cancer and challenges with chemotherapy. It then introduces various nanoparticles being explored for cancer applications, such as quantum dots, iron oxide, and gold nanoparticles. The document discusses the enhanced permeability and retention effect that allows nanoparticles to passively target tumors. It provides the example of Doxil, an FDA-approved liposomal drug delivery system. Other nanomedicine examples discussed include Abraxane protein-bound paclitaxel nanoparticles. The document covers topics like tumor tissue targeting, overcoming drug resistance, vascular and cellular targets, and using heat-generating nanoparticles for thermal ablation of cancer cells.
This document summarizes a study that compared the cancer targeting abilities of doxorubicin-loaded multiwalled carbon nanotubes (MWCNTs) functionalized with either estrone or folic acid. Both in vitro and in vivo experiments using breast cancer cells found that the estrone-functionalized nanotubes showed preferential uptake and greater antitumor activity compared to other formulations, likely due to overexpression of estrogen receptors on the cancer cells. Pharmacokinetic studies also confirmed increased cancer targeting of the ligand-functionalized MWCNTs. The estrone formulation in particular significantly extended survival time in a mouse model compared to free doxorubicin and a control group.
This document summarizes the work of Dr. Horacio Cabral in the area of nanomedicine for cancer diagnosis and treatment. It discusses (1) how polymeric nanodevices can be engineered to selectively target cancer cells and reduce toxicity compared to traditional chemotherapy, (2) research using in vivo imaging to observe the behavior and distribution of nanodevices in tumors over time, and (3) ongoing clinical trials evaluating nanomedicine formulations to treat various cancer types. The overall aim is to develop theranostic nanomedicines that can both diagnose and treat cancer with higher precision and lower side effects.
Nanoparticles show promise for drug delivery applications in the pharmaceutical industry. They can increase drug solubility and bioavailability, target drug delivery, and potentially allow drugs to avoid generic competition through novel delivery methods. In particular, niosomes, nanocrystals, nanoclusters, micelles, and other nanoscale carriers are being investigated for controlled and targeted drug delivery using biocompatible polymers, lipids, and surfactants. These nanocarriers aim to improve drug therapies by more efficient transport and release of pharmaceutical compounds in the body.
Nanotechnology essentially restructures molecules to make materials lighter, stronger, more penetrating or absorbant, among many innovative qualities. In cancer research, it offers a unique opportunity to study and interact with normal and cancer cells in real time, at the molecular and cellular scales, and during the various stages of the cancer process. For cancer researchers, a special interest lies in ligand-targeted therapeutic nanoparticles (TNP), which are expected to selectively deliver drugs and especially cytotoxic agents specifically to tumor cells and enhance intracellular drug accumulation. Targeting can be achieved by various mechanisms. For example, nanoparticles with numerous targeting ligands can provide multi-valent binding to the surface of tumor cells with high receptor density (as opposed to low receptor density on normal cells) or nanoparticle agents can enhance permeability and retention (EPR) effect to exit blood vessels in the tumor, to target surface receptors on tumor cells, and to enter tumor cells by endocytosis before releasing their drug payloads.
In this presentation we shall look at nanotechnology in drug development with a focus on anticancers and the advantages of nanoparticles as therapeutic platform technology. Approved nanotech based drugs and their clinical trials will be discussed. Two specific clinical trial case studies will be focused on along at some length with a mention of some ongoing clinical trials of nanotherapeutics. We shall also take a look at the future direction of nanotechnology based therapeutics.
The document discusses nanotechnology and its applications in pharmaceuticals and cosmetics. It provides definitions and history of nanotechnology. It describes various nanostructures used for drug delivery such as liposomes, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, etc. It discusses how nanotechnology can help in targeted drug delivery, overcoming drug resistance and reducing toxicity. The document also discusses use of nanotechnology in cosmetics for delivery of active ingredients to deeper skin layers and for UV protection.
The document discusses nanotechnology and nanoparticles. It provides background on the history of nanotechnology, defining it as the study and control of matter at the nanoscale, between 1 to 100 nanometers. It discusses different types of nanoparticles used for drug delivery, including liposomes, solid nanoparticles, polymeric nanoparticles, nanocapsules, nanospheres, dendrimers, nanotubes, nanowires, and nanocrystals. The document also provides examples of biomedical applications of nanotechnology such as targeted drug delivery for cancer treatment.
Nanotechnology and its Application in Cancer TreatmentHasnat Tariq
Nanotechnology
Nanomaterials
Nanostructures
Nanoparticles
Unexpected Optical Properties of Nanoparticles
Synthesis of Nanoparticles
Nanotechnology in Cancer Treatment
Role of Sulfur NPs in Cancer Treatment
Human Tumour Cell Lines Used in Research
Ehrlich ascites carcinoma (EAC)
Sulfur Nanoparticles Preparation
MTT Assay
Sulphorhodamine-B (SRB) Assay
Median lethal dose (LD 50)
Experimental design
FT-IR Characterization of Sulfur Nanoparticles
SEM Characterization of Sulfur Nanoparticles
EDS Characterization of Sulfur Nanoparticles
XRD Characterization of Sulfur Nanoparticles
Chemical Studies on Sulfur Nanoparticles In Vitro
Biochemical investigations
Conclusion
Applications of Nanoparticles in cancer treatment
Nanoshells
Nano X-Ray therapy
Drug Delivery by Nanoparticles
This document discusses the use of nanotechnology for cancer treatment. It begins with background on cancer and challenges with chemotherapy. It then introduces various nanoparticles being explored for cancer applications, such as quantum dots, iron oxide, and gold nanoparticles. The document discusses the enhanced permeability and retention effect that allows nanoparticles to passively target tumors. It provides the example of Doxil, an FDA-approved liposomal drug delivery system. Other nanomedicine examples discussed include Abraxane protein-bound paclitaxel nanoparticles. The document covers topics like tumor tissue targeting, overcoming drug resistance, vascular and cellular targets, and using heat-generating nanoparticles for thermal ablation of cancer cells.
This document summarizes a study that compared the cancer targeting abilities of doxorubicin-loaded multiwalled carbon nanotubes (MWCNTs) functionalized with either estrone or folic acid. Both in vitro and in vivo experiments using breast cancer cells found that the estrone-functionalized nanotubes showed preferential uptake and greater antitumor activity compared to other formulations, likely due to overexpression of estrogen receptors on the cancer cells. Pharmacokinetic studies also confirmed increased cancer targeting of the ligand-functionalized MWCNTs. The estrone formulation in particular significantly extended survival time in a mouse model compared to free doxorubicin and a control group.
This document discusses the use of nanotechnology for cancer treatment. It begins with background on cancer and current chemotherapy approaches. It then introduces the field of cancer nanotechnology, which uses nanoparticles like quantum dots, liposomes, and polymeric nanoparticles. These nanoparticles have unique properties that can help address limitations of chemotherapy like nonspecific toxicity. The document discusses how nanoparticles accumulate in tumors through the enhanced permeability and retention effect and can be used for targeted drug delivery and imaging of cancer at the molecular level with less harm to healthy tissue compared to chemotherapy. Overall, the application of nanotechnology has potential to improve outcomes for cancer treatment.
Nanoparticle based oral delivery of vaccinesAshok Patidar
Nanoparticle based oral delivery of vaccines presents an attractive alternative to other delivery routes. Nanoparticles can protect vaccine antigens from gastrointestinal fluids and transport them across the intestinal barrier for uptake by immune cells. Various nanoparticle formulations are being explored as oral vaccine carriers due to their ability to co-deliver antigens and adjuvants. However, challenges remain in ensuring sufficient antigen integrity and transportation. Further development is needed to design robust and scalable nanoparticle vaccine formulations.
This document summarizes a study on developing a targeted nano drug delivery system for treating breast cancer using docetaxel. The objectives are to formulate a docetaxel nanosuspension to improve its bioavailability and target it to cancer cells using antibody drug conjugates. The plan involves preformulation studies, developing and characterizing the nanosuspension, testing release kinetics and cell viability, selecting an optimized formulation, and conducting stability studies. The approach aims to enhance docetaxel's solubility and therapeutic effects while reducing dose and side effects.
Doxorubicin Final Chemotherapy Project 12 9 2014Angela Busbee
Doxorubicin is a chemotherapy drug used to treat various cancers including breast cancer, leukemia, lymphoma, bladder cancer, and others. It is administered intravenously and has significant side effects including heart damage, nausea, hair loss, and fertility issues. The document provides details on dosages, administration procedures, effectiveness for different cancer types, side effects, and precautions for doxorubicin use.
Nanoparticles can be functionalized for biomedical applications by modifying their surface with multiple components in a defined order from the innermost to outermost. Common steps include adding a drug to the core, then a targeting ligand on the outer layer. Possible ligands include antibodies, peptides, aptamers and other molecules that bind receptors overexpressed on target cells. Aptamers have advantages over antibodies like controlled synthesis and lack of immunogenicity. Peptides identified from in vivo phage display libraries can also serve as targeting ligands. The choice of ligand depends on the drug and intended application.
The document discusses various aspects of nanotechnology-based drug delivery. It describes different types of nanoparticles that can be used for drug delivery, including lipid-based nanoparticles, polymer-based nanoparticles, metal-based nanoparticles, and biological nanoparticles. It also discusses challenges and priority areas of nanotechnology in drug delivery, such as cancer nanotechnology, DNA vaccines, and oral/pulmonary delivery of proteins and peptides. Specific nanocarriers and technologies covered include liposomes, niosomes, dendrimers, micelles, carbon 60, carbon nanotubes, and polymeric nanoparticles.
Nanotechnology is science, engineering, and technology conducted at the nanoscale, which is about 1 to 100 nanometers. Physicist Richard Feynman, the father of nanotechnology.
Drug delivery refers to approaches, formulations, technologies, and systems for transporting a pharmaceutical compound in the body some time based on nanoparticles as needed to safely achieve its desired therapeutic effect.
Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biological tissues.
RECENT ADVANCES IN MICRO AND NANO DRUG DELIVERY SYSTEMSVijitha J
This document discusses recent advances in micro and nano drug delivery systems. It describes how nanomedicine uses nanoparticles smaller than 100nm for diagnosis, treatment, and prevention of diseases. Various types of nanoparticles are discussed for drug delivery, including metal-based, lipid-based, polymer-based, and biological nanoparticles. Specific examples provided include gold nanoparticles that can self-assemble into plasmonic vesicles for stimuli-responsive drug release, silica-gold nanoshells for thermal ablation of cancer cells, and liposomes for encapsulation of both hydrophobic and hydrophilic drugs. The mechanisms of polymeric nanoparticles, lipid nanoparticles, and chitosan carriers for drug delivery are also summarized. The document concludes by discussing the potential of nanoparticles for
A nanocarrier is nano material being used as a transport module for another substance, such as a drug. Commonly used nanocarriers include micelles, polymers, carbon-based materials, liposomes and other substances.Nanocarriers are currently used in drug delivery and their unique characteristics demonstrate potential use in chemotherapy. Nanocarriers include polymer conjugates, polymeric nanoparticles, lipid-based carriers, dendrimers, carbon nanotubes, and gold Nanoparticles.Lipid-based carriers include both liposomes and micelles.
Examples of gold nanoparticles are gold nanoshells and nanocages.Different types of nonmaterial being used in nano carriers allows for hydrophobic and hydrophilic drugs to be delivered throughout the body.
potential problem with nanocarriers is unwanted toxicity from the type of nonmaterial being used. Inorganic nonmaterial can also be toxic to the human body if it accumulates in certain cell organelles new research is being conducted to invent more effective, safer nanocarriers.
Nano pharmaceuticals offer the ability to detect diseases at much earlier stages and the diagnostic applications could build upon conventional procedures using nano particles.
Nano pharmaceuticals represent an emerging field where the sizes of the drug particle or a therapeutic delivery system work at the nanoscale.
Nano pharmaceuticals have enormous potential in addressing this failure of traditional therapeutics which offers site-specific targeting of active agents.
Magnetic nanoparticles, bound to a suitable antibody, are used to label specific molecules, structures or microorganisms.
Gold nanoparticles tagged with short segments of DNA can be used for detection of genetic sequence in a sample.
Multicolor optical coding for biological assays has been achieved by embedding different-sized quantum dots into polymeric microbeads.
Nan pore technology for analysis of nucleic acids converts strings of nucleotides directly into electronic signatures.C-dots (Cornell dots) are the smallest silica-based nanoparticles with the size <10 nm.
There are three main reasons for the popularity of herbal medicine
1. There is a growing concern over the reliance and safety of drugs.
2. Modern medicine is failing to effectively treat many of the most common health condition.
3. Many natural measures are being shown to produce better results than drugs or surgery without the side effects
Drug delivery involves transporting pharmaceutical compounds in the body to safely achieve their desired effects using technologies and systems. It concerns both the quantity and duration of drug presence. For example, protein drugs must be delivered via injection or nano-needles. Nanoparticles like liposomes, dendrimers, fullerenes, nanoshells, quantum dots, and nanorobots can provide targeted drug delivery, improved solubility, constant drug release rates, and increased stability.
Novel drug delivery system nanotechnologyShamal Ghosh
This presentation discusses novel drug delivery systems using nanotechnology. It begins by introducing drug delivery and targeted drug delivery. It then discusses nanotechnology and some fields that use nanotechnology, such as medicine, energy, information and communication, and heavy industries. The presentation goes on to describe dendrimers, liposomes, and micelles as nanocarriers for drug delivery and their mechanisms. It discusses how these nanocarriers can improve drug solubility, stability, targeting ability, and reduce toxicity for delivering drugs to treat diseases.
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.
Nanoparticles between 1-100 nanometers in size can be used to deliver drugs in the body. They allow changing the pharmacokinetic properties of drugs without altering the active compound. Biodegradable polymeric nanoparticles have attracted interest as potential drug carriers that can target specific organs and tissues and deliver proteins, peptides, and genes orally. Nanoparticles must be able to travel through blood vessels and cross cell layers to reach their target site. Their small size allows them to potentially penetrate tissues and cells to provide localized drug delivery.
Targeted drug delivery systems aim to increase the concentration of drugs in specific tissues while reducing side effects. The document discusses various drug delivery carrier technologies including lipid-based carriers like liposomes, polymer-based carriers, inorganic nanoparticles, magnetic particles, nucleic acid/peptide carriers, and cell-based delivery systems. It also covers the technology value chain and key innovations in targeted delivery systems for diseases like cancer and neurological disorders. While targeted delivery offers advantages, challenges remain around costs, long-term effects, and developing multi-pronged targeting approaches.
This document discusses various aspects of nano drug delivery. It describes how nanoscale materials can improve drug bioavailability and minimize side effects by transporting drug molecules to targeted locations. It also discusses how nanotools have been used for medical diagnostics. Different routes of drug administration are outlined including oral, nasal, ophthalmic, parenteral, and others. Targeted drug delivery seeks to optimize a drug's effects by localizing it to the site of action. Nanoparticles can help achieve targeted delivery and enhance transdermal drug applications.
This document discusses the role of nanotechnology in pharmacology and drug delivery. It begins with definitions of nanotechnology and nanobiotechnology, then describes applications of nanobiotechnology including nanopharmacology. The key roles of nanotechnology in drug discovery and development, and drug delivery systems are summarized. Specific nanocarrier platforms like liposomes, polymeric nanoparticles, dendrimers, and nanocrystals are discussed in terms of their advantages and challenges for drug delivery. The role of nanodrugs in personalized medicine is also mentioned.
Nanoparticles for drug delivery by shreyaShreya Modi
This document discusses the advancement of nanotechnology and nanoparticles for cancer diagnosis and drug delivery. It outlines several challenges in developing effective nanoscale drug delivery systems, as well as properties of nanomaterials that make them suitable for drug delivery. Various nanodevices are described that could be used for targeted drug delivery, including liposomes, nanoshells, dendrimers, micelles, nanowires, nanotubes, quantum dots, and potential future nanorobots. Advantages of nanoparticle drug delivery systems include smaller size, higher bioavailability, and ability to target drugs directly to cells and nuclei. The only disadvantage mentioned is difficulty determining proper dosages.
Introduction • Macro scale difficulties • How Nanotechnology able give solution & Working mechanism • Specific Advantages • Method of preparation • Polymers used for preparation of nanoparticles & nano capsules • Nanomaterials of Health Antibacterial effect & Drug delivery system • Drug delivery real world examples
This document describes a study investigating the cancer targeting potential of docetaxel (DTX) loaded onto multi-walled carbon nanotubes (MWCNTs) conjugated with folic acid (FA) and poly(ethylene glycol) (PEG). DTX was loaded onto both FA-PEG-conjugated MWCNTs (DTX/FA-PEG-MWCNTs) and plain MWCNTs (DTX/MWCNTs). In vitro studies showed the DTX/FA-PEG-MWCNTs had higher cytotoxicity against MCF-7 breast cancer cells and arrested cells in the G2 phase more than DTX/MWCNTs or free drug. Pharmacokinetic studies in mice
This document discusses nanomedicine and various nanoscale structures that can be used for medical applications. It begins by explaining how nanotechnology allows analysis and repair of the human body at the molecular level. It then describes various nanoscale structures like liposomes, dendrimers, carbon nanotubes, quantum dots, mesoporous silica nanoparticles and their properties. These nanoparticles can be used for targeted drug delivery, imaging and diagnosis. The document also discusses some current and potential applications of these nanotechnologies in areas like cancer treatment, biomolecular sensing and gene therapy.
This document discusses nanomedicine and its potential applications. Nanomedicine uses engineered nanodevices and nanostructures to monitor, repair, construct and control human biological systems at the molecular level. The goals of nanomedicine include improved diagnostics, treatment and prevention through a personalized single platform that integrates detection, diagnostics, treatment. Some potential applications discussed include using nanoparticles to deliver drugs precisely to tumor sites, detecting cancer at the molecular level, and developing multifunctional therapeutics. While nanomedicine is not fully realized yet, it could change medicine by making therapies more effective, economical and safe compared to current methods.
This document discusses the use of nanotechnology for cancer treatment. It begins with background on cancer and current chemotherapy approaches. It then introduces the field of cancer nanotechnology, which uses nanoparticles like quantum dots, liposomes, and polymeric nanoparticles. These nanoparticles have unique properties that can help address limitations of chemotherapy like nonspecific toxicity. The document discusses how nanoparticles accumulate in tumors through the enhanced permeability and retention effect and can be used for targeted drug delivery and imaging of cancer at the molecular level with less harm to healthy tissue compared to chemotherapy. Overall, the application of nanotechnology has potential to improve outcomes for cancer treatment.
Nanoparticle based oral delivery of vaccinesAshok Patidar
Nanoparticle based oral delivery of vaccines presents an attractive alternative to other delivery routes. Nanoparticles can protect vaccine antigens from gastrointestinal fluids and transport them across the intestinal barrier for uptake by immune cells. Various nanoparticle formulations are being explored as oral vaccine carriers due to their ability to co-deliver antigens and adjuvants. However, challenges remain in ensuring sufficient antigen integrity and transportation. Further development is needed to design robust and scalable nanoparticle vaccine formulations.
This document summarizes a study on developing a targeted nano drug delivery system for treating breast cancer using docetaxel. The objectives are to formulate a docetaxel nanosuspension to improve its bioavailability and target it to cancer cells using antibody drug conjugates. The plan involves preformulation studies, developing and characterizing the nanosuspension, testing release kinetics and cell viability, selecting an optimized formulation, and conducting stability studies. The approach aims to enhance docetaxel's solubility and therapeutic effects while reducing dose and side effects.
Doxorubicin Final Chemotherapy Project 12 9 2014Angela Busbee
Doxorubicin is a chemotherapy drug used to treat various cancers including breast cancer, leukemia, lymphoma, bladder cancer, and others. It is administered intravenously and has significant side effects including heart damage, nausea, hair loss, and fertility issues. The document provides details on dosages, administration procedures, effectiveness for different cancer types, side effects, and precautions for doxorubicin use.
Nanoparticles can be functionalized for biomedical applications by modifying their surface with multiple components in a defined order from the innermost to outermost. Common steps include adding a drug to the core, then a targeting ligand on the outer layer. Possible ligands include antibodies, peptides, aptamers and other molecules that bind receptors overexpressed on target cells. Aptamers have advantages over antibodies like controlled synthesis and lack of immunogenicity. Peptides identified from in vivo phage display libraries can also serve as targeting ligands. The choice of ligand depends on the drug and intended application.
The document discusses various aspects of nanotechnology-based drug delivery. It describes different types of nanoparticles that can be used for drug delivery, including lipid-based nanoparticles, polymer-based nanoparticles, metal-based nanoparticles, and biological nanoparticles. It also discusses challenges and priority areas of nanotechnology in drug delivery, such as cancer nanotechnology, DNA vaccines, and oral/pulmonary delivery of proteins and peptides. Specific nanocarriers and technologies covered include liposomes, niosomes, dendrimers, micelles, carbon 60, carbon nanotubes, and polymeric nanoparticles.
Nanotechnology is science, engineering, and technology conducted at the nanoscale, which is about 1 to 100 nanometers. Physicist Richard Feynman, the father of nanotechnology.
Drug delivery refers to approaches, formulations, technologies, and systems for transporting a pharmaceutical compound in the body some time based on nanoparticles as needed to safely achieve its desired therapeutic effect.
Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biological tissues.
RECENT ADVANCES IN MICRO AND NANO DRUG DELIVERY SYSTEMSVijitha J
This document discusses recent advances in micro and nano drug delivery systems. It describes how nanomedicine uses nanoparticles smaller than 100nm for diagnosis, treatment, and prevention of diseases. Various types of nanoparticles are discussed for drug delivery, including metal-based, lipid-based, polymer-based, and biological nanoparticles. Specific examples provided include gold nanoparticles that can self-assemble into plasmonic vesicles for stimuli-responsive drug release, silica-gold nanoshells for thermal ablation of cancer cells, and liposomes for encapsulation of both hydrophobic and hydrophilic drugs. The mechanisms of polymeric nanoparticles, lipid nanoparticles, and chitosan carriers for drug delivery are also summarized. The document concludes by discussing the potential of nanoparticles for
A nanocarrier is nano material being used as a transport module for another substance, such as a drug. Commonly used nanocarriers include micelles, polymers, carbon-based materials, liposomes and other substances.Nanocarriers are currently used in drug delivery and their unique characteristics demonstrate potential use in chemotherapy. Nanocarriers include polymer conjugates, polymeric nanoparticles, lipid-based carriers, dendrimers, carbon nanotubes, and gold Nanoparticles.Lipid-based carriers include both liposomes and micelles.
Examples of gold nanoparticles are gold nanoshells and nanocages.Different types of nonmaterial being used in nano carriers allows for hydrophobic and hydrophilic drugs to be delivered throughout the body.
potential problem with nanocarriers is unwanted toxicity from the type of nonmaterial being used. Inorganic nonmaterial can also be toxic to the human body if it accumulates in certain cell organelles new research is being conducted to invent more effective, safer nanocarriers.
Nano pharmaceuticals offer the ability to detect diseases at much earlier stages and the diagnostic applications could build upon conventional procedures using nano particles.
Nano pharmaceuticals represent an emerging field where the sizes of the drug particle or a therapeutic delivery system work at the nanoscale.
Nano pharmaceuticals have enormous potential in addressing this failure of traditional therapeutics which offers site-specific targeting of active agents.
Magnetic nanoparticles, bound to a suitable antibody, are used to label specific molecules, structures or microorganisms.
Gold nanoparticles tagged with short segments of DNA can be used for detection of genetic sequence in a sample.
Multicolor optical coding for biological assays has been achieved by embedding different-sized quantum dots into polymeric microbeads.
Nan pore technology for analysis of nucleic acids converts strings of nucleotides directly into electronic signatures.C-dots (Cornell dots) are the smallest silica-based nanoparticles with the size <10 nm.
There are three main reasons for the popularity of herbal medicine
1. There is a growing concern over the reliance and safety of drugs.
2. Modern medicine is failing to effectively treat many of the most common health condition.
3. Many natural measures are being shown to produce better results than drugs or surgery without the side effects
Drug delivery involves transporting pharmaceutical compounds in the body to safely achieve their desired effects using technologies and systems. It concerns both the quantity and duration of drug presence. For example, protein drugs must be delivered via injection or nano-needles. Nanoparticles like liposomes, dendrimers, fullerenes, nanoshells, quantum dots, and nanorobots can provide targeted drug delivery, improved solubility, constant drug release rates, and increased stability.
Novel drug delivery system nanotechnologyShamal Ghosh
This presentation discusses novel drug delivery systems using nanotechnology. It begins by introducing drug delivery and targeted drug delivery. It then discusses nanotechnology and some fields that use nanotechnology, such as medicine, energy, information and communication, and heavy industries. The presentation goes on to describe dendrimers, liposomes, and micelles as nanocarriers for drug delivery and their mechanisms. It discusses how these nanocarriers can improve drug solubility, stability, targeting ability, and reduce toxicity for delivering drugs to treat diseases.
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.
Nanoparticles between 1-100 nanometers in size can be used to deliver drugs in the body. They allow changing the pharmacokinetic properties of drugs without altering the active compound. Biodegradable polymeric nanoparticles have attracted interest as potential drug carriers that can target specific organs and tissues and deliver proteins, peptides, and genes orally. Nanoparticles must be able to travel through blood vessels and cross cell layers to reach their target site. Their small size allows them to potentially penetrate tissues and cells to provide localized drug delivery.
Targeted drug delivery systems aim to increase the concentration of drugs in specific tissues while reducing side effects. The document discusses various drug delivery carrier technologies including lipid-based carriers like liposomes, polymer-based carriers, inorganic nanoparticles, magnetic particles, nucleic acid/peptide carriers, and cell-based delivery systems. It also covers the technology value chain and key innovations in targeted delivery systems for diseases like cancer and neurological disorders. While targeted delivery offers advantages, challenges remain around costs, long-term effects, and developing multi-pronged targeting approaches.
This document discusses various aspects of nano drug delivery. It describes how nanoscale materials can improve drug bioavailability and minimize side effects by transporting drug molecules to targeted locations. It also discusses how nanotools have been used for medical diagnostics. Different routes of drug administration are outlined including oral, nasal, ophthalmic, parenteral, and others. Targeted drug delivery seeks to optimize a drug's effects by localizing it to the site of action. Nanoparticles can help achieve targeted delivery and enhance transdermal drug applications.
This document discusses the role of nanotechnology in pharmacology and drug delivery. It begins with definitions of nanotechnology and nanobiotechnology, then describes applications of nanobiotechnology including nanopharmacology. The key roles of nanotechnology in drug discovery and development, and drug delivery systems are summarized. Specific nanocarrier platforms like liposomes, polymeric nanoparticles, dendrimers, and nanocrystals are discussed in terms of their advantages and challenges for drug delivery. The role of nanodrugs in personalized medicine is also mentioned.
Nanoparticles for drug delivery by shreyaShreya Modi
This document discusses the advancement of nanotechnology and nanoparticles for cancer diagnosis and drug delivery. It outlines several challenges in developing effective nanoscale drug delivery systems, as well as properties of nanomaterials that make them suitable for drug delivery. Various nanodevices are described that could be used for targeted drug delivery, including liposomes, nanoshells, dendrimers, micelles, nanowires, nanotubes, quantum dots, and potential future nanorobots. Advantages of nanoparticle drug delivery systems include smaller size, higher bioavailability, and ability to target drugs directly to cells and nuclei. The only disadvantage mentioned is difficulty determining proper dosages.
Introduction • Macro scale difficulties • How Nanotechnology able give solution & Working mechanism • Specific Advantages • Method of preparation • Polymers used for preparation of nanoparticles & nano capsules • Nanomaterials of Health Antibacterial effect & Drug delivery system • Drug delivery real world examples
This document describes a study investigating the cancer targeting potential of docetaxel (DTX) loaded onto multi-walled carbon nanotubes (MWCNTs) conjugated with folic acid (FA) and poly(ethylene glycol) (PEG). DTX was loaded onto both FA-PEG-conjugated MWCNTs (DTX/FA-PEG-MWCNTs) and plain MWCNTs (DTX/MWCNTs). In vitro studies showed the DTX/FA-PEG-MWCNTs had higher cytotoxicity against MCF-7 breast cancer cells and arrested cells in the G2 phase more than DTX/MWCNTs or free drug. Pharmacokinetic studies in mice
This document discusses nanomedicine and various nanoscale structures that can be used for medical applications. It begins by explaining how nanotechnology allows analysis and repair of the human body at the molecular level. It then describes various nanoscale structures like liposomes, dendrimers, carbon nanotubes, quantum dots, mesoporous silica nanoparticles and their properties. These nanoparticles can be used for targeted drug delivery, imaging and diagnosis. The document also discusses some current and potential applications of these nanotechnologies in areas like cancer treatment, biomolecular sensing and gene therapy.
This document discusses nanomedicine and its potential applications. Nanomedicine uses engineered nanodevices and nanostructures to monitor, repair, construct and control human biological systems at the molecular level. The goals of nanomedicine include improved diagnostics, treatment and prevention through a personalized single platform that integrates detection, diagnostics, treatment. Some potential applications discussed include using nanoparticles to deliver drugs precisely to tumor sites, detecting cancer at the molecular level, and developing multifunctional therapeutics. While nanomedicine is not fully realized yet, it could change medicine by making therapies more effective, economical and safe compared to current methods.
Nanomedicine is an interdisciplinary field that uses nanotechnology for medical applications. It aims to diagnose, treat, and prevent disease at the molecular level using nano-scale tools. The document outlines the history of nanomedicine from Richard Feynman's 1959 talk introducing nanotechnology to current applications. Key applications discussed include drug delivery using nanoparticles like liposomes, imaging contrast agents, and miniaturized medical devices. Challenges also remain around potential toxicities of nanomaterials.
Nanomedicine involves monitoring, repairing, constructing and controlling human biological systems at the molecular level using engineered nanodevices and nanostructures. It can be used for diagnosis, prevention and treatment of disease. Current areas of nanomedicine development include drug delivery, biopharmaceutics, implantable materials and devices, and diagnostic tools. Nanomedicine shows promise for a variety of medical applications and may offer more economical and effective ways to diagnose and treat disease in the future.
Nanotechnology involves manipulating matter at the atomic or molecular scale, typically 100 nanometers or smaller. Richard Feynman first suggested the possibility of nanomachines in 1959. Albert Hibbs later suggested using nanomachines for medical purposes like surgery. Current applications of nanotechnology in medicine include more targeted drug delivery, cancer treatment using gold nanoparticles, microsurgery using nanoscale instruments, medical robotics, and tissue engineering. While nanomedicine holds promise, it also raises social, economic, ethical, and safety issues that warrant careful consideration and oversight to ensure its safe and equitable development and use.
Nanotechnology can be used to improve drug delivery in 3 key ways:
1) Nanoparticles can effectively target drugs to specific areas, like tumors, improving treatment and reducing side effects. Different types of nanoparticles like gold nanorods, quantum dots, and liposomes are being developed for targeted delivery.
2) Nanoparticles can help protect drugs from degradation and control their release in the body over extended time periods, improving compliance. This allows drugs to be administered less frequently.
3) Nanotechnology has the potential to lower drug costs by allowing conventional drugs to be delivered more effectively in low doses using nanoparticle carriers, extending their patent lifetimes.
NOAEL Cancer Therapy is a novel anti-cancer therapy to overcome conventional chemotherapy by controlling toxicity, based on restless & repeated ‘below-NOAEL‘ doses of Polytaxel for complete regression of tumor without severe adverse effects Polytaxel: the first ‘pain-free’ anti-cancer drug developed for NOAEL Cancer Therapy, based on the platform technology of polyphosphazene conjugation
NOAEL Cancer Therapy’s first xenograft test result on ‘hard-to-treat’ pancreatic cancer model indicates possibility that pancreatic cancer can be completely treated with below-NOAEL doses
Nanotechnology shows promise for improving cancer treatment. Nanoparticles can be engineered to selectively target tumors using passive and active targeting methods. Passive targeting relies on the enhanced permeability and retention effect whereby nanoparticles accumulate in leaky tumor vasculature and are trapped there. Drugs encapsulated in nanoparticles like Doxil have shown improved efficacy with less toxicity compared to free drugs due to passive targeting. Active targeting attaches molecules to nanoparticles that bind specific cellular receptors overexpressed on cancer cells. Many nanotherapies are in clinical trials including PET imaging agents and immune-stimulating adenovirus nanoparticles.
Oncodesign aacr 2018 morab-202 a folate receptor alpha-targeted antibody-dr...Florence Fombertasse
Folate receptor alpha (FRA) is a membrane protein with high affinity for binding and transporting folate into cells. Overexpression of FRA may confer a growth advantage to tumors by increasing folate uptake and affecting cell proliferation via alternative cell signaling pathways (1). FRA levels have been found to be elevated in tumors of epithelial origin compared to normal tissue as cancers of the breast (including TNBC (2)), colon, lungs and ovary (3).
In this study, we report the development of MORAb-202, an anti-FRA antibody-drug conjugate (ADC), consisting of a FRA-binding antibody (MORAb-003, farletuzumab) with a cathepsin-cleavable form of eribulin (eribulin mesylate, marketed as Halaven®), a highly potent anti-mitotic agent that induces cell-cycle arrest and cell death by targeting microtubules.*
We first study expression of FRA on a large panel of tumors patient-derived xenograft (PDX) and Cancer Cell Line-derived Xenograft (CDX). Then, we performed in vitro and in vivo anti-proliferation assays and compare antitumor activity of MORAb-202 with free eribulin accordingly to the FRA expression level. FRA expression was found to be determinant in the sensitivity of tumor cells to the cytotoxic effect of the ADC. Moreover, in case of high expression of FRA, MORAb-202 showed a higher antitumor activity compared with free eribulin.
These results suggest that FRA expression could be used as a response-predictive biomarker for this targeted therapy. The ability to identify and treat patients with an effective therapy based on the known expression of the tumor marker is a key point in predictive medicine progress. These findings support the clinical development of MORAb-202 ADC as a novel targeted therapy for patients with FRA-expressing tumors.
The ADC described in this abstract is investigational, as efficacy and safety have not been established. There is no guarantee that this ADC will be available commercially.
This visual guide provides information on adverse events, efficacy data, and indications for various chemotherapy drugs including pegylated liposomal doxorubicin (PLD), paclitaxel, docetaxel, epirubicin, gemcitabine, and bortezomib. It shows that PLD has fewer adverse events compared to conventional doxorubicin and a lower risk of cardiac events. It also indicates that PLD, gemcitabine, paclitaxel, and docetaxel have demonstrated efficacy in various cancer types either as monotherapy or in combination with other drugs.
This document summarizes a study that synthesized lipid carriers containing the anticancer drug doxorubicin (Dox) and tested their efficacy on HeLa and HCT116 cells. The carriers were around 200 nm in size. Treatment with 1 μM Dox delivered via the new carriers decreased survival of resistant HeLa cells by over 50%, while the blank carriers did not impair survival of sensitive HCT116 cells. This validated assay shows potential for determining efficacy of drug delivery systems.
1) Hypoxic cell sensitizers are agents that increase the lethal effects of radiation specifically on hypoxic tumor cells. An ideal sensitizer selectively sensitizes hypoxic cells at concentrations that do not greatly increase toxicity to normal tissues.
2) Several hypoxic cell sensitizers have been evaluated clinically including nitroimidazoles like misonidazole, metronidazole, and nimorazole. Nimorazole showed benefit for head and neck cancers with less toxicity.
3) Other approaches to overcoming tumor hypoxia include hyperbaric oxygen, carbogen breathing, blood transfusions, and bioreductive drugs that selectively kill hypoxic cells. A meta-analysis found that
Treatment Of Potentially Resectable Pancreatic Cancerfondas vakalis
1. Conventional treatment for resectable pancreatic cancer involving surgery and adjuvant chemoradiation has shown limited success, with few long-term survivors and significant treatment-related toxicity.
2. Preoperative chemoradiation using gemcitabine has shown promise in improving resectability and survival rates compared to postoperative chemoradiation or surgery alone, while avoiding unnecessary surgeries.
3. Combining gemcitabine with newer chemotherapy agents like capecitabine may allow higher drug doses with reduced toxicity when combined with radiation, improving patient outcomes.
Our fourth webinar in the MDC Connects Series 2021 | A Guide to Complex Medicines.
This slide deck takes a closer look at precision drug delivery with therapeutic microbubbles and the promise that they bring.
Louise Coletta, University of Leeds
Beta and alpha emitters are commonly used radiopharmaceuticals in nuclear medicine therapy. Beta emitters can cause more side effects due to their longer range and lower linear energy transfer compared to alpha emitters. Ra-223 is an alpha-emitting radiopharmaceutical used to treat castration-resistant prostate cancer with bone metastases. It localizes to bone sites and delivers a high dose of radiation to bone tumors while sparing bone marrow due to the short range of alpha particles. Clinical trials have shown Ra-223 improves survival compared to placebo in patients who do not respond to docetaxel.
The document summarizes several clinical trials related to prostate cancer treatment. It provides details on trials such as PIVOT, ProtecT, TAX327 which compared radical prostatectomy vs observation, active monitoring vs surgery or radiation, and docetaxel vs mitoxantrone for advanced prostate cancer. It also summarizes larger ongoing trials like STAMPEDE and LATITUDE that are evaluating multiple treatment strategies for high risk or metastatic prostate cancer.
Nanotechnology shows promise for improving cancer treatment. Nanoparticles can be engineered with unique optical and magnetic properties and conjugated with targeting ligands to selectively deliver anti-cancer drugs to tumors. The enhanced permeability and retention effect enables nanoparticles to passively accumulate in tumors due to their leaky vasculature and poor lymphatic drainage. This allows for higher drug concentrations in tumors and fewer side effects compared to conventional chemotherapy. However, challenges remain around overcoming drug resistance mechanisms and ensuring nanoparticles reach poorly vascularized tumor regions.
1) Chemotherapy options for advanced prostate cancer have expanded significantly since the 1980s, with docetaxel and cabazitaxel approved based on trials showing improved survival.
2) Landmark trials in 2004 established docetaxel as providing a survival benefit over mitoxantrone for castration-resistant prostate cancer (CRPC). Subsequent trials tested docetaxel combinations without additional benefit.
3) New hormone therapies like abiraterone and enzalutamide provide alternatives or additions to chemotherapy for metastatic CRPC, but optimal sequencing remains unclear given new options.
Norbert Sipos: Principles of cancer therapyKatalin Cseh
The document discusses principles of cancer therapy including chemotherapy and radiation therapy. It covers topics like evaluating malignancies, determining likelihood of response to treatment, cell cycle specifics of chemotherapy, and principles of combination chemotherapy. The document also provides details on treating specific cancers like vulvar cancer through surgery, radiation, and chemotherapy.
Effect of Hyperlipidemia on the Pharmacokinetics/Pharmacodynamics of Ketocona...Dalia A. Hamdy
Hyperlipidemia can influence the pharmacokinetics and pharmacodynamics of some highly lipophilic drugs like ketoconazole by altering protein binding, distribution to tissues, and drug metabolism. This study investigated the effects of induced hyperlipidemia on the stereoselective pharmacokinetics of ketoconazole enantiomers in rats as well as its interaction with midazolam. Key findings include hyperlipidemia causing higher volume of distribution for ketoconazole and decreasing its liver uptake, as well as potentiating the drug interaction between ketoconazole and midazolam by decreasing midazolam clearance.
This document summarizes research on using ultrasound-triggered release of anticancer agents from alginate-chitosen hydrogels. Hydrogel beads were developed that could encapsulate multiple drugs, including doxorubicin and temozolomide. Application of ultrasound caused pulsatile, on-demand release of the drugs. In vitro tests showed the ultrasound-triggered release resulted in decreased cell viability compared to no ultrasound treatment. Further work will focus on controlling sequential release of multiple drugs and tuning the hydrogel degradation rate.
Theranostics involves using radiolabeled agents for both diagnosing and treating diseases. Iodine-131 was one of the first theranostic agents used for both imaging and treating thyroid conditions. Other promising theranostic nuclides discussed include iodine-123, iodine-124, gallium-68, lutetium-177, copper-64, copper-67, tin-117m, and fluorine-18 FDG which shows potential for imaging and cytotoxic effects against cancer cells. Effective theranostic agents require properties like appropriate half-lives and radiation types to enable both diagnostic imaging and therapeutic doses to diseased sites.
This document discusses ThermoDox, a liposomal formulation of doxorubicin designed for image-guided drug delivery in combination with localized hyperthermia. ThermoDox utilizes lyso-thermosensitive liposomal (LTSL) technology to encapsulate doxorubicin and selectively release it at temperatures slightly above normal body temperature. When combined with radiofrequency ablation, localized heating from RFA triggers the release of doxorubicin from ThermoDox at the tumor site, allowing for higher concentrations with less systemic toxicity compared to free doxorubicin. A phase III clinical trial evaluated ThermoDox in combination with RFA for the treatment of hepatocellular carcinoma and found improved overall survival compared to RFA alone.
Radiosensitizers are agents that increase the lethal effects of radiation when administered with radiotherapy. They work through various mechanisms like increasing DNA damage, inhibiting repair, and modulating biological response. Common types include physical agents like hyperthermia, chemical agents like nitroimidazoles to target hypoxic cells, and biological modifiers like cetuximab. Effective radiosensitizers improve the therapeutic ratio by increasing tumor cell killing while minimizing harm to normal tissues. Combining radiosensitizers with radiotherapy can improve outcomes for many cancer types.
Induction chemotherapy followed by concurrent ct rt versus ct-rt in advanced ...Santam Chakraborty
Induction chemotherapy followed by concurrent chemoradiation (CT-RT) has been studied as an alternative to primary CT-RT for locally advanced head and neck cancers. Meta-analyses have found induction chemotherapy provides no survival benefit compared to primary CT-RT and is associated with increased toxicity. Recent large randomized trials could not demonstrate an improvement with induction chemotherapy due to inadequate accrual and poor compliance with subsequent CT-RT. While induction chemotherapy may improve organ preservation or outcomes for select subgroups like HPV-negative cancers, current evidence indicates primary CT-RT remains the standard of care for most patients.
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Selective Estrogen Receptor Downregulators (SERDs): Fulvestrant is a SERD that degrades estrogen receptors and is used in cases where resistance to other endocrine therapies develops.
Combination Therapies
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Alberto Gavizón- Simposio Internacional 'Terapias oncológicas avanzadas'
1. SYMPOSIUM ON ADVANCED ONCOLOGICAL THERAPIES
Areces Foundation, Madrid, Oct 2014
Efficacy and Safety of Cancer
Nanomedicines: The Clinical Perspective
Alberto A. Gabizon, MD, PhD
Professor and Chairman,
Shaare Zedek Oncology Institute
Hebrew University-School of Medicine
Jerusalem, ISRAEL
2. Disclosures
• Receives Grant Support from Janssen
Pharmaceuticals (DOXIL®)
• Founder and Director of Lipomedix
Pharmaceuticals (PROMITIL®)
• SAB Member of Cristal Therapeutics (CriPEC®)
3. Nanomedicine in Cancer Therapy:
Engineering nano-scale systems for drug delivery
Nanoparticle
6. 1. Liposomes can display in vivo vastly different PK-BD
profiles
2. There is a correlation between liposome circulation
time and deposition in tumors
Changes in lipid composition result in:
- 60-fold increase in the fraction of recovered dose in blood.
- 4-fold decrease of the recovered dose in liver and spleen,
- 25-fold increase of the liposome concentration in tumor.
Proc. Natl. Acad. Sci. USA, 1988
Liposome formulations with prolonged circulation time in blood
and enhanced uptake by tumors
A. GABIZON AND D. PAPAHADJOPOULOS
7. Pegylated Liposomal Doxorubicin (DOXIL) – The case
for long-circulating systems
Ligand Targeting of Liposomal Drugs: The relevance
for specific drugs
Co-encapsulation of Drugs in Liposomes –
Bisphosphonates and chemotherapeutic agents
Pegylated Liposomal Mitomycin Prodrug (PROMITIL):
A double safety valve
8. Pegylated Liposomal Doxorubicin (DOXIL, Caelyx)
1. PEG Coating (Stealth Effect): long circulation time
2. Ammonium sulfate drug loading gradient: stability in circulation
PEG
Doxorubicin
Lipid Bilayer
Phospholipid+Cholesterol
80-90 nm
Cryo-TEM
“coffee bean”
DOXIL vial for
clinical use
9. Plasma Levels in Humans: DOXIL vs. doxorubicin
- Impressive change in PK profile
1000-fold increase in AUC
Hours After Infusion
Doxorubicin (μg/mL)
0 4 8 12 16 20 24
25 .0
10.0
2.5
1 .0
0 .2
0 .1
DOXIL 50mg/m2
Doxorubicin 50mg/m2
Gabizon et al., Cancer Res. 1994
10. DOXIL: doxorubicin remains in liposome-encapsulated
form in circulation
Doxorubicin (μg/mL)
10.0 Total Doxorubicin
Total Doxorubicin
0 1 2 3 4 5 6 7
25.0
2.5
1.0
0.2
0.1
Encapsulated Doxorubicin
Days After Infusion
Gabizon et al., Cancer Res. 1994
11. Gamma Scintigraphy after Injection of
Lung
Tumor
[DTPA-In111] Stealth Liposomes
Liver,
Spleen
Spleen
Bone
Marrow
Posterior view 48h
Kaposi Sarcom
Harrington et al., Clin. Cancer Res. 2001
12. Normal liver
Normal liver
Tumor
Tumor
Conventional liposomes do not target liver tumors
(Gabizon et al. BJC 1991)
13. Blood Vessels: The Achyless Heel of Cancer
Extravasation of liposomes across tumor vessel:
Skin-fold window in vivo model (R. Jain et al.)
15. DOXIL - Mechanism Of Action: EPR Effect
Extravasation and Release of Liposomal Drug
Cargo in Tumor Interstitial Fluid
Tumor compartment:
Interstitial fluid
Tumor Cells
Vascular
space
5
No Functional Lymphatics
17. DOXIL vs. Doxorubicin in Tumors
μg Drug/gm Tumor
50 100 150 200
Hours
DOXIL
Doxorubicin
8
6
4
2
0
30- fold increase in AUC
0 5 10 15 20
160
140
120
100
80
60
40
20
0
DOXIL
Free DXR
Dose mg/kg
g doxorubicin-equiv. / g
Human Xenograft
Mouse M109 Tumor
Dose dependency
EPR also seen in human tumor
s.c. xenografts (Vaage et al.)
Increasing dose
favors DOXIL for
tumor delivery
18. COMPARING DIFFERENT NANOMEDICINES:
Accumulation in tumors correlates with circulation half-life
B16F10 s.c. tumour levels
Time (h)
Tumour accumulation (% dose/g tumour)
DOXIL®
0 20 40 60 80
15
10
5
0
HPMA-Dox
PAMAM (gen 3,5)
Dendrimer-DOX
DOX
Time (h)
Levels in blood (% dose)
DOXIL®
HPMA-Dox
PAMAM (gen 3,5)
Dendrimer-DOX
DOX
0 20 40 60 80 100
100
10
1
0.1
0.01
Blood clearance
(all 5 mg/kg)
Sat and Duncan 1999
19. Anti-Tumor Effect of DOXIL is >4-fold than
doxorubicin (DXR) in M109 mouse tumor*
Median Tumor Weight (% Cures)
Treatment given on I.V. day 15
at the indicated doses (mg/kg).
Three weeks later, on day 36,
mice sacrificed, tumors dissected
and weighed.
Values inside bars:
% Tumor-Free Mice
800
700
600
500
400
300
200
100
0
Control DXR
2.5
P<0.05
DOXIL
2.5
DXR
10
DOXIL
10
0 17
29
11
27
* Also demonstrated for mouse 3LL and human N87 Gabizon et al, 2002
20. DOXIL Clinical Proofs of Added Value
• Cardiac function: Major reduction of cardiotoxicity as compared to free
doxorubicin in all settings. (2000)
• AIDS-related Kaposi’s Sarcoma: Superior efficacy over former
conventional therapy (1995)
• Recurrent Ovarian Cancer: Superior efficacy and improved safety
profile over comparator drug (topotecan) (1998)
• Metastatic Breast Cancer: Equivalent efficacy and reduced
cardiotoxicity compared to free doxorubicin (2003)
• Multiple Myeloma: Equivalent efficacy and improved safety profile
compared to free doxorubicin combo. Superior efficacy in combination with
bortezomib over single agent bortezomib. (2007)
21. Doxil in Ovarian Ca: Major Improvement
in Survival in “Pt-Sensitive” Patients*
DOXIL (n=109)
Topotecan (n=111)
0 20 40 60 80 100 120 140
Weeks Since First Dose
100
90
80
70
60
50
40
30
20
10
0
P=.008 DOXIL
25.2 mths
Topotecan
15.6 mths
Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322.
* Median survival for all patients:
DOXIL=15mth; Topotecan=13mth
(p=0.025)
22. Reduced rate of cardiac events with DOXIL (vs doxorubicin)
O’Brien M E R et al. Ann Oncol 2004;15:440-449
PLD
50 mg/m2 q4w
Doxorubicin,
60 mg/m2 q3w
Hazard Ratio
(95% CI)
Cardiac
Events
6.6% 25.7% 3.16
(1.58-6.31)
CHF 0 5.3%
23. Long-term response to pegylated liposomal doxorubicin
in patients with metastatic soft tissue sarcomas
Computed tomography scan of the chest (a) shows a mass 6.4x3.9 cm (maximal
size slice) in the left lower lobe of the lung involving chest wall. Patient treated
with pegylated liposomal doxorubicin (PLD) for 30 months. (b) Marked decrease
in the size of the mass to 2.6x1.1 cm (Grenader et al, AntiCancer Drugs, 2009)
27. Chemical structure: thermosensitive
poly(ethylene glycol)-b-poly(N-
(2hydroxypropyl)-methacrylamide-lactate)
(mPEG-b-pHPMAmLacn) block copolymers
(1) Micelle formation and encapsulation of hydrophobic drug derivatives by
rapid heating; (2) Copolymerization of methacrylated lactate side chains and
drug derivatives in the micelle core; (3) Hydrolytic liberation of lactate
moieties, drugs and drug linkers, leading to micellar destabilization and drug
release.
28. CriPec® docetaxel vs Taxotere
Increased efficacy – PK profile
10000 Taxotere 30 mg/kg
1000
100
10
1
0.01
EFF-12-004 0 EF2F4-13-006 48 72 96
31
100
75
0 14 28 42 56
2000
1750
1500
1250
1000
750
500
250
50
25
s.c. MDA-MB-231 breast xenografts in
nude mice (n=10±SD)
0
vehicle
Taxotere 30 mg/kg
CriPec docetaxel 90 mg/kg
single dose
time (days)
tumour volume (mm3)
48 hours 96 hours
0
Taxotere 30 mg/kg
CriPec® docetaxel 30 mg/kg
**
***
total docetaxel
in tumour (ng/mg)
CriPec® docetaxel 90 mg/kg
4 days 7 days
100
75
50
25
0
Taxotere 30 mg/kg
*** ***
total docetaxel
in tumour (ng/mg)
0.1
CriPec docetaxel 90 mg/kg
time post administration (hours)
total docetaxel in blood
(μg/mL)
29. Ligand targeting of liposomal drugs to a receptor-expressing tumor
The rate limiting step of liposome localization in tumors is extravasation !
Goren et al., 1996; Gabizon et al., 2003
30. A1
In Vitro uptake of folate-targeted liposomes (A1-2)
labeled with rhodamine by M109-HiFR tumor cells.
Note extensive internalization after 4 h incubation.
Nontargeted liposomes are not taken up (not shown)
31. Micellar insertion of lipophilic ligands into preformed liposomes
Pharmaceutical approach to design of ligand-targeted liposomes
• Adding lipophilic ligands to
preformed (drug- loaded)
liposomes
Blood
• Stable retention Vessel
of ligand*
• Maintaining liposome
long circulation time
•Demonstrated for Folate and anti-Her2
(Shmeeda et al, JCR, 2009)
32. Targeting of Doxil with anti-Her2 ligand (HT-PLD) enhances
cytotoxic effect on Her2+ tumor cells but not more than Free Dox
Shmeeda et al., JCR 2008
SKBR-3 breast carcinoma
34. Targeting of L-ZOL with Folate Ligand (FTL-ZOL) enhances cytotoxic
effect on FR+ tumor cells much more than Free ZOL
0 2 4 6 8 10
110
100
90
80
70
60
50
40
30
20
10
0
25 50 75 100125150175200
Free ZOL
L-ZOL
FTL-ZOL
Free Dox
Concentration (ZOL, Dox) M
Growth Inhibition (% Control)
IGROV1 ovarian carcinoma
FTL-ZOL is as cytotoxic
as Free Dox, and ~100-
fold more cytotoxic than
Free ZOL and L-ZOL!
Shmeeda et al., J Control Rel 2010
35. Enhanced tumor-sensitizing effect of FR-targeted liposomal NBP (LZ-FR),
on Vγ9-V2 T cell destruction of autologous ovarian cancer spheres .
Study of Drs. John Maher and Ana Parente-Pereira (KCL)
36. Adoptive Gamma-Delta T Cell immunotherapy of epithelial
ovarian cancer potentiated by liposomal alendronic acid
Ana C. Parente-Pereira al. (John Maher’s Lab, J. Immuol, in press))
Survival
37. Rationale for combining bisphosphonates with
doxorubicin in the same liposome
• Double attack on tumor cells and tumor-infiltrating macrophages
• Different MoA’s, Non-overlapping toxicities
• Possible immunological anti-tumor effects
• Co-delivery ensures timely co-exposure to both agents
Bisphosphonate
Doxorubicin
39. Cryo-TEM before and after Dox loading (PLAD formulation):
Note round vesicles with precipitated salt of doxorubicin
alendronate in the interior water phase
Before Dox After Dox
40. PK of PLAD: Slow clearance from blood (t½ =15-20 h) with similar “Stealth”
profile as DOXIL. PLAD i.v.10mg/kg, Sabra mice - Results based on Dox plasma levels
Similar clearance profile for H3-ALD label
24 hours
41. Superior activity of PLAD over PLD (DOXIL) in M109R tumor model
100
90
80
70
60
50
40
30
20
10
Untreated Table-Tumor Growth
5 10 15 20 25 30 35 40
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Days
PLAD vs PLD p=0.0001
PLAD vs PLA+PLD p=0.0101
PLD Table -Tumor Growth
Untreated
0 5 10 15 20 25 30 35 40
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Days
PLAD Table -Tumor Growth
0 5 10 15 20 25 30 35 40
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Days
Time to treatment failure - M109R
5 10 15 20 25 30 35 40
0
PLD 5mg/kg d.7,14,21
PLAD 5mg/kg d.7,14,21
Days after tumor inoculation
Percent survival with tumor4mm
PLA+PLD 5mg/kg d.7,14,21
Similar results in 4T1 tumor model
42. Liposomal Prodrug Approach- Rationale
• Long-circulating liposomes are required for selective
accumulation in tumors based on the EPR effect
• For effective payload retention, long circulation
imposes stringent stability requirements.
• Attachment of drugs to bilayer-compatible lipids is a
known way of ensuring prolonged association with a
liposome.
• The choice of the linkage is critical for the release rate
of the active drug from the Prodrug.
44. Mitomycin-C Lipid-based Prodrug (MLP)
A prodrug designed for liposomal delivery
Drug moiety
– Latent toxicity in the bound form
Linkage: benzyl urethane p-substituted by a disulfide
(dithiobenzyl, DTB)
– Stable until thiolytically cleaved by either endogenous of exogenous thiols
Diacyl glycerol-type lipid anchor
– Provides avid association with liposomal membrane
45. Pegylated Liposomal Formulation of Mitomycin-C Lipophilic
Prodrug (PL-MLP) - PROMITIL®
Lipophilic prodrug in
bilayer
Internal water phase
(drug-free)
Lipid Membrane
(Phospholipid +/-
cholesterol)
Polyethylene Glycol
for RES evasion & tumor
accumulation
N N
CH3O
O
H2N
O
O
O
CH3
NH2
O
O S
O
C17H35
O
C17H35
O
S
O
Vesicle
Size:
80-110nm
CryoTEM
of Promitil
24+ month Shelf Stability at 5oC
46. Activation of Prodrug in PL-MLP by free thiols
(Cytotoxicity of PL-MLP in M109 cells 72 h, 37 °C DTT)
100-fold increase of cytotoxicity of PL-MLP No change of Free MMC cytotoxicity
Free MMC
PL-MLP
PL-MLP+DTT
Free MMC
Free MMC+DTT
47. Intracellular Delivery of PL-MLP by Folate
Targeting enhances uptake and cytotoxicity
w/o added reducing agent
KB CELLS
Poster 41 – Yogita P. Patil et al.
48. PK analysis of PL-MLP in Sprague-Dawley Rats:
• Long half-life (14.5h) as compared to 0.25h for MMC;
• Cmax levels of PL-MLP are ~200 fold greater than for MMC
• AUC of PL-MLP ~1,000 fold greater than that for MMC
• MMC levels in PL-MLP-injected animals undetectable or minimal
0 10 20 30 40 50 60 70 80 90
100
10
Male Rats, Total MLP
Female Rats, Total MLP
800
4
Free MMC
T1/2=14.5h
T1/2=0.25h
Hours after injection
MLP g/ml plasma (SEM)
~15% of Cmax
at 24h
49. Tissue Distribution of Promitil (24h)
MLP levels in mice are relatively lower than Liposome (H3-Chol) levels,
suggesting that MLP is quickly metabolized.
In tumor-bearing mice, the highest levels of MLP were found in tumor,
suggesting relatively slower processing of MLP in tumor tissue.
20
18
16
14
12
10
8
6
4
2
0
spleen tumor kidney liver
μgMLP/gtisssue
Biodistribution in tumor bearing mice
BLLQ
12
10
8
6
4
2
0
Spleen Kidney Heart Lung Liver
%ID/gm of tissue
Biodistribution of MLP in normal mice
MLP
3H-Chol
50. Superior efficacy of Promitil in human tumor models over comparators
A2780/AD Ovarian Ca
2400
2000
1600
1200
800
400
0
- Plain Lip./No Rx
- Free Dox 2.5mg/kg
- MMC 4mg/kg
- Cisplatin 6mg/kg
- DOXIL 10mg/kg
- PL-MLP A/B
15mg/kg
0 10 20 30 40 50
Tumor Volume (mm3)
Time (days)
1100 Control
1000
900
800
700
600
500
400
300
200
150
100
50
0
Campto 75mg/kgx3
PL-MLP 15mg/kgx3
10 20 30 40 50 60 70 80
PL-MLP:
8 PR, 2 CR
p<0.0001
Inj. d.14,21,28
Day of study
MeanTumor Volume SEM (mm3)
N87 Gastric Ca
0 20 40
100
90
80
70
60
50
40
30
20
10
0
Vehicle
Gemcitabine 120mg/kgq3dx4
PL-MLP 15mg/kgqwx3
Panc-1 CA
50 55 60 65 70 75
Day of Study
Percent remaining mice
p=0.016
53. Promitil in Chemoradiotherapy
In vivo Efficacy of Promitil + XRT in Ca-Skin Tumor Model
The combination of Promitil and 5-Fluorouracil
resulted in the greatest radiosensitization.
54. Promitil First-in-Man Phase 1 Study
(Nov2012)
Biweekly clinical and
AE assessments
Weekly clinical and
AE assessments
Current Cohort - CRC only (n=27)
Selected Dose=2 to 3mg/kg
w or w/o Capecitabine
START
START
Obtain informed
consent. Screen
subjects by
criteria; obtain
history document.
Day 29 Day 57
Clinical and AE
assessments
3 subjects
0.5 mg/kg
Weekly clinical and
AE assessments
Day -21 Day 1 Day 85 1 YEAR
Biweekly clinical and
AE assessments
Obtain informed
Cohort A
START
Cohort D
Cohort B
Obtain informed
consent. Screen
subjects by
criteria; obtain
history document.
Day 29 Day 57
Clinical and AE
assessments
Weekly clinical and
AE assessments
Weekly clinical and
AE assessments
3 subjects
1.0 mg/kg
Day -21 Day 1 Day 85 1 YEAR
Obtain informed
consent. Screen
subjects by
criteria; obtain
history document.
Weekly clinical and
Biweekly clinical and
Weekly clinical and
AE assessments
AE assessments
AE assessments
Day -21 Day 1 Day 29 Day 57
Day 85 Cohort C
3 subjects
1.5 mg/kg
3 subjects
2.0 mg/kg
PK PK
55. PK of Promitil in humans
Half-Life unchanged between
0.5-2mg/kg dose
0.5 1.0 1.5 2.0
50
45
40
35
30
25
20
15
10
5
0
T1/2 MLP 1st Cycle
T1/2 MLP 3rd Cycle
Dose MLP, mg/kg
MLP, Hours (SEM)
• High Plasma Levels
• Long T1/2 (~1 day)
• No sig levels of free MMC in
plasma)
• No change of PK with repeated
treatment
1.5mg/kg
0 10 20 30 40 50 60 70
3rd Cycle
0 10 20 30 40 50 60 70
100
10
1
100
10
1
0.1
160 170
MLP, g/ml plasma
0.5mg/kg
1mg/kg
1.5mg/kg
2mg/kg
Hours after infusion
0.1
160 170
MLP, g/ml plasma
0.5mg/kg
1mg/kg
2mg/kg
1st Cycle
Hours after infusion
56. 1 8 15 22 29
600
550
500
450
400
350
300
250
200
150
100
50
0
01-01M 0.5mg/kg
01-02F 0.5mg/kg
01-03M 1mg/kg
01-04F 1mg/kg
01-05M 1mg/kg
01-06F 1.5mg/kg
01-07M 1.5mg/kg
02-31M 0.5mg/kg
02-33M 1.5mg/kg
02-35F 2mg/kg
02-36F 2mg/kg
02-38F 2mg/kg
Days
Platelets x103/l
No dose limiting Thrombocytopenia
up to 2mg/kg
Promitil Safety:
• Infusion acute reaction in 2
patients
• Nausea and fatigue
• No hairloss
• No skin toxicity
• No mucosal toxicity
• No liver, lung, kidney or heart
toxicity
• No Dose-limiting toxicity up to
3.5 mg/kg in 1st cycle
• Delayed thromocytopenia after
3rd cycle resulted in MTD of 3
mg/kg
57. Response to Promitil in a Melanoma Patient:
Disappearance of Ascites, and Shrinkage of tumor mass between Nov 2012 to May 2013
58. Longest responder (Colon Ca) to Promitil (12+ mth) with good safety profile
Sustained decrease of CEA tumor marker - Stable disease (CT-scan)
59. PROMITIL Clinical Phase Interim Summary
- Phase I Study in cancer patients
Start dose: 0.5mg/kg.
Maximal dose: 3.5mg/kg.
- 27 patients accrued. MTD stablished at
3mg/kg due to delayed thrombocytopenia –
Results confirm preclinical observations of
reduced toxicity vs. free MMC (~3 Fold)
-PK observations: high plasma levels, long half-life,
slow plasma clearance, and small volume
of distribution
- Phase 1B continuation study in Colon CA -3rd
line therapy- ongoing: 27 patients
60. Take home Message
for Nanomedicines
• Different drugs / Different problems
Different solutions
• Most effective weapon Exploiting EPR
• Targeting important for specific drugs
• Know the PK/Clearance and Drug Release of
your system before attempting anything else
61. Combining
Therapeutics with
Imaging may help
to detect EPR and
predict Efficacy
Karathanasis et al., Radiology 2009
Nanotheranostics
DOXIL
Poor
imaging
Good imaging
62. Acknowledgments:
• Lipomedix: Patricia Ohana, PhD
• Exptal. Oncology SZMC Lab:
Hilary Shmeeda PhD
Yasmine Amitay PhD
Yogita Patil, PhD
Jenny Gorin, M.Sc.
Lidia Mak
Dina Tzemach
Collaborators:
• Samuel Zalipsky, PhD (Promitil, San
Francisco)
• Irene La-Beck, PhD (Abilene, TX)
• Andrew Wang, MD (UNC)
• Franco Muggia, MD (NYU)
• Nano Charact. Lab (NCI)
• John Maher, M.D., Ana Parente, PhD,
Rafael Torres, PhD (KCL, London)
• Thomas Andresen, PhD (DTU, DK)
• Yechezkel Barenholz, Ph.D. (DOXIL,
HU, Jerusalem)
Liposome Community
63. Mouse – ‘Free’ 64Cu
1 h pi
Mouse – 64Cu-liposomes
1 h pi
Mouse – ‘Free’ 64Cu
24 h pi
Mouse – 64Cu-liposomes
24 h pi
Alendronate-Copper64
PET Labeling
From: Torres-Martin de Rosales Lab