Controlled and Targeted Drug Delivery Using nanoparticles

7/31/2019 Controlled and Targeted Drug Delivery Using nanoparticles

1/27

CONTROLLED AND

TARGETED DRUG DELIVERY

USING NANOPARTICLES

Presented By:Anjali Bansal

B.Tech-M.Tech(BT)

JV-B/09/1162


2/27

CONTENTS

1. Introduction

2. Use of nanotechnology in Drug Delivery

3. Nanoparticle platforms for targeted drug delivery

Liposomes

Polymeric nanoparticles

Lipid- Polymer hybrid NP

Dendrimers

4. Optimal Design of nanoparticles

Size

Surface Charge

PEGylation

Ligand Functionalization


3/27

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


4/27

INTRODUCTION

TARGETED DRUG DELIVERY-pharmacologically active agent or medicament is selectivelytargeted or delivered only to its site of action and not to the non-target 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. Example-tumour cells but not to normal cells,

To a specific organ/tissues by complexing with the carrier thatrecognizes the target.

REASON FOR DRUG TARGETING:

In the treatment or prevention of diseases.

To achieve a desired pharmacological response at a selected siteswithout undesirable interaction at other sites.

The drug have a specific action with minimum side effects & bettertherapeutic index. Example- in cancer chemotherapy and enzyme

replacement therapy.


5/27

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 nanoparticlescan allow us to visualize the site of drug delivery or monitor the in

vivo efficacy of the therapeutic agent.


6/27

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.


7/27

Liposomes

Liposomes are non-toxic, non-hemolytic and non-immunogenic even upon repeatedinjections; they arebiocompatible and biodegradable .

Artificial, single, or multilaminar

vesicles made with bilayeredmembrane structures, composed ofnatural or synthetic amphiphiliclipid molecules.

Also allows for the delivery ofbioactive macromolecules (e.g.,

DNA) for therapeutic applications. Ligand-conjugated liposomes

enhance targeted drug delivery.


8/27

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 therapeuticmolecules.


9/27

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 amphiphilicpolymers 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.


10/27

Lipid-Polymer Hybrid Nanoparticles

Integrate the unique advantages of bothpolymeric 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.


11/27

Dendrimers 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 enzyme-

sensitive linkages, stimulus-

responsive dendrimers can be

generated.


12/27

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


13/27

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


14/27

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 chargedparticles from attachment by blood proteins, leading to prolonged

circulation.


15/27

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.


16/27

Targeting Ligands 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.


17/27

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.


18/27

Aptamers Nucleic acid aptamers are single-

stranded DNA or RNAoligonucleotides with well-

defined, 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


19/27

Peptides

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-targetingdomains and the isolation of new cell-specific peptide ligands.

Peptide-conjugated nanoparticles have been widely used for

targeting cancer cells and tumor vasculature.


20/27

Sugars

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 expressionis 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.


21/27

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 areoverexpressed in many types of tumor cells.

Effective in treating ovarian,

breast, lung, renal, and

colon cancers.

High affinity and specificity

toward cellular receptors.


22/27

Controlled Drug Delivery 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. Polymer molecular weight

2. The copolymer composition

3. The nature of any excipients added to the microsphere formulation

(e.g., for stabilization of the therapeutics)

4. The microsphere size

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.


23/27

Polymers

BulkEroding

SurfaceEroding

Depending on the rate of

hydrolysis of their functional

groups

Bulk Eroding polymers( Burst of drug):

1. Example: PLG2. 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 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.


24/27

Features of Controlled Drug

DeliveryADVANTAGES:

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.


25/27

REFERENCES 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/1424-8247/3/6/1761

Controlled Drug delivery system presentation by Dr. Basavaraj K.

Nanjwade,KLE Universitys College of Pharmacy,BELGAUM- 590010,

India


26/27

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


27/27

Documents

Controlled and Targeted Drug Delivery Using nanoparticles