Advanced Drug Delivery Systems

• Advanced drug delivery systems involve various nanoparticles like silica-based, carbon-based, metal-based, and polymer-based NPs, liposomes, QDots, and magnetic NPs.
• These systems are used for drug loading and delivery, acting as anti-bacterial, anti-fungal, and anti-viral agents.
• They also serve in biosensors, contrast agents for medical diagnostics, cell studies, photoacoustic/photothermal imaging, and magnetically assisted imaging/hyperthermia.
• The systems enable bioseparation/purification and immunoassay/biomedical diagnosis.

Nanocrystal and Aggregates

• Drug loading capacity is up to 90%.
• Stabilizers are used.
• Nanocrystals of the drug are present.

Liposomes

• Drug loading is up to 62%.
• The drug is crystallized in aqueous fluid.
• Lipid soluble drugs are present in the biolayer.

Polymeric Micelle

• Drug loading is up to 50%.
• Consists of a hydrophilic shell and hydrophobic core.

Protein-Based Nanoparticles

• Can achieve up to 90% drug loading.
• Involves drugs wrapped by protein.

Dendrimer

• Can load up to 50% drugs.
• Drugs can be encapsulated.
• Drugs can be covalently attached.

Silica Nanoparticle

• Drug loading is up to 40%.
• Involves encapsulated drugs.

Polymer-Drug Conjugate

• 75% drug loading is possible.
• Conjugated drugs are present.
• Polymers are invovled in delivery

Learning objectives

• A framework for designing targeted delivery systems is important.
• Nanoparticles, microparticles, dendrimers, nanomicelles, liposomes, implants, nanofibers, hydrogels, cellular carriers, composite nanosystems, and intelligent nanocarriers.
• Endogenous and exogenous stimuli responses should be understood.
• Barriers for nano drug delivery should be considered.
• Delivery routes and targets in the tumor microenvironment need consideration.

Introduction to Advanced Drug Delivery Systems

• Medical agents are specifically delivered to diseased tissue for diagnosis or treatment.
• Delivery refers to the ability to transport an agent from outside the body to a targeted site within the body.
• Nanomaterials are promising delivery vehicles.
• Examples of agents delivered include small or large drugs, nucleic acids, inorganic contrast agents, monoclonal antibody immunotherapies, and gene editors.
• Accumulation in off-target locations can cause harmful side effects reducing the efficacy, therefore design is important

Polymeric Nanoparticles and Microparticles

• They are biocompatible colloidal systems, sized 1-1000 nm and 1-1000 µm, respectively.
• FYARRO, an mTOR inhibitor indicated for the treatment of perivascular epithelioid cell tumor (PEComa), is an example.
• PEComa is a rare and aggressive soft tissue sarcoma.
• FYARRO uses nanoparticle albumin-bound (nab) technology to deliver high levels of the drug Sirolimus (rapamycin) to tumors.
• Tumors may be in the body but are most frequently at visceral, retroperitoneal, and abdominopelvic sites.

Nanomicelles

• These are self-assembled systems sized ~1–100 nm made from biodegradable/biocompatible amphiphilic block polymers.
• They encapsulate poorly water-soluble drugs in the core and highly water-soluble drugs in the outer hydrophilic shell.
• CEQUA is the first and only FDA-approved cyclosporine nanomicelle using NCELL Technology.
• CEQUA is a 0.09% cyclosporine ophthalmic solution indicated to increase tear production in patients with keratoconjunctivitis sicca (dry eye).
• The cyclosporine in CEQUA is a calcineurin inhibitor immunosuppressant.
• NCELL nanomicelles encapsulate cyclosporine molecules within a hydrophobic core, protected by a hydrophilic outer layer allowing penetration into corneal and conjunctival cells and delivery of cyclosporine into the ocular tissues.
• Cyclosporine reduces inflammation to increase tear production.

Dendrimers

• Branched polymeric systems are in the 10-100 nm size range.
• They have terminal end groups of amine/hydroxyl/carboxyl groups that conjugate targeting ligands and/or therapeutic molecules.
• Drugs can be entrapped in the dendrimer network through hydrogen bonds or conjugated.

Nanofibers (NFs)

• Fibers have diameters in the nanometer range.
• Electrospinning technique is used to produce polymeric NFs.
• High drug loading efficiency, surface area and porosity.

Hydrogels

• Porous, soft, and high-water-content structures are suitable for encapsulating water-soluble drugs, including proteins and peptides.
• Designed from natural or synthetic polymers.
• High water content and soft nature of hydrogel may result in a rapid release of biomolecules from the gel matrix.

Clinically Approved Hydrogel Products

• Medtronic's INFUSE® (around $750 million) and Endo's Vantas® (around $20 million) are examples, Vantas is now discontinued.
• Medtronic's INFUSE® Bone Graft includes recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) on an absorbable collagen sponge (ACS).
• BMPs play a role in bone and cartilage formation as well as repair of musculoskeletal tissues.
• Six steps are involved in the Action for rhBMP-2/ACS mechanism, including implantation of rhBMP-2/ACS, chemotaxis of mesenchymal stem cells, stem cell proliferation into differentiation of osteoblasts, bone and angiongenesis, and remodeling.

Liposomes

• The vesicles are lipid-based with phospholipid bilayers enclosing an aqueous core ranging in size from 0.1 to 10 μm.
• Liposomes are the first nano drug delivery systems translated into real-time clinical applications.
• Doxil, Ambisome and DepoFoam are types.
• Doxil (Sequus Pharmaceuticals) was FAD approved in 1996.

Doxil Liposomes

• PEGylated liposomes are used for treating Kaposi's sarcoma in AIDS patients who progress after prior chemotherapy or are intolerant to this therapy.
• They are also used in ovarian and metastatic breast cancer therapy.
• In circulation, liposomes containing doxorubicin have a half-life of approximately 55 hours for humans.
• 85 nm liposomal vehicles infiltrate the tissue compartment.
• The doxorubicin is released in the intestinal fluid because of the presence of oxidizing agents and enzymes.

Implants

• The controlled drug release is over an extended period.
• There are invasive implantation devices used to circumvent physiological barriers.
• It's advantages include sustained and local drug release to diseased tissues alongside limited side effects.
• Vitrasert and Retisert are non-biodegradable implants used to treat uveitis.
• Retisert provides sustained release of fluocinolone acetonide for 3 years.
• Biodegradable implants like Surodex and Ozurdex (Allergan) contain dexamethasone and treat macular edema and are bioerodible.

Gliadel Wafer

• A carmustine implant for intracranial use
• Carmustine wafer is its generic name
• Treating newly diagnosed gliomas and recurrent glioblastoma uses surgery and radiation
• 8 wafers is the maximum and are implanted in the cavity where the malignant glioma as been removed

Cellular Carriers

• Camouflaged RBCs have been studied a lot.
• They are the most abundant cells in humans and can circulate up to 120 days.
• Drugs or NCs can be loaded on circulatory cells using physical, chemical, or biological methods.
• Benefits include increased circulation half-life with inherent targeting ability to diseased sites such as tumor.
• The drug is released from the carrier at a trigger by an external or internal stimulus.

Composite Nanosystems/Nanoformulation

• Nanoparticles in a suspension.
• Pentablock (PB) Copolymer based Macromolecule is encapsulated
• Thermosensitive PB Copolymer suspends the PB Copolymer.
• This is to avoid burst release and long term release of the macromulecules.

Intelligent Nanocarriers

• Nano/microrobots are drug and cell carrier devices.
• It is a simple robotic system make up of a payload and shell.
• It is directed to a specific site, with external forces as guidance.
• It ensures better targeting capacities to pathogenic tissues and cells.
• They have ligands that are bio-inspired from cell membrane machinery.
• Nanoswimmers, nanoengines, 3D-motion nanomachines, microbots, nanofish, and nanorockets are examples.
• Intraluminal area has the directional alignment and propulsion
• Four components of the system a propulsion and delivery to accomplish tasks in controllabe bodies

Polymers in Stimuli

• They can be classified into endogenous or exogenous materials.
• pH, oxidative stress, redox potential, enzymes, or temperature are examples of endogenous.
• Temperature, magnetic fields, ultrasounds, light, and electric fields are examples of exogenous.

Barriers for Nano Drug Delivery

• The delivery of nano drugs includes RES
• Liver sinusoidal endothelial cell
• Extracellular matrix

Delivery Routes and Targets

• They need to be deliver drugs to the tumor site and penetrating of normal tissues
• ENhanced permitbaility is a benefit alongside retaining them to the same tumor types
• Transcytosis is important using recpetor-binding moieties to improve specificity