Nanomedicine current status and future prospects
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Detailed idea on nanotechnology, nanomedicine, types, uses, pharmacotherapy, and future prospects of the nanotechnology. Drug delivery systems, Pharmacokinetics and pharmacodynamics of the nanoparticles are dealt in detail
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Nanomedicine current status and future prospects
- 1. Dr. Siddhartha Dutta Mamc New Delhi
- 2. Introduction Nanotechnology Engineered Nano- Materials PK of ENM Types of ENM Approved ENMs & ENMs under clinical investigation Future prospects
- 3. “Nanos” means DWARF One-billionth part of something “Nanoscience: Involves research and technology development at nanoscale(0.1 nm to 100nm range)” NIH started in the year 2000 the National Nanotechnology Initiative
- 5. Nanoporous ceramic filters were indeed already being used in the19th century to separate viruses 1902 structures smaller than 4 nanometers were successfully detected in ruby glasses using the ultra microscope developed by Richard Zsigmondy Proposed by Richard Feynman in his book titled “There’s Plenty of Room at the Bottom” Why cannot we write the entire 24 volumes of the Encyclopedia Britannica on the head of a pin?”
- 6. The understanding and control of matter at dimensions between approximately 1 and 100 nanometers (nm), where unique phenomena enable novel applications not feasible when working with bulk materials or even with single atoms or molecules
- 8. Why Nano- therapeutics?? Better PK Improved dosing requirements Controlled release of drugsFaster Biochemical reaction Better Side Effect profile Smaller & Faster devices
- 9. 1-100 nm Man- made Properties that arise as a result of nano-sized dimension
- 12. Fouling or opsonization of NPs by proteins. How to prevent fouling? 1. Neutral Antifouling coats Phosphatidylcholine groups, sulfobetaines and carboxybetaine 2. Steric repulsion-Hydrophilic polymer coats PEG, polyoxazolines, HPMA, polysaccharides, such as chitosan, dextran, and hyaluronic acid
- 16. The concept here is to envelop a targeted nanoparticle with an antifouling coating, which will prevent biological entities from accessing the targeting ligands Once the nanoparticle is delivered to the tumoral area, which then is cleaved away, exposing the ligands and allowing for binding to the intended cellular targets
- 17. Drug delivery vehicles by Gregoriadis(1970) “Old drugs in new clothing” Aqueous inner space, or several of them, which are surrounded by one or more phospholipid bilayers Diameters ranging 50-200 nm
- 18. Better efficacy & safety Alters PK of a free drug by: 1. Enhanced permeability and retention effect (EPR effect) 2. Targeting of the mononuclear phagocytic system (MPS) 3. Multilamellar liposomes (MLVs) are the liposomes of choice when using them as a slow or sustained release drug carrier
- 19. Name Description Mechanism of action Approval/ Indication AmBisome Amphotericin B encapsulated in 60- 70 nm liposomes Mononuclear phagocytic system targeting FDA 1997 Systemic fungal infection DaunoXo me Daunorubicin citrate encapsulated in 45 nm liposomes Passive targeting FDA 1996 HIV- related Kaposi sarcoma DepoCyt Cytarabine encapsulated in multivesicular 20 μm liposomes Sustained release: cytotoxic conc. Of drug in CSF for more than 14 days after a single 50 mg injection FDA 2007 Lymphomatous malignant meningitis DepoDur Morphine sulphate encapsulated in 17- 23 μm multivesicular liposomes Sustained release FDA 2004 Treatment of chronic pain in patients requiring long term daily round-the- clock opioid analgesic (epidural space)26-02-2018 21
- 20. Name Description Mechanism of action Approval/ Indication Doxil Doxorubicin hydrochloride encapsulated in 100 nm Stealth liposomes Passive targeting FDA 1995 AIDS related Kaposi sarcoma Multiple myeloma Ovarian cancer Inflexal V Influenza virus antigens on surface of 150 nm liposomes Liposomes mimic native virus structure Switzerland 1997 Influenza vaccine Marqibo Vincristine sulphate in 100 nm liposomes Passive targeting FDA 2012 Acute lymphoid leukemia Mepact Mifamurtide incorporated into multilamellar liposomes Mononuclear phagocytic system targeting Europe 2009 Non metastatizing resectable osteocarcoma Myocet Doxorubicin in 180 nm liposomes Mononuclear phagocytic system targeting Europe 2000 Metastatic breast cancer Visudyne Verteporfin in liposomes Drug solubilisation FDA 2000 Photodynamic therapy of age related macular degeneration, pathological myopia, ocular histoplasmosis syndrome 22
- 21. FEATURES PREPARATION ROA Solid core – drug dissolved or dispersed in solid high melting fat matrix Surfactant added for physical stabilization (poloxamer 188, polyorbate 80, lecithin) High pressure homogenization Microemulsion formation Precipitation Parenteral Pulmonary Topical Oral delivery of lipid nano pellets
- 22. Advantages Nontoxic compared to polymeric nanoparticles Cationic SLN can be effective, potent non viral transfection agent Lipid components degrade slowly – provide long lasting exposure to immune system
- 23. PEGylation of biologically active macromolecules generally Increases their hydrodynamic radius Prolongs their circulation and retention time Decrease their proteolysis Decreases their renal excretion Shields antigenic determinants from immune detection without obstructing the substrate- interaction site
- 24. Name Description Approval/ Indication Adagen Adenosine deaminase FDA 1990 Severe Combined Immunodeficiency Syndrome Cimzia Antibody (TNF-α) FDA 2008 Crohns disease Rheumatoid arthritis Neulasta Filgrastim FDA 2002 Febrile neutropenia Oncaspar L- asparaginase FDA 1994 Acute lymphoblastic leukemia Pegasys Interferon α-2b FDA 2002 Hepatitis B and C PegIntron Interferon α-2b FDA 2002 Hepatitis C Somavert Human growth hormone receptor antagonist FDA 2003 Acromegaly Macugen Anti- VEGF FDA 2004 Intravitreal neovascular age related macular degeneration Mircera Erythropoeitin receptor activator FDA 2007 Anemia associated with chronic renal
- 25. NPs with a core of silica & a coating of thin metallic shell (gold) Can be guided to particular tissues such as cancer cells On exposure to infrared rays they are heated up to cause selective tissue destruction
- 27. Artificial macromolecules Tree like structures Atoms arranged in many branches Multivalent property Covalent attachment of special targeting moieties (sugar, folic acid, antibody, biotin, EGFs) to achieve active targeting drugs to tumor tissues
- 29. Carbon allotrope Fullerenes are closed hollow cages consisting of carbon atoms interconnected in pentagonal and hexagonal rings. Bucky balls Light used to produce reactive oxygen from molecular oxygen trigger apoptosis destroy most organic molecules nearby (like tumors) Investigated for ability to "interrupt” allergy/immune response Prevent mast cells from releasing histamine into blood & tissues Bind to free radicals better than other anti-oxidants
- 30. Self-assembling sheet of atoms arranged in the form of tubes and thread-like structures of nanoscale range Carbon based cage like structures – nanotubes and fullerenes Single walled and double walled Single walled more promising for drug and gene delivery system
- 31. Modified gold nanoparticles (GNPs) Rod, multipod, star or a hollow structure such as shell, box, cage Have promising applications in Fields of drug delivery Photothermal therapy in oncology Due to their Unique optical & photothermal properties Ability to modify the surface & conjugate drugs/ molecules with gold nanomaterial
- 32. Albumin has gained significant attention as a potential carrier for therapeutic agents Albumin particles alter the PK of the free drug, subsequently leading to its passive accumulation at the site of solid tumors via the EPR effect Abraxane®, which comprises130 nm-sized nanoparticles prepared from albumin with conjugated paclitaxel
- 33. Name Description Mechanism of action Approval/ Indication Abraxane Nanoparticles (130 nm) formed by albumin with conjugated paclitaxel Passive targeting FDA 2005 Metastatic breast cancer, non-small-cell lung cancer Kadcyla Immunoconjugate. Monoclonal antibody (against human epidermal growth factor receptor-2) No mechanism attributable to nano size FDA 2013 Metastatic breast cancer Ontak Recombinant fusion protein of fragment A of diphtheria toxin and subunit binding to interleukin-2 receptor Fusionproteinbindsto IL-2receptor,followed byreceptor-mediated endocytosis;fragmentA ofdiphtheriatoxinthen releasedintocytosol whereitinhibitsprotein synthesis FDA 1994/2006 Primary cutaneous T-cell lymphoma
- 34. Composed of 100% water-insoluble drug without any added excipient or any associated nanocarrier system Increase in saturation solubility it increases with decreasing particle size below 1000 nm Noyes and Whitney equation(1897) Increase of dissolution velocity by surface area enlargement Drug nanocrystals possess increased Saturation solubility, which in turn increases the concentration Gradient between gut lumen and blood, and thereby increases the absorption by passive diffusion
- 35. Name Description Mechanism of action Approval/ Indication Emend Aprepitant Increased dissolution rate FDA 2003 Emesis, antiemetic (oral) Megace ES Megestrol acetate FDA 2005 Anorexia, cachexia (oral) Rapamune Rapamycin (sirolimus) FDA 2002 Immunosuppressant (oral) Tricor Fenofibrate FDA 2004 Hypercholesterolemia, hypertriglyceridemia (oral) Triglide Fenofibrate FDA 2005 37
- 37. Name Description Mechanism of action Approval/ Indication Fungizone Lyophilized powder of amphotericin B with added sodium deoxycholate. Forms upon reconstitution colloidal (micellar) dispersion Drug solubilization: Rendering drug biocompatible and enhancing ease of administration after Iv injection FDA 1966 Systemic fungal infections (Iv) Diprivan Oil in water emulsion of propofol Drug solubilisation FDA 1989 Induction and maintenance of anesthesia Estrasorb Emulsion of estradiol in soyabean oil Drug solubilisation FDA 2003 Hormone replacement therapy
- 38. Name Description Mechanism of action Approval/ Indication Copaxone Glatiramer Based on its resemblance to myelin basic protein, glatiramer is thought to divert as a “decoy” an autoimmune response against myelin FDA 2014 Multiple sclerosis (SC) Eligard Leuprolide acetate incorporated in NP composed of PLGH copolymer Sustained release FDA 2002 Advanced prostate cancer (SC) Genexol Paclitaxel Passive targeting South Korea 2001 Metastatic breast cancer, pancreatic cancer (Iv) Opaxio Paclitaxel Passive targeting FDA 2012 Glioblastoma Renagel Cross-linked poly allylamine hydrochloride Phosphate binding FDA 2000 Hyperphosphatemia (oral) Zinostatin stimalame r Conjugate protein or copolymer of styrenemaleic acid and an antitumor Passive targeting Japan 1994 Primary unresectable hepatocellular carcinoma
- 39. Name Description Mechanism of action Approval/ Indication Feridex Superparamagnetic iron oxide nanoparticles coated with dextran MPS targeting: 80% taken up by liver and up to 10% by spleen within minutes of administration. Tumor tissues do not take up these particles and thus retain their native signal intensity FDA 1996 Liver/spleen lesion MRI Feraheme Superparamagnetic iron oxide nanoparticles coated with dextran. MPS targeting FDA 2009 Treatment of iron deficiency anemia in adults with chronic kidney disease NanoTher m Aminosilane-coated superparamagnetic iron oxide 15 nm nanoparticles Thermal ablation Europe 2013 Local ablation in glioblastoma, prostate, and pancreatic cancer
- 52. Nanotechnology offers potential developments in pharmaceuticals, medical imaging and diagnosis, cancer treatment, implantable materials, tissue regeneration, and even multifunctional platforms combining several of these modes of action into packages a fraction the size of a cell
Editor's Notes
- With patent expirations on the rise, pharmaceutical companies are looking forward for new competitive strategies. There is enormous excitement regarding nanomedicine potential in the diagnostics and therapy arenas. Specifically, drug delivery via nanoparticles presents novel agents (drugs or genes ) offering solutions to previous fundamental problems ranging from poor solubility to a lack of target specificity. (NNI) as a federal government program in order to promote nanoscience-related research and development
- Nanomedicine is a young science. Bottom-up manufacturing although the term “nano” does not occur a single time in it, this paper is regarded as the founding text of nanotechnology. even mentioned the use of tiny machines in medicine: “[...] it would be interesting in surgery if you could swallow the surgeon. You put the mechanical surgeon inside the blood vessel and it goes into the heart and “looks” around Other small machines might be permanently incorporated in the body to assist some inadequately functioning organ” the bottom-up approach revolves around the construction of nanostructures atom for atom by physical and chemical methods and by using and controlled manipulation of the self-organizing forces of atoms and molecules. Ths theory of “molecular engineering” became popular in 1986 when Engines of Creation Nanotech approach Add material until the product has been created Eg. Biological systems In bottom-up methods, nanomaterials are fabricated from build up of atoms or molecules in a controlled manner that is regulated by thermodynamic means such as self-assembly.
- NIH defied in its NNI nanotechnology as Nanotechnology At the nanoscale, the physical, chemical, and biological properties of materials differ in fundamental and valuable ways from the properties of individual atoms and molecules or bulk matter. Currently, nanoparticle applications in medicine are geared towards drug discovery and drug delivery.
- Antimicrobial dressing covered with nanocrystalline sliver that rapidly kills a broad spectrum of bacteria in as little as 30 mins. The first nanoparticle based injectable drug formulation was approved by the FDA : Under name Abraxane. It contains albumin bound Paclitaxel for the treatment of metastatic breast cancer. Targeted delivery Drug delivery Protein & peptide delivery CANCER Surgery Tissue engineering Antibiotic resistance Cell repair machines Nanotherapeutics has the capacity to incorporate, encapsulate, or conjugate a variety of drugs to target specific cell populations and to offer tunable and site-specific drug release
- Use of nanocarriers for these conditions allows for local or directed delivery, prolonged effect of the drug, facilitated delivery into target cells, and reduction of the shear effects of blood flow. Liposome technology research culminated in 1995 in the US Food and Drug Administration (FDA) approval of Doxil®, “the fist FDA approved nanodrug” The exploration of colloidal systems, ie, systems containing nanometer sized components, for biomedical research was, however, launched already more than 50 years ago3–5 and efforts to explore colloidal (nano) particles for drug delivery date back about 40 years.6 For example, efforts to reduce the cardiotoxicity of anthracyclines via encapsulation into nanosized phospholipid vesicles (liposomes) began at the end of the 1970s
- Pharmaceutical: drug instability, low solubility…. PK: short t half, poor absorption… PD: low speicificity
- (i) sizes, ranging from few tens of nanometers (e.g. dendrimers, gold and iron-oxide nanoparticles) to few hundreds of nanometers (e.g. polymeric and lipid-based particles) to micron-sized particles; (ii) shapes, from the classical spherical particles to discoidal, hemispherical, cylindrical and conical; (iii) surface functionalizations, with a broad range of electrostatic charges and bio-molecule conjugations
- Schematic diagram showing the complex behaviors of nanoparticles under in vivo conditions. Upon systemic injection, nanoparticles encounter several physiological behaviors before they can reach the intended targets, including protein adsorption and opsonization in the blood, uptake by the liver and other reticuloendothelial organs, renal excretion, extravasation across leaky vasculatures (often found in solid tumors), and binding to receptors on diseased cells, leading to subsequent internalization. These problems include the complex interactions between nanoparticles and biological systems in vivo, the rapid uptake and clearance of nanoparticles by the (RES) organs ), active versus passive targeting, and the limited penetration of nanoparticles into solid tumors
- proteins compose 75% dry wt (body) >90% of dry wt of plasma Np often delivered iv & upon exposure to the blood, they immediately encounter a complex and crowded mixture of ions, small molecules, proteins, and cells. key initial interactions with blood components are rough physical association with plasma proteins, often called opsonization or biofouling High-affinity association with proteins is undesirable, as it masks the targeting or molecular recognition properties of the np process leads to a shell of adsorbed proteins on np surface called corona most frequent proteins-globular albumins, fibronectin, complement proteins, fibrinogen, immunoglobulins, & apolipoproteins key to minimize fouling is to offset the attractive potential btw np & proteins by using surface chemical modifications designed to increase the adsorption barrier Coatings resistant to protein adsorption are often electrostatically nearly neutral and exhibit a high degree of surface flexibility and entropy. phosphatidylcholine groups (anionic phosphate and cationic ammonium), sulfobetaines (anionic sulfate and cationic ammonium), and carboxybetaine (anionic carboxylate and cationic ammonium)
- (Targeting molecules anchored to surface are able to bind to their target if the surrounding polymers are sparsely grafted and adopt short mushroom-like confmns. With the use of higher grafting densities to push the polymers into brush-like conformation, the particle is able to resist biofouling but will block a surface-anchored molecule from binding to its target Ideal situation involves tethering the targeting ligand to the end of the polymer chain and surrounding it by densely grafted polymers of the same length adopting a brush-like conformation. This design resists biofouling while orienting the ligand on the outer surface, where it can bind to its target. However, if the ligand is tethered to a polymer that is much longer than its neighboring polymers, the extra length can fold back and bury the ligand, which hinders its ability to bind.
- ( a) small pores within the vessel(gap jucn of endotlal cells in normal tissue, extravasation of np is inhibited,stay in the circulation. ( b) Tumoral -leaky vasculature with large pores, np extravasation is facilitated, after which np can migrate through the interstitium. ( c) np that are passively targeted, otherwise have no affinity ligands for cell receptors, may perfuse the tissue, exhibiting cell-free channels. ( d) Actively targeted np are likely to be bound with the first cells they encounter, significantly slowing the transport within cell-free channels ( e) Passively targeted particles have little mobility to pass cell-dense layers without a leaky or cell-free channel to diffuse in. ( f) Actively targeted particles may be able to travel beyond dense layers of cells by being taken up by the cells and trans cytosed or exo cytosed to the other side. Combination of these conditions leads to an increased accumulation of circulating nanoparticles in the tumor interstitium, which is called the enhanced permeation and retention (EPR) effect
- For efficient cellular delivery, np must have a high affinity to the cell receptors and then develop enough ligand-receptor binding pairs to overcome the energetic barrier of wrapping the cellular membrane around the particle for internalization Both the binding affinity and subsequent cellular internalization can be enhanced by multivalent binding, in ligand-receptor pairs B. Positive cooperativity of binding among the multiple complexes, as binding of one ligand on the np will localize neighboring ligands closer to other receptors, facilitating further binding events. Mulval binding affinity (often called avidity) is depen on both monoval binding affinity and number of lig-recep bndg pairs(valency) binding affinity to targeted cells is generally seen to increase with an increasing number of ligands per particle,
- technical and fundamental barriers to in vivo nanoparticle delivery and targeting, including biofouling, RES uptake, poor tissue penetration, and limited endosomal release problems could be overcome or mitigated by the designing smart or intelligent nanostructures, such as stimuli-responsive nanoparticles and multistage/mothership delivery vehicles One strategy is the use of pH sheddable coatings, which can respond to the slightly more acidic environments within tumoral areas-pH detachable PEG outer layers upon liposomes Polymers(PNIPAAM, which phase transitions from solvated extended coils to shrunken states upon heating, can act as temperature activated doors to the drugs encased withininduction of temperature increases for drug release can come from plasmonic nanoparticles, which efficiently convert photon energy to heat when irradiated with near-infrared (NIR) light Localization and therapy may be performed through a single type of stimulus. For example, magnetic nanoparticles under the influence of external magnetic fields can be guided to the tumor site Once at the tumor site, an alternating magnetic field can be applied to agitate the nanoparticles to increase the local temperature, killing nearby cancer cells through a process called magnetic ablation
- lipid bilayer composite structures composed primarily of phospholipids formed from phospholipids and cholesterol major advantages of using liposomes (altered PK, improved bioavailability, and reduced toxicity) in aqueous medium;Doxil (liposomal doxorubicin), DaunoXome (liposomal daunorubicin), and Visudyne (liposomal verteporfin)
- limited by numerous factors including (a) their relatively fast clearance, which demonstrates a pronounced dependence on size, and ( b) their tendency to localize in the tissues of the mononuclear phagocyte system (MPS), particularly in the liver and spleen.
- Gene delivery to cells CFTR gene
- half-life and the volume of distribution of(AMB) administered as Amphotec® seems almost identicalto that of the free drug,64 suggesting that Amphotec® quickly disintegrates (IV) injection Solid lipid nanoparticle leading to drug enriched cell
- developed already in the early 1970s and patented in 1979. Consequently, Enzon Pharmaceuticals ( NJ, USA) founded in 1981, a successful biotech company which brought a large variety of PEGylated protein pharmaceuticals to the market
- PEGYLATED PROTEINS, POLYPETIDES, APTAMERS
- By irradiating area of tumor with an infrared laser, which passes through flesh without heating it, the gold is heated sufficiently to cause death to cancer cells
- spherical in shape, dendrons and dendrimers possess a large cavity that can be utilized for passive entrapment and eventual release of drugs or other cargoes. highly branched macromolecular ENMs that can incorporate either synthetic polymeric building blocks or natural components (structure presents numerous conjugation sites for cargoes or targeting moieties
- ROS-problems include promotion of tumour metastasis, ‘ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis’ neurodegeneration and other degenerative diseases associated with aging high capacity for radical quenching – they readily accept the lone electrons of radicals into their extended conjugated system non-human primates with Parkinson's disease, was responsible for improved motor function.
- SINGLE WALLED NANOTUBES MULTI WALLED NANOTUBES
- As particle size continues to increase toward the bulk limit, surface plasmon resonance wavelengths move into the IR portion of the spectrum and most visible wavelengths are reflected, giving the nanoparticles clear or translucent color attractive as therapeutic agents as gold approved and used for tx of human diseases (RA) ability to scatter visible light can be used as contrast agents. easy to synthesize shown to enhance sensitivity to external beam radiatn generate heat in response to NIR light – photothermal ablation SC model of colon ca mice treated with TNF-conjugated gold nanoparticles showed improved survival than those treated with TNF alone
- Micronization is a suitable way to successfully enhance the bioavailability of drugs where the dissolution velocity is the rate limiting step the size reduction leads to an increased surface area and thus according to the noyes-whitney equation () to an increased dissolution velocity. Therefore, drug nanocrystals possess increased saturation solubility. fenofibrate nanocrystal formulation
- composed of 100% water-insoluble drug without any added excipient or any associated nanocarrier system.
- No other apparent function of micelles, which dissociate into monomers following dilution in circulation
- Ferumoxytol releases iron insidemacrophages of the MPS system Currently under development as a novel imaging agent for MRI-based diagnosis of cancer and cardiovascular diseases Exposure to a magnetic fild that changes its Nanotherm- polarity 100,000 times per second causes these particles to signifiantly increase their core temperature. Depending on the length of exposure to the oscillating magnetic fild, the achievable intratumoral temperatures vary and either directly destroy tumor cells (thermal ablation) or sensitize them for chemotherapy (hyperthermia).
- Most of the products approved before the year 2000 were therapeutics, rather than devices. However, in the last decade, approval for therapeutics appears to have remained fairly steady, whereas there is a marked increase in the number of medical devices Device categories included in vitro testing, in vivo imaging, in vivo device coatings, bone substitutes, dental, medical dressings/textiles, cancer treatment, surgical devices, drug delivery, tissue engineering, and other
- Recent advances have led to the development of biodegradable nanostructures for drug delivery iron oxide nanocrystals for magnetic resonance imaging, and luminescent quantum dots for multiplexed molecular diagnosis and in vivo imaging