भारतीय प्रौद्योगिकी संस्थान दिल्ली
Indian Institute of Technology Delhi
Drug Delivery Systems
Biomaterials for Controlled Release
Biomaterials for Controlled Release
• External v/s Internal
• Synthetic v/s Natural
• Properties: Physical, chemical, surface, mechanical
• Biocompatibility: Host reactions to the polymer
• Biodegradability:
• Erodible v/s Non-erodible
• Bulk v/s Surface Erosion
Biodegradability
• Degradation by biological molecules: enzymatic or microbial
• Bioerosion: Erosion of polymer into water soluble products under
physiological conditions. This include both physical and chemical
processes.
• PLA or PLGA: Bioerodible (since they erode by backbone hydrolysis).
Physical Bioerosion
• Bulk erosion:
• The rate of water penetration into the polymeric device exceeds
the rate at which the polymer is eroded (i.e. transformed into
water soluble products).
• E.g. Most hydrophilic polymer, porous matrix
• Surface Erosion:
• The rate of water penetration into the polymeric device is slower
than the rate of polymer erosion.
• E.g. Hydrolytic surface erosion, polyanhydrides and
polyorthoesters.
Factors affecting hydrolytic erosion
• Chemical stability of the backbone: how labile the linkages are
• Hydrophobicity or hydrophilicity of monomers
• Morphology of the polymer
• Crystallinity
Oxidative Bioerosion
• Free radical initiated oxidation of polymers
• E.g. Polyethers and polyamides
Host-Induced:
• Activated phagocytic cells (macrophages and neutrophills).
• Produce superoxide ion or hydrogen peroxide ions (all of which
are powerful oxidants).
Could be environment mediated:
• Crack on the device
• metal ion induced oxidation
Measuring Bioerosion
• In vivo
• In vitro
Polymers
• Homopolymers
• Random Copolymers
• Alternative Copolymers
• Block Copolymers
• Graft Copolymers
Polymers- Different Sizes and Shapes
Polymers-Types
Polymers-Nomenclature
• Polyesters
• Polyethers
• Polyanhydrides
• Polyamides etc.
Polymers-Properties
• Molecular weight
• Polydispersity Index
• Light Scattering
• Viscosity
• Morphological properties: Amorphous or crystalline
• Tm, Tg
• Mechanical properties
Choosing Biomedical Polymer
• Application….Application
• Route of administration
• Biocompatibility
• Biodegradability
Strategies and materials
• Hydrogels
• Nanoparticles and microparticles
• Liposomes
• Dendrimers
• Responsive DDS
• Targeted DDS
Hydrogels
What are they??
• Hydrogels are 3D network of polymer chains crosslinked to form
matrices with high water content.
•
• Widely used in drug delivery and tissue engineering applications.
• Tunable physical, chemical and biological properties.
Swelling Controlled Matrix (Hydrogels)
Advantages
Low burst effect
Controllable swelling/release rates
Suitable for various drug
Disadvantages
Very short release period
Not suitable for all delivery route (actual implant is changing the size)
Hydrogels Classification
Polymers used in hydrogels preparation
Polymers used in hydrogels preparation
Hydrogels Synthesis process
Hydrogels Synthesis process
Hydrogels Synthesis- from Hydrophobic polymers
Hydrogels Synthesis process
Structure and Properties of Hydrogels
Polymer volume fraction in the swollen state
• measure of amount of fluid that a hydrogel can incorporate into
its structure
• Determined by equilibrium swelling experiments
Effective molecular weight of polymer between crosslinks
• Measure of the degree of crosslinking in polymer gel
Network Mesh or pore size
• Measure of network porosity
Effect of Morphology on Drug Release
Nanoparticles and Microparticles
• NPs : Really really small particles: 10-1000nm. And MPs= >1um
(typically 1-100um).
• Have very large surface area to volume ratio.
• Act as a controlled release depot system similar to matrices, reservoirs
and hydrogels.
• Increase the specific delivery of the drug to the target tissue.
• Injectable (no need of surgical implantation).
• Patient Compliant.
• Convenient way to deliver the hydrophilic molecules to the cells.
• Improves stability to the drug molecules- Increase shelf life.
Nanoparticles
Transport and interactions of nanoparticles in the kidneys
Du, B., Yu, M. & Zheng, J. Transport and interactions of nanoparticles in the kidneys. Nat Rev Mater 3, 358–374 (2018). https://doi.org/10.1038/s41578-018-0038-3
Nanoparticles
Transport and interactions of nanoparticles in the kidneys
Du, B., Yu, M. & Zheng, J. Transport and interactions of nanoparticles in the kidneys. Nat Rev Mater 3, 358–374 (2018). https://doi.org/10.1038/s41578-018-0038-3
Synthesis
Synthesis
Particle mediated delivery
• Particle size, shape and charge
• Polydispersity
• Carrier composition
• Encapsulation Efficiency (percent drug present in final formulation)
• Encapsulation ratio (weight percent of drug in formulation)
• Stability (physical and chemical)
Particle mediated delivery
https://pubs.rsc.org/en/content/articlehtml/2011/cs/c0cs00003e
Proton Sponge Effect
• Particles are designed to carry secondary and tertiary
amines
o Buffer the pH of endosomes.
o Results in proton influx through endosomal proton
pumps.
o Followed by chloride ion transport.
o Leads to osmotic swelling and bursting of vesicles.
PEI (poly ethylene imine) is widely used polymer for this
phenomenon.
Conjugation of peptides that can create pore in endosomal
membrane.
Dendrimers
• Very High Mw
polymer
• Very dense surface
surrounds a relatively
hollow core
• Dendrimers are synthetic, tree-like macromolecules with a
wide range of applications in medicine and biomedical
areas.
• Dendrimers have a well-defined spherical structure, are
highly branched, and have many functional groups. They are
also compatible with biological systems.
Liposomes
• Very simple NP system.
• Have capabilities to
encapsulate both
hydrophilic and
hydrophobic drugs.
Powdered lipid derived from water phase/cell phase – added into the
organic solvent- Freeze dry or high vacuum
•Journal of Liposome Research 28(10):1-30 DOI:10.1080/08982104.2017.1381115
Liposomes- Shortcoming
• Very short life
• Poor Scale up
• Cost
PEG- Stealth material
Polyethylene glycol (PEG) is a polymer that is often used to give
nanoparticles a "stealth" property, which helps them evade the body's
immune system and stay in the bloodstream longer.
PEG is considered safe and non-toxic, and is generally recognized as safe
(GRAS) by the FDA and the European Medical Agency (EMA).
PEG- Stealth material
How PEG works
•PEG's hydrophilic chains create a steric repulsion that prevents biological
components like antibodies and plasma proteins from approaching the
nanoparticles. This reduces phagocytosis, which is the process by which the
body clears nanoparticles from the bloodstream.
Limitations of PEG
•Long clearance time: PEG can take a long time to be cleared from the body.
•Nonbiodegradability: PEG is not biodegradable.
•Accelerated blood clearance: PEG can cause accelerated blood clearance
(ABC), which is when the body rapidly clears PEGylated nanoparticles. ABC can
happen when the body produces anti-PEG IgM antibodies.
•Tissue accumulation: High molecular weight PEG (>40 kDa) can accumulate in
tissue.
Responsive Drug Delivery Systems
❑ Responsive drug delivery systems (RDDS) are smart systems that can respond to specific internal or
external stimuli, releasing drugs in a controlled manner in response to changes in the environment.
❑ These systems remain inactive until exposed to certain stimuli, after which they trigger drug release at
the site of action.
Responsive Drug Delivery Systems
Internal Stimuli External Stimuli
➢ pH - responsive systems ➢ Light - responsive systems
➢ Enzymes - responsive systems ➢ Ultrasound - responsive systems
➢ Redox-responsive systems ➢ Electric Field - responsive systems
➢Temperature - responsive systems ➢ Magnetic Field - responsive systems
pH - responsive systems
Description Eudragit® L100-55 :
➢ Dissolution above pH 5.5
➢ Drug release in mid to upper small intestine
➢ Increases solubility of poorly soluble drugs in
amorphous solid dispersions
Enzymes - responsive systems
Figure: Schematic illustration of construction of the siRNA
and paclitaxel loaded micelle PPTN and subsequent
activation in response to MMP-2/9
https://pmc.ncbi.nlm.nih.gov/articles/PMC7406800/
Temperature - responsive systems
N-Isopropylacrylamide (NIPAM) is a biocompatible monomeric unit that can be used in the formation of stimuli responsive
polymers due to its temperature sensitive properties, which include temperature-based volumetric and phase changes.
These properties change when the temperature of the solution reaches a lower critical solution temperature (LCST).
Monomer used in the preparation of thermally sensitive, water-swellable hydrogels.
NIPAM can be used to prepare poly (NIPAM) based thermosetting polymers, which can be used for a variety of
applications such as tissue engineering, cell culture, biomedical coating, drug delivery, and muscle regeneration.
Light - responsive systems
Mechanism of light-triggered photoisomerization of Spiropyran
Spiropyrans consist of Indoline and Chromene moieties, which are conjugated together by a spiro junction
and have a perpendicular spatial disposition in respect to each other. Light-triggering of this conformer
results in cleavage of C–O bond and ring-opening followed by a cis–trans isomerization by rotation about
the central C–C bond
https://link.springer.com/article/10.1007/s13346-022-01196-5#Fig5
Ultrasound - responsive systems
Magnetic Field - responsive systems
Magnetically responsive nanofibrous ceramic scaffolds for on-demand motion and
drug delivery
https://www.sciencedirect.com/science/article/pii/S2452199X22001025#:~:text=The%20Hb
%20loaded%20HA/Fe,4%20sandwich%20scaffold%20by%20absorption.
Responsive Drug Delivery Systems
❑ Importance
◦ Precision in targeting specific cells or
tissues.
◦ Minimization of side effects and
enhanced therapeutic efficacy.
◦ Ability to control the timing, dosage,
and location of drug release
Responsive Drug Delivery Systems
Applications :
➢ Cancer Therapy
➢ Diabetes Management
➢ Autoimmune Diseases
➢ Infectious Diseases
➢ Neurological Disorders
Targeted Drug Delivery Systems
Targeted drug delivery systems (TDDS) are designed to deliver drugs specifically to the intended
site of action, minimizing systemic exposure and reducing side effects.
Importance:
o Enhanced therapeutic efficacy
o Reduced toxicity
o Improved patient compliance
o Personalized medicine
Targeted Drug Delivery Systems (TDDS)
Why TDDS ?
Pharmacokinetic reason Pharmacodynamic reason Pharmaceutical reason
o Poor Absorption o Low Specificity of drug o Drug Instability
o Short Half Life o Low Therapeutic Index o Low Solubility
o Large Volume of Distribution
Targeted Drug Delivery Systems (TDDS)
Types of Targeting Strategies
❖ Passive targeting:
• Based on the unique physiology or pathology of the target site
• Examples: Enhanced permeability and retention (EPR) effect, leaky vasculature in tumors
❖ Active targeting:
• Employing ligands or carriers that bind to specific receptors or molecules on the target site
• Examples: Antibody-drug conjugates (ADCs), receptor-targeted drug delivery
Targeted Drug Delivery Systems (TDDS)
Advantages of TDDS
Advantages:
❖ Increased therapeutic efficacy
❖ Reduced toxicity
❖ Improved patient compliance
❖ Personalized medicine
Targeted Drug Delivery Systems (TDDS)
Challenges of TDDS
Challenges:
❖ Complex design and fabrication
❖ Potential for off-target effects
❖ Variability in response to targeting strategies
❖ Regulatory hurdles
Advances and Future scope of DDS
Biomaterial Design to harness the immune system
Biomaterials can be designed to harness the immune system in a variety of ways, including:
•Immuno-evasive: These biomaterials can suppress, mimic, or be inert to the immune system.
•Immuno-activating: These biomaterials can enhance or activate the immune system.
•Mimicking infection: Biomaterials can be designed to mimic a localized infection to attract and
activate dendritic cells (DCs).
•Releasing immunomodulatory factors: Biomaterials can be engineered to release anti-
inflammatory cytokines to promote a tolerogenic immune response.
•Controlling surface properties: Biomaterials with specific surface properties, such as charge and
hydrophobicity, can affect the activation and differentiation of immune cells.
Advances and Future scope of DDS
Vaccine Delivery: Delivering vaccine Ag to APCs: a particle-based approach
Advances and Future scope of DDS
Cell and Gene Therapies: Future of Medicine
Gene therapy has the potential to be a transformative medical treatment that could cure diseases and
improve quality of life. It could be used to treat a wide range of conditions, including:
• Cancer
• Cystic fibrosis
• Heart disease
• Diabetes
• Hemophilia
• AIDS
• Spinal muscular atrophy
• Sickle cell disease
Advances and Future scope of DDS
Cell and Gene Therapies: Future of Medicine
Gene therapy works by replacing a faulty gene with a healthy one, or by introducing a
working gene to take over the function of a malfunctioning one. It could also involve
adding a new gene to produce a therapeutic protein
Cell and Gene Therapies: Future of Medicine
Advances and Future scope of DDS
Cancer Vaccine and Immunotherapies
Cancer vaccines are a form of immunotherapy that can help educate the immune system
about what cancer cells “look like” so that it can recognize and eliminate them
Cancer Vaccine and Immunotherapies
Example: Hydrogels
Nanotoxicity
• Inhalation
• Ingestion
Particle
Entry • Dermal Contact
• Once Inside, particles can react with circulating proteins, cell membranes.
Cells and Affecting cell viability, disruption of cellular function- initiate the toxicity
protein
Interaction
• Elicit the immune response leading to inflammation that can contribute to
Inflammator further cellular damage and leading to chronic inflammation.
y responses
• Oxidative stress induction by generating the Reactive Oxygen Species (ROS).
Resulting in damage to lipid, DNA and proteins- affecting the cellular health and
Oxidative
essential functioning- leading to long term biological consequences.
Stress
Nanotoxicity
Host Responses to Biomaterials
Inflammation and Wound Healing
Inflammation and Wound Healing
Sequences of host reaction following implantation
Inflammation and Wound Healing
Foreign Body Responses: The typical non–inflammatory response of an
inert biomaterial, Intended to isolate foreign bodies from healthy
tissues.
Acute Inflammation: Fluid and plasma protein exudation, accumulation
of neutrophils.
Chronic Inflammation: Localization of lymphocytes and macrophages.
Particularly irritating biomaterials, produce a foreign body granuloma
with activated macrophages and giant cells.
Scarring: Formation of new blood vessels, Deposition of collagen
Wound Healing
Granulation Tissue Foreign body giant cells
Inflammation and Wound Healing
Foreign Body Responses: The typical non–inflammatory response of an
inert biomaterial, Intended to isolate foreign bodies from healthy
tissues.
Acute Inflammation: Fluid and plasma protein exudation, accumulation
of neutrophils.
Chronic Inflammation: Localization of lymphocytes and macrophages.
Particularly irritating biomaterials, produce a foreign body granuloma
with activated macrophages and giant cells.
Scarring: Formation of new blood vessels, Deposition of collagen
Inflammation and Wound Healing
Complement Pathway
Anti-Inflammatory Strategies
