Drug Delivery By Divya Geetha Kavitha Saranya Ramya Shanmugapriya

Targeted Drug Delivery An Insight into the Recent Trends in Drug Delivery Systems

Targeting 

Objective 

Provide therapeutic concentrations of drugs at the site of action



Reduce systemic toxicity



Increase patient compliance

Types of Targeting 

Active & Passive



Organ, Cellular & Subcellular



Site directed & Site avoidance targeting

Other Types of Targeting 

Biochemical



Biomechanical



Biophysical



Bioadhesive



Carrier Dependent



Carrier Independent

Approaches to Targeting  Retrometabolic 

Individual drug molecules chemically modified to target particularly to the disease site.

 Carrier 

Systems:

– Based Systems:

Drug is first packaged non-covalently into a synthetic Carrier that is then targeted to the disease site.

Carrier Types 

Microspheres



Monoclonal Antibodies



Nanoparticles



Liposomes

Bind chromosomal DNA in target tumor cell

Specifically binding to tumor cell

Two-Step Targeting

Reverse Targeting

Prodrugs Targeting specific organs

Prodrugs  Compounds

that undergo biotransformation prior to exhibiting pharmacological effect  Need for prodrugs  Organic drugs elicit response by interacting with receptors at the site of action.  Barriers for the drug

Overcoming Barriers Chemically linking pro-moiety to form prodrug ↓ Biotransformation ↓ Release of parent drug ↓ Barrier is circumvented

Classification Based on organ or system    

Brain Liver Kidney Lymphatics

Based on administration route     

Nasal Ocular Parenteral Transdermal Buccal

Targeting the Brain Delivery of drugs to brain is limited by BBB Eg. L-dopa

Targeting the Liver Site selective transport pathways  Bile acid transport system eg: chlorambucil  Hepatic receptor mediated endocytosis eg: acyclovir

Targeting the Kidney 



 

Selective accumulation of dopamine in kidney IP administration of prodrug Prodrug→ Drug by catalytic action of enzymes that posses high activity in the kidney eg: sulphamethaxazole

Lymphatic Targeting



  

Oral drug enters systemic circulation through portal blood or intestinal lymphatics Properties of drug and formulation Portal blood → first pass metabolism Intestinal lymphatics → only for highly lipophillic compounds

So, prodrugs used for  drugs that undergo extensive first pass metabolism  for local lymphatic delivery

Disease State Cancer  In diseased state elevated level of specific enzyme can be associated with cancer cells than normal cells  Selective activation of prodrugs through metabolism at desired site of action eg: Breast cancer

Magnetic Drug Targeting The Biophysical Targeting Technique

Magnetic Drug Targeting  using

magnetic nanoparticles (ferrofluids)

 enhancing

efficacy  minimum side effects  ferromagnetic

element (e.g. an implant) is placed in a magnetic field, it becomes magnetically energized

 Magnetic

implants – Transdermal Injection  Optimization of intratumoral magnetic particle concentration Factors:  particle size  magnetic field strength  delivery capability of FF complex  method of injection

 Studies

conducted - squamous cell carcinoma  Experimental animal used – Rabbits  Treated with FFs bound to mitoxantrone (FFMTX)  FF – MTX injected – i.a, i.v  Result: No signs of toxicity

Advantages  Magnetic

drug targeting is used to treat malignant tumors loco-regionally without systemic toxicity.

 Magnetic

particles used as “carrier system” for a variety of anticancer agents, e.g. radionuclides, cancer – specific antibodies, and genes

LIPOSOMES Successful carrier systems in drug targeting

A brief introduction… •What are Liposomes? •Why do we need Liposomes?

Why Liposomes? •Solubilization •Protection •Duration of action •Directing potential •Internalization •Amplification

TYPES 1. CONVENTIONAL

2. STEALTH LIPOSOMES

DRUG INCORPORATION  Encapsulation

 Partitioning

 Reverse

loading

OBSTACLES  Non-specific

 Cross

 Low

clearance

endothelium and basement membrane

endocytic capacity

Antibody- Directed Drugs Emerging Cancer Therapeutics

 Cancer

treatment- Double-edged sword

 Earlier-

surgery, radiation and chemotherapy

 Approaches-

 Use

target proteins or deliver drugs

of ANTIBODIES as ‘magic bullets’

Antibodies & Antigens



Antibodies are proteins used by the immune system against foreign molecules called antigens

Antibody- Antigen Interaction 

Antibody- Antigen binding forms the basis for such methods



Binding is based on affinity between them



Specificity

Types of antibodies  Polyclonal

antibodies

 Monoclonal

antibodies



Naked or Un-conjugated



Conjugated

Monoclonal Antibody Technology 

Hybridoma technology  



Murine monoclonals Chimeric - ‘humanized’ murine monoclonals

Phage - display library technology

Un-conjugated Antibodies  Mechanisms

     

of action

Antibody-dependent cellular cytotoxicity (ADCC) Complement-mediated cytotoxicity (CMC) Apoptosis or Programmed cell-death Prevent formation of new blood vessels Block cytotoxicity - inhibiting antigens Prevent cell adhesion and metastasis

Conjugated Monoclonal Antibodies  Conjugation       

with

Drugs Toxins Enzymes Radio-isotopes Proteins Killer Cells Liposomes

Various functions of therapeutic monoclonals

Antibody- Drug Conjugates  Cytotoxic

drugs e.g antifolates,vinca alkaloids,anthracyclines

   

not tumour - specific go to rapidly proliferating cells increased toxicity against normal cells given in sub - optimal doses

SOLUTION : Antibody- drug conjugates

Action of drug immunoconjugates   





Monoclonal antibodies as delivery vehicles Conjugate is inactive Selectivity towards cells with respective antigens Internalized by cell via receptor-mediated endocytosis Parent (active) drug is released into the cell

Improving drug immunoconjugates 

Use of ‘ linkers’



Increased drug loading



Highly cytotoxic drugs



Chemical conjugation

Toxins •

• • • •

From bacterial origin e.g. Pseudomonas exotoxin, Staphylococcal enterotoxin A, Ricin toxin A Enzymes Highly cytotoxtic agents Single molecule sufficient Need modifications • Remove normal cells binding sites • Avoid rapid clearance

Immunotoxins 





For solid and hematological tumours e.g. cutaneous T-cell lymphoma Toxin immunogenicity, vascular leak syndrome and hepatocyte injury Improvements via  

PEG - ylation Humanized toxins RNase

Antibody-directed enzyme prodrug therapy (ADEPT) 

Two step approach



Antibody- enzyme conjugate attached to cell Weakly toxic prodrug converted to active agent by the enzyme





Three classes of enzymesI, II and III

Proteins- Cytokines Cytokines are  

 

immunoregulatory molecules activate immune responses by increasing tumour immunogenicity act locally or to some distance effect: damage tumour vasculature

e.g. Interleukine-2 (IL-2) Tumour necrosis factor- α (TNF- α )

Antibody- Cytokine fusion proteins  



Earlier- direct injection into tumour But neither localized nor accessible Need to fuse them with tumourspecific Abs  





Does not impair binding and response Stimulates innate and adaptive immunity (B cells and nature killer cells), Increases antigen immunogenicity

Combinations used to prevent side effects

Radio- Immunoconjugates  Radio-isotopes

coupled to antibodies  Uptake- less than 0.01% per g of tumour  Continuously present  Choice of radionuclide  

α emitters - Bismuth β emitters  

Medium energy - Iodine High energy - Yttrium

Challenges with use of radioimmunoconjugates  Problem:  

Radiation exposure to bone marrow due to residence in blood stream Radio-resistance of solid tumours

 Solution:  

Engineered antibody fragments Multi-step pre-targeting using bi-specific antibodies or diabodies  

Un-labeled diabody sent in Hapten (small drug) enclosed in labeled peptide

Bi-specific antibody therapy

Evolving New Approaches  Induce

 Block

tumour cell death- apoptosis

protein expression at RNA level- siRNA

 Target

co-stimulatory molecules

 Enrich

immunomodulatory molecules

Conclusions 

Immunogenicity, selectivity and penetration



Fully human antibodies



Characterization of antigens and their antibodies



Solid tumour targets



Target tumour vasculature

ISSUES IN DRUG TARGETING 

Protein folding and amino acid sequencing



Loss of antigen from target cell



Immunological response to targeting agent



Oral administration not feasible



Less number of available target cells

CHALLENGES …  Avoiding

 Tumour

liver uptake

cells create physical barrier

 Pharmacokinetic

parameters of the drug

preparations  Validation

of targeting concept

CONCLUSION Drug targeting should be incorporated in the earliest stages of drug development… it is rational, selective and wave of the future. One can continue to expect for the future, a series of new drugs  that are conveniently delivered  that is given by mouth  that have very modest side effect profiles  that control the disease by novel mechanisms, and  that will, for the first time, control a series of diseases that were once thought as incurable...

Our Team  Divya.

M  Geetha. D  Kavita Sree. S  Ramya Gopal  Saranya. J  Shanmuga Priya. R