BONE MARROW TARGETING AND TARGETING by thilak0505

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									  BONE MARROW TARGETING AND
TARGETING TO LYSOSOMAL DISEASES




                      By

               SOMESHWAR.K
                      M.PHARM.
                      II - SEMESTER

         Department of Pharmaceutics
      University College of Pharmaceutical
                   Sciences,
            KAKATIYA UNIVERSITY
               Warangal - 506009
                       CONTENTS

   Introduction
   Physiology of bone marrow
    Bone marrow targets for drug delivery
   Colloidal carriers for bone marrow targeting
           Nanospheres/nanoparticles
           Liposomes
   Lysosomal storage diseases
   Targeting exogenous enzymes
   Conclusion
   References

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                INTRODUCTION

   The main problems currently associated with systemic
drug administration are:

1. Even biodistribution of pharmaceuticals throughout
   the body;

2. The lack of drug specific affinity toward a pathological
   site;

3. The necessity of a large total dose of a drug;

4. Non-specific toxicity and other adverse side-effects.


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                        Drug targeting
                Targeted drug delivery (TDD) is an event
where, a drug-carrier complex or conjugate delivers the
drug(s) exclusively to preselected cells in a specified manner.

              TDD implies for selective and effective
localization of pharmacologically active moiety at a
predetermined target in a therapeutic concentration, while
restricting its access to non-target normal cellular linings,
thus minimizing the toxic effects and maximizing therapeutic
index.




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    The concept of drug targeting includes a
coordinated behavior of three components:


(a) Drug;

(b) Targeting moiety - cell, tissue, inside of a cell,
                                    etc.


(c) Pharmaceutical carrier -
          colloidal carriers, cellular carriers, polymer
based systems, macromolecular carriers.

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          LEVELS OF TARGETING

Passive targeting

Inverse targeting
Active targeting
                     - First order targeting
                     - Second order targeting
                     - Third order targeting

Physical targeting
Dual targeting
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      PHYSIOLOGY OF BONE MARROW

   Bone marrow is the flexible tissue found in the hollow
interior of bones. In adults, marrow in large bones produces
new blood cells. It constitutes 4% of total body weight, i.e.
approximately 2.6 kg in adults.

       There are two types of bone marrow:
          - Red marrow
          - Yellow marrow




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 Red bone marrow consists of hematopoietic or blood forming
  tissue which produces white blood cells and red blood cells.

 Within the marrow haemopoietic progenitor cells at various
  stages of development replenish the peripheral blood cells
  populations.

 The major vascular constituents of bone marrow are called as
  sinuses.

 These blood vessels are relatively large forming a barrier i.e.
  Marrow Blood Barrier (MBB) between the Hematopoietic
  compartment and the circulation.

 The walls of MBB consists of continuous endothelium and a
  discontinuous adventitial cell layer . The MBB serves to
  control cellular traffic in and out of the marrow.
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 BONE MARROW TARGETS FOR DRUG
           DELIVERY
1. Reticuloendothelial system (RES)

    The RES of organism is usually very effective in
     removing small foreign colloidal particles
     administered intravenously.

    The kupffer cells of liver and the macrophages of the
     spleen constitute 80-95% of phagocytic cells of this
     system and it is here that the particles are normally
     deposited.

    For the particles to reach the bone marrow this uptake
     by kupffer cells and macrophages should be
     prevented. http://pharmacy2011foru.blogspot.
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2. Sinusoidal capillaries

   The endothelium of bone marrow sinusoids removes
    particulate materials from the blood.

   The endothelium is not only capable of phagocytic
    uptake and storage of particles but also provides for
    the transmural passage of particulate material to the
    extra vascular spaces where the particles are
    phagocytosed by central macrophages.




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.




    Capillary endothelial barrier




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 MARROW (STEM CELL) TRANSPLANTATION

    The homing of progenitor cells to the marrow has
provided the basis for treatment of certain diseases of
haemopoietic origin by bone marrow transplantation.

         Certain genetic diseases which are characterised
by a generalized absence of a specific enzyme such as
adenosine deaminase (ADA) deficiency in severe combined
immunodeficiency, and glucose cerebrosidase deficiency in
Gaucher’s disease are treated.



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            COLLOIDAL CARRIERS FOR
            BONE MARROW TARGETING

              The ability of the bone marrow to remove the
    particulate matters from the circulation, opens up an idea for
    the delivery of therapeutic agents by means of colloidal drug
    carrier systems such as

   Liposomes
   Nanospheres
   Emulsions
   Microspheres


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 With all these carrier systems a high proportions of the
  dose still reaches the liver and spleen within few minutes
  after intravenous administration.

 Since intravenously administered colloidal particles are
  normally removed efficiently by RES cells of liver and
  spleen , only a small fraction of these particles reaches
  the bone marrow.

 Modification of the surfaces of the particles by a polymer
  in order to provide a hydrophilic barrier minimize the
  uptake of the plasma components.
                E.g. poly(ethylene oxide) (PEO),
  polysorbate (Tween-80) and lauryl ethers (Brij-35).

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     NANOSPHERES/NANOPARTICLES

Poloxomer 407

 Non-ionic block copolymer.

 It contains a central block of hydrophobic polyoxypropylene
  ( POP) flanked by blocks of hydrophilic polyoxyethylene
  (POE).

 Polystyrene microspheres are surface labeled with iodine-
  131 .these labeled particles are incubated for 24hours with a
  2% w/v solution of poloxomer 407.

 This provides a coating layer over the particles
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 Both the coated and uncoated particles were administered
  intravenously to rabbits.
 The blood samples were taken and radioactivity was
  measured using gamma counter.
 Gamma camera scans of rabbits clearly demonstrated that
  the uncoated polystyrene particles were largely taken up
  by liver and spleen after injection while the Poloxomer
  407 coated particles were apparently deposited in bone
  marrow.
 The uptake of uncoated particles by liver/spleen region
  occurred rapidly and efficiently with 90% of the particles
  being deposited in these organs within 2 min.
 The Poloxomer 407 coated particles showed a marked
  decreased liver/spleen activity.
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Polyalkylcyanoacrylate nanoparticles

(Gibaud Et al., 1999)

 Doxorubicin & stimulating growth factor (rhG-CSF) are the
  model compounds

 Histological studies showed rapid capture of nanoparticles by
  bone marrow macrophages as soon as 15 min after injection

 Doxorubicin nanoparticles administered were more toxic than
  free doxorubicin on all blood and marrow cells

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                        LIPOSOMES

 Phospholipids vesicles (Liposomes) have been widely
  investigated as potential carriers for drugs, genes , proteins
  because their capsular structure permits encapsulation of
  various therapeutic agents.

 Advantage of using Liposomes as drug delivery carriers is
  that their pharmacokinetics can be controlled by modifying
  surface characteristics.

 Liposomes composed of equimolar amounts of cholesterol
  and either saturated phospholipids or sphingomyelin
  exhibited low tendency for accumulation in kupffer cells
  following intravascular administration.
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 Their uptake from blood to spleen and bone marrow remains
  relatively high.

 25% of the injected dose of vesicles, formed from equimolar
  amounts of cholesterol and disteroyl phosphatidylcholine ,
  were localized in rat bone marrow 72 hours post intravenous
  administration.
Immunoliposomes
        Liposomes appended with antibodies or their fragments,
  as target oriented moieties are known as immunoliposomes.
             Immunoliposomes bearing poly-(ethylene glycol)-
  coupled monoclonal antibody linked via cleavable disulphide
  bond can be used for ex vivo applications as sorting of
  hematopoietic stem cells

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    LYSOSOMAL STORAGE DISEASES
   Lysosomal storage diseases (LSDs) are a group of
    approximately 40 rare inherited metabolic disorders that
    result from defects in lysosomal function.

   LSDs are caused by lysosomal dysfunction usually as a
    consequence of deficiency of a single enzyme required for
    the metabolism of lipids, glycoproteins (sugar containing
    proteins) or mucopolysaccharides.

   Like other genetic diseases, individuals inherit lysosomal
    storage diseases from their parents. Although each disorder
    results from different gene mutations that translate into a
    deficiency in enzyme activity, they all share a common
    biochemical characteristic – all lysosomal disorders
    originate from an abnormal accumulation of substances
    inside the lysosome.
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                Based on the chemical nature of the
    accumulating materials LSDs are categorized into:

   Lipid storage disorders (Sphingolipidoses) -
    Sphingolipidoses are caused by genetic defects in a series
    of lysosomal enzymes and other proteins essential for the
    catabolism of sphingolipids.
            E.g. Gaucher’s disease, Niemann -Pick disease,
    Fabry’s disease, Tay-sach’s disease.

   Mucopolysaccharidoses - Mucopolysaccharidoses are
    caused by genetic enzymatic defects in the degradation of
    carbohydrate chains of glycosaminoglycans.
          E.g. Hurler Syndrome, Hunter syndrome,
    Mucolipidosis.

   Glycogen storage disorders - Glycoprotein disorders result
    from defects in lysosomal hydrolases.
          E.g. Pompe disease, Sialidosis.
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Principal manifestations, stored lipids in sphingolipidoses

DISEASE        SIGNS AND                   MAJOR LIPID           ENZYME DEFECT
               SYMPTOMS                    ACCUMULATION
Faber’s        Mental retardation,         ceramide              ceramidase
disease        dermatitis

Gaucher’s      Spleen and liver            glucoceribroside      Glucoceribroside
disease        enlargement, erosion                              β- glucosidase
               of long bones
Niemann -      Spleen and liver            sphingomyelin         sphingomyelinase
pick disease   enlargement

Fabry’s        Reddish purple skin    ceramidetrihexoside        Ceramidetrihexoside
disease        rashes, kidney failure                            α- galactosidase


Tay-sach’s     Red spot in retina,        ganglioside            Hexosaminidase A
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               blindness, muscular
disease                                    com/
               weakness
    TARGETING EXOGENOUS ENZYMES

Direct the major portion of enzymes to the
 storage cells.

Intracellular trafficking of the enzyme.




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               Conclusion
Improvement of existing approaches to
 diagnosis and treatment of various diseases
 involving bone marrow.

Combination with gene delivery and controlled
 expression of enzymes and carrier proteins is a
 promising strategy.




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                  References
S.P.Vyas and Roop K. Khar; targeted &
 Controlled drug delivery: Novel Carrier Systems,

S.P.Vyas and V.K.Dixit; pharmaceutical
 biotechnology,

James Swarbrick and James C.Boylan;
 Encyclopedia of pharmaceutical technology; third
 edition; volume2,

 Garret M. Ihler; methods of drug delivery.
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S.M. Moghimi; Exploiting bone marrow
 microvascular structure for drug delivery and future
 therapies; Advanced Drug Delivery Reviews 17
 (1995) 61-73,

P.B. Malafaya, G.A. Silva, E.T. Baran, R.L. Reis;
 Drug delivery therapies I: General trends and its
 importance on bone tissue engineering applications;
 Current Opinion in Solid State and Materials
 Science 6 (2002) 283–295

 www.pharmainfo.net.com
 www.wikipedia.org
 www.informaworld.com
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