CONTENT
 Introduction
 Tumor tissue vs normal tissue
 Barriers to Tumor Targeting

✓ Heterogeneity with
respect to blood flow.

✓ Overexpression of efflux
transporters.

 Approaches
✓ Passive Targeting
✓ Active targeting
✓ Physical Targeting

 Reference

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INTRODUCTION:
 Tumor is an abnormal mass of tissue which is a classic sign

of inflammation.

 It is a fluid-filled lesion that may or may not be formed by
an abnormal growth of neoplastic cells that appears
enlarged in size.

 Types –
✓Benign tumor(Non-cancerous)

✓Malignant tumor(Cancerous)

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TUMOR TISSUE VS NORMAL TISSUE:

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Barriers to Tumor Targeting:

 Mainly two barriers are there:

I. Heterogeneity with respect to
blood flow.

II. Overexpression of efflux
transporters.

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i. Heterogeneity with respect to blood flow

 As unregulated growth of tumor vasculature occur, nonuniform
distribution of blood vessels across the tumor may occour that lead
to patches of very high blood supply to almost negligible supply.

 This heterogeneity leads to uneven distribution of administered
drug often leading to poor therapeutic response.

 Such altered distribution also usually ends up in partial exposure of
drug to the cells, thereby drastically increasing the multiple drug
resistance with the tumor cells.

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іі Overexpression of efflux transporters
 Achievement of therapeutic responses of drug with cancer cells

is further challenged by over expression of efflux transporters,
often referred to as ATP binding cassette (ABC) transporters
such as P-glycoprotein , multidrug resistance proteins (MRP-1, –
2), etc.

 Most of the anticancer drugs are substrates of such efflux
transporters.

 Subsequently, other factors such as diffusional barrier due to
high intercapillary distance, cell density, and extracellular matrix
components also pose potential barrier to tumor delivery of
therapeutics.

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Approaches:

Mainly three approaches are there for tumor targeting

i. Passive Targeting
ii. Active targeting
iii. Physical Targeting

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І. Passive targeting

 Passive targeting involves therapeutic exploitation of the natural
distribution pattern of a drug-carrier construct in-vivo.

 For e.g., the role of reticuloendothelial system (RES) in clearing
foreign particulate materials from blood permits drug
encapsulated in particulate carriers like liposomes to be passively
targeted to macrophages.

 Passive targeting is based on drug accumulation in the areas
around the tumors with leaky vasculature ,commonly referred to
Enhanced Permeation and Retention (EPR) effect.

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EPR effect
 As cell proliferation leads to formation of solid mass, cells in the interior

starts getting deprived of the nutrients which leads to cell death and this
lead to fenestrations within the size of 200–2,000 nm.

 The presence of fenestrations results in poor resistance to the extravasation
of macromolecules to the tumor microenvironment and contributes to the
enhanced permeation part of EPR.

 The principal factors affecting EPR effect includes vessel architecture,
interstitial fluid composition, extracellular matrix composition etc.

 Simultaneously, it has also been found that tumor mass is associated with
non uniform lymphatic drainage and experience a huge physical stress
owing to rapid growth in the dimensions of the tumor mass. This leads to
the severe compromise in the drainage functionality of the vessels and
contributes to the retention part of EPR effect.

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Surface Engineering of Colloidal Carriers for
Stealth Characteristics
 The colloidal carriers by virtue of their inherent properties are

rapidly taken up by the mononuclear phagocyte system (MPS)
via process of opsonization.

 Usually, the opsonins interact with the colloidal carriers via
forces such as van der Waal’s forces, weak electrostatic forces,
ionic forces, etc.

 In purview of this, hydrophobic and charged particles are rapidly
processed by RES and significant prolongation in the circulation
half-life can be achieved by surface functionalizing PEG chains
forming “stealth” systems.

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 A variety of natural materials such as dextrans, pullulans, gangliosides,

etc. have been employed for proving stealth characteristics to the
colloidal carriers.

 Mechanistically, the stealth characteristics are imparted by steric
barrier, shielding of anionic charge, and binding with dysopsonins.

 The synthetic alternative of the natural polymers for imparting
“stealthness” includes polyethylene glycol and their derivatives which
have been widely explored and are often associated with numerous
advantages such as simple anchoring process, biocompatibility, high
solubility, stability, ease of availability at relatively inexpensive cost,
flexibility in functionalization, etc.

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 Although fascinating, the PEGylation of colloidal carriers is also

associated with a variety of drawbacks such as Significantly higher
hydrophilicity hinders the efficient hydration of polar head groups of
phospholipids leading to poor stability and problems of drug leaching,
often necessitating higher levels of cholesterol to prevent aggregation
and phase separation.

 Secondly, there have been some instances of immunogenicity by
PEGylated colloidal carriers resulting in hypersensitivity reactions.

 The activation of complement system and induction of anti-PEG
antibodies (IgM) has been observed to rapidly clear off the circulating
PEGylated colloidal carrier by a mechanism called ABC phenomenon
and is highly detrimental on appreciation in bioavailability, passive
targeting, and ultimately efficacy of the system.

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 Further the long term safety of the PEGs is also scarcely established

particularly the biological fate. In purview of this, physiological
metabolism of PEGs (<400 Da) includes alcohol dehydrogenase
mediated oxidation leading to formation of toxic diacid and hydroxyl
acid metabolites.

 On the other hand, the renal clearance cutoff for PEGs is 30–50 kDa,
further narrowing the limits for its clinical use. Hence, a series of
alternative synthetic derivatives are currently being explored which
include vinyl based lipopolymers, polyoxazolines based lipopolymers,
polyamino based lipopolymers, zwitterionic lipopolymers, etc.

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Active Targeting

 Active targeting refers to the attachment of marker component
to the colloidal carrier system which is specifically recognized by
the target in concern may it be either from organelle or organ.

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1.Albumin Based Targeting

 Albumin plays a critical role in maintaining the homeostasis by
mobilizing key endogenous hydrophobic molecules.

 It specially binds via non-covalent interactions and executes the
transport of molecules in concern by transcytosis across the
endothelial cells into interstitial space.

 Paclitaxel bound albumin nanoparticle represents the classical
example for establishing the potential of albumin based delivery of
anticancer drugs.

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2.Vitamin Based Targeting

 The vitamins employed for targeting potential includes folate,
vitamin B 12 , thiamine, and biotin.

 The principal advantages associated with vitamins, particularly folic
acid, includes stability over shelf and physiological conditions,
relatively inexpensive, nontoxic, non-immunogenic, endogenous
wide flexibility for diverse chemical reactions, and relatively higher
over expression of folate receptors on most of the cancers.

 It has been noted that folate functionalized colloidal carrier systems
are preferably absorbed by receptor mediated endocytosis. Folate
functionalized nanoparticles have been widely explored for its
potential in preferentially localizing the therapeutics in the vicinity
of the tumor tisswuwews.D. uloMix.com 17

3.Transferrin Based Targeting

 Transferrin receptors are also exclusively over expressed in most of
major types of tumors including lung, lymphomas and breast cancers
in the order of ~10-fold .

 The important feature of employing transferrin as targeting ligand is
its capability for enabling the transcytosis across blood brain barrier.

 Sahoo et al. exhaustively explored the potential of transferrin
conjugated paclitaxel loaded nanoparticles for variety types of cancer
including breast cancer and prostate cancer.

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4.Lectin Based Targeting

 Lectins represent a class of cyto-adhesive targeting ligands which is
moderately recognized by glycans on the glycosylated cell surface
proteins and lipids. Most of the cell surface expresses peculiar glycan
arrays which can be sensed differentially and hence this could be a
viable strategy as regards targeting perspectives.

 The targeting potential of lectins has been explored in a wide field of
applications including gastrointestinal targeting, nasal delivery,
pulmonary delivery, buccal cavity, ocular drug delivery, and brain
delivery.

 Targeting of liver targeting has also been quite possible using lectins
for delivering drugs and genes.

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5.Peptide Based Targeting

 Peptide based tumor targeting strategy is considered as most
promising because relatively higher stability and smaller size of
tumor specific peptides. The peptides employed for tumor targeting
could be either monomeric, homodimeric, heterodimeric ,oligomeric
or tetrameric in nature.

 Cyclic RGD(Arginylglycylaspartic acid) peptide anchored liposomes
were previously prepared preferentially targeting anticancer drug 5-
fluorouracil to tumor vasculature.

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III. Physical Targeting
 A variety of physical approaches have also been explored for their

potential to preferentially localize anticancer medicaments in the
vicinity of tumors.

 The physical stimuli for drug targeting may either be endogenous such
as pH, temperature, redox potentials, etc., or be exogenous, i.e.,
employment of external forces such as magnetic, ultrasound, etc.

 As discussed earlier, the tumor microenvironment is slightly acidic
and exhibits mild hyperthermia which could be specifically exploited
as a stimulus for physical targeting.

 Stimuli responsive colloidal systems have been designed and
developed that tend to degrade at acidic pH and/or elevated
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 Example of pH sensitive physical targeting Co-delivery of
doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for
combination therapy of cancer.

 doxorubicin also exhibited rapid and thermo-responsive drug release
while possessing a biodegradable character from thermosensitive
micelles composed of Poly(N-isopropylacrylamide-co-N,N-
dimethylacrylamide) block copolymer.

 On the other hand, magnet assisted tumor targeting approaches
have also widely been explored considering its immense potential.

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 In this particular system, the drug in concern is immobilized on

ferromagnetic colloidal carriers and allowed to circulate in body.
The external magnetic field is applied at the site of action which
localizes the circulating carriers leading to exceptional tumor
levels of drugs.

 In the first human trials of magnetic drug targeting, the
chemotherapy drug epidoxorubicin was attached to 100 nm
diameter bio-compatible iron-core particles, these particles were
administered systemically, and an external magnet was used to
concentrate the therapy to inoperable but shallow tumors.

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 Similarly, the circulating colloidal carrier may be accumulated at

the desired site of action using ultrasound energy.

 Significantly higher tumor levels of doxorubicin were noted from
polymeric micelles upon imparting external ultrasound as
compared to that of free drug counterpart.

 The driving force for preferential localization herein is the
destabilization of colloidal carrier upon exposure of high energy
external force.