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Presented By: Anjali Bansal B.Tech-M.Tech(BT) JV-B/09/1162

1. 2. 3. Introduction Use of nanotechnology in Drug Delivery Nanoparticle platforms for targeted drug delivery

Liposomes Polymeric nanoparticles Lipid- Polymer hybrid NP Dendrimers

Size Surface Charge PEGylation Ligand Functionalization

4. Optimal Design of nanoparticles

CONTENTS Continued
5. Targeting Ligands
Antibody and antibody fragments Aptamers Peptides Sugars Small Molecules

6. Controlled Drug Delivery 7. Features of Controlled Drug Delivery 8. References

TARGETED DRUG DELIVERY -pharmacologically active agent or medicament is selectively targeted or delivered only to its site of action and not to the nontarget organs or tissues or cells. The drug may be delivered : To the capillary bed of the active sites, To the specific type of cell ,even an intracellular region. Exampletumour cells but not to normal cells, To a specific organ/tissues by complexing with the carrier that recognizes the target. REASON FOR DRUG TARGETING: In the treatment or prevention of diseases. To achieve a desired pharmacological response at a selected sites without undesirable interaction at other sites. The drug have a specific action with minimum side effects & better therapeutic index. Example- in cancer chemotherapy and enzyme replacement therapy.

Use Of Nanotechnology in Drug Delivery

Therapeutic nanoparticle technologies revolutionize the drug development process. Special Feature: unique physiochemical properties. Improves the therapeutic index of drugs. Improves the bioavailability of water-insoluble drugs. Protect the therapeutic agents from physiological barriers. Enable the development of novel classes of bioactive macromolecules (e.g., DNA and siRNA). The incorporation of imaging contrast agents within nanoparticles can allow us to visualize the site of drug delivery or monitor the in vivo efficacy of the therapeutic agent.

Nanoparticle platforms for Targeted Drug Delivery

Four major classes: 1. Liposomal platforms 2. Polymeric nanoparticles 3. Lipid-polymer hybrid NP 4. Dendrimers These platforms enhance the pharmacological properties and therapeutic index of drugs. These can encapsulate drugs with high loading efficiency and protect them from undesired effects of external conditions.

Liposomes are non-toxic, nonhemolytic and nonimmunogenic even upon repeated injections; they are biocompatible and biodegradable . Artificial, single, or multilaminar vesicles made with bilayered membrane structures, composed of natural or synthetic amphiphilic lipid molecules. Also allows for the delivery of bioactive macromolecules (e.g., DNA) for therapeutic applications. Ligand-conjugated liposomes enhance targeted drug delivery.

Advantages of liposomes: 1. Favourable safety profiles. 2. Improves therapeutic index of drugs. 3. Long systemic circulation half-life. 4. Ease of surface modifications. 5. Delivery of bioactive molecules. 6. Rapid Metabolism of drugs. Disadvantages: 1. Immediate uptake and clearance by the RES system. 2. Their relatively low stability in vitro. 3. Do not readily allow for sustained release of therapeutic molecules.

Polymeric Nanoparticles
The drug is either physically entrapped in or covalently bound to the polymer matrix. Polymeric micelles can be formed by self assembly of amphiphilic polymers with two or more polymer chains of different hydrophobicity. In aqueous environments, these block copolymers can spontaneously self-assemble into core-shell nanostructures, with a hydrophobic core and a hydrophilic shell.

Lipid-Polymer Hybrid Nanoparticles

Integrate the unique advantages of both polymeric nanoparticle and liposome systems, while overcoming some of their limitations. High drug encapsulation yield, tunable and sustained drug release profile. Excellent serum stability, long circulation half-life. Potential for differential targeting of cells or tissues. Synthesized using a simple process.

Dendrimers are synthetic, branched macromolecules with a well-defined chemical structure, consisting of an initiator core and multiple layers with active terminal groups. Carries drugs via covalent conjugation to the multivalent surfaces or encapsulation in the cavities of the cores through hydrophobic interaction, hydrogen bond, or chemical linkage. can also carry bioactive macromolecules such as DNA by condensing them through electrostatic interactions. By use of pH or enzymesensitive linkages, stimulusresponsive dendrimers can be generated.

Optimal Design of Nanoparticles

Significant challenge for the successful development of therapeutic nanoparticles-rapid clearance during systemic delivery. Some factors need to be considered for optimal design of nanoparticles: 1. Size 2. Surface charge 3. PEGylation 4. Ligand Functionalization

1. Size: Size plays an importanat role in long circulation and biodistribution of nanoparticles. Nanoparticles smaller than 10 nm-cleared by kidneys or through extravasation Larger nanoparticles-higher tendency to be cleared by cells of the mononuclear phagocyte system. Nanoparticles <100 nm have a higher potential to circulate in the blood for long periods of time and experience reduced hepatic filtration. 2. Surface Charge Surface charge of nanoparticles could affect their uptake by the phagocytic cells. Neutrally charged particles have demonstrated much lower opsonization rates than charged particles. Positively charged nanoparticles generate a higher immune response (complement activation and conjugate activation) compared to neutral or negatively charged nanoparticle formulations.

For example, nanoparticles with a primary amine at the surface promote higher rates of phagocytic uptake when compared to those having sulfate, hydroxyl, or carboxyl groups at the surface. 3. PEGylation: Surface modification of nanoparticles with PEG. high flexibility and hydrophilicity, and low toxicity and immunogenicity. reduce nanoparticle accumulation in off-target organs such as liver and spleen. PEG shell on the nanoparticle surface shields hydrophobic or charged particles from attachment by blood proteins, leading to prolonged circulation.

Length, shape, and density of PEG chains on the nanoparticle surface largely affect its surface hydrophilicity and phagocytosis. 4. Ligand Functionalization: Conjugation of targeting ligands to the surface on PEGylated nanoparticles affect their biodistribution. Targeting ligands improves the cell-or tissue- specific delivery of nanoparticles. Favorable tumor targeting, while minimizing nanoparticle accumulation in the liver and spleen. Narrow window of ligand density for favorable tumor targeting.

Successful development of targeted nanoparticles depends on the targeting ligands. Factors to be considered includes : ligand biocompatibility, cell specificity, binding affinity, purity of the ligand size and charge of the ligand molecule their ease of modification and conjugation to the nanoparticles. Choice also depends on the production cost, scalability, and stability in mass production. Five different classes of targeting ligands includes: antibodies and antibody fragments, aptamers, peptides, sugars, and small molecules.

Targeting Ligands

Antibody and Antibody fragments

Important class of targeting ligands . High degree of specificity for cellular receptors and a wide range of binding affinities. Hybridoma technology have led to the development of chimeric, humanized, and fully human mAbs to reduce their immunogenicity. Compared to mAbs, antibody fragments have demonstrated higher potential for the engineering of targeted nanoparticles as they are smaller in size and lack the complement activation region of mAbs, while retaining the antigen binding specificity.

Nucleic acid aptamers are singlestranded DNA or RNA oligonucleotides with welldefined, three-dimensional structures. Can recognize a wide variety of molecules ( e.g. , proteins, phospholipids, sugars, and nucleic acids) with high affinity and specificity. When compared with antibodies, aptamers exhibit lower immunogenicity and a relatively smaller size compared with ~150 kD for antibodies, which enables better tissue penetration.


Selection of Aptamers by SELEX( Systematic evoultion of ligands by exponential enrichment) method

Peptide ligands have shown significant targeting potential because of their small size, high stability, and relative ease of large-scale synthesis with excellent quality control. The development of phage display techniques and other screening methods has enabled the discovery of new peptide-targeting domains and the isolation of new cell-specific peptide ligands. Peptide-conjugated nanoparticles have been widely used for targeting cancer cells and tumor vasculature.

Specific sugar molecules ( e.g. , lactose, galactose, and mannose) can recognize lectins that are overexpressed on the surface of numerous cancer cells. For example, galactose could recognize the asialoglycoprotein receptor which is expressed on hepatocytes, and its high expression is retained on primary liver cancer cells. To compensate for the weak binding affinity of carbohydrates,multiple or multivalent molecules should be conjugated to the surface of nanoparticles to achieve multivalent interactions.

Small Molecules
Small molecules have also attracted considerable attention as potential targeting ligands due to their low molecular weights, low production costs, and easy conjugation with nanoparticles. Allows the functionalization of multiple ligand molecules on single nanoparticles. Folic acid, which is essential in many metabolic processes for cell survival, has shown high specificity in recognizing folate receptors that are overexpressed in many types of tumor cells. Effective in treating ovarian, breast, lung, renal, and colon cancers. High affinity and specificity toward cellular receptors.

Employ devices such as polymer-based disks, rods, pellets, or microparticles. Best used method: biodegradable polymer microspheres. Commercial products based on polymer microspheres - Lupron Depot and Nutropin Depot Factors affecting drug release in microspheres:
1. 2. 3. 4. Polymer molecular weight The copolymer composition The nature of any excipients added to the microsphere formulation (e.g., for stabilization of the therapeutics) The microsphere size

Controlled Drug Delivery

Stabilization of drug during fabrication- Stabilizers are added. For example, to improve the encapsulation of bovine serum albumin (BSA) in microspheres of poly(-caprolactone) (PCL), Yang et al. included poly(vinyl alcohol) (PVA) in the BSA solution.

Depending on the rate of hydrolysis of their functional groups


Bulk Eroding polymers( Burst of drug): Bulk 1. Example: PLG Eroding 2. Readily allow permeation of water into the polymer matrix 3. Degrade throughout the microsphere matrix. 4. 50 % of the total drug load released during the first few hours of incubation.

Surface Eroding

Surface-Eroding polymers: 1. Example: polyanhydrides 2. Composed of relatively hydrophobic monomers linked by labile bonds. 3. Able to resist the penetration of water into the polymer bulk, while degrading quickly into oligomers and monomers at the polymer/water interface via hydrolysis. 4. Drug is released primarily at the surface as the polymer breaks down around it. 5. Drug release proceeds at a constant velocity.

Features of Controlled Drug Delivery

ADVANTAGES: Eliminate over or underdosing. Maintain drug levels in desired range. Increased patient compliance and convenience. Prevention of side effects. Increase the efficacy of currently used drugs. DISADVANATAGES: Large-scale manufacturing. Inactivation of drug during fabrication.

Clinical Cancer Research , Therapeutic nanoparticles for drug delivery in cancer, Kwangjae cho, Xu Wang, Shuming nie, et al. downloaded from http://clincancerres.aacrjournals.org/content/14/5/1310.full http://ne.ucsd.edu/faculty/l7zhang/research.php http://www.azonano.com/article.aspx?ArticleID=1222 Review article on Aptamers for Targeted Drug Delivery Partha Ray and Rebekah R. White, Department of Surgery, Duke University Medical Center, DUMC Box 103035, Durham, NC 27710, USA, downloaded from http://www.mdpi.com/14248247/3/6/1761 Controlled Drug delivery system presentation by Dr. Basavaraj K. Nanjwade,KLE Universitys College of Pharmacy,BELGAUM- 590010, India

References continued..
Controlled and novel drug delivery by N.K. JAIN Microspheres for Drug Delivery,Kyekyoon Kevin Kim and Daniel W. Pack,University of Illinois at Urbana-Champaign Nanoparticle Technologies for Cancer Therapy Frank Alexis, Eric M. Pridgen, Robert Langer, and Omid C. Farokhzad