Makalenin Adı: Active targeting schemes for nanoparticle systems in cancer therapeutics

Fikirler:Tümör hücrelerinden salınan maddeler ve yüzeylerinde fazla eksprese olan reseptörlerden(ileride varlar)
hangileri aptamerlerle kullanılmaya daha uygun????

Hangi ca e odaklı olmak daha mantıklı???

Makalenin Özeti:

Makale kanser tedavisine dair hedefleri 3 ana başlıkta sınıflamış ve hepsinin tek tek açıklamış.1.antianjiyogenik
hedefler 2.kontrolsüz h. Proliferasyonunun hedeflenmesi 3.direkt tümör hücrelerinin hedeflenmesi.Nanopartikül
kullanımı da oldukça iş görecek gibi anlatılmış.

**** In this review, the cancer targets for current nanoparticle systems have been organized according to selected
characteristics of tumor growth and metastasis. These targets are the neovasculature of angiogenesis, uncontrolled
cell growth, and direct tumor targeting.
There is large overlap between these divisions which reflects the heterogeneity of tumor biology and the large
potential for multiple targeting schemes using the same ligand.

APTAMER sadece tümör hücresinin hedeflenmesi başlığındaki prostat ca hedeflerinde PSMA ya karşı geliştirilen
aptamerdi.

Temel amaç da sağlıklı hücrelere zarar vermeden tümör hücrelerinin azaltmak, yok etmek ve hastanın yaşam
kalitesini ve survivalını iyileştirmektir.Nanopartiküller de bu konuda oldukça umut vadeden moleküller:
****Nanoparticle systems offer major improvements in therapeutics through site specificity, their ability to escape
from multi-drug resistance, and the efficient delivery of an agent [1].

1.1. Current nanoparticle systems for cancer therapies

Tümörün özelliklerine göre pekçok farklı nanopartikül geliştirilmiştir mesela;

***For example, hydrophilic surfaces can be used to provide the nanoparticles with stealth properties for longer
circulation times andpositively charged surfaces can enhance endocytosis

Kullanılan nanopartiküller ise şunlar;

****The types of nanoparticles currently used in research for cancer therapeutic
applications include dendrimers [3], liposomes [4], polymeric nanoparticles [5], micelles [6], protein nanoparticles
[7], ceramic nanoparticles [8], viral nanoparticles [9], metallic nanoparticles [10], and
carbon nanotubes [11].

Nanopartiküller RES ten kaçıp dolaşımda uzun süre kalınmasını sağlar:

*****Functionalization of nanoparticles to create a stealth surface from opsonization, the adherence of serum
proteins to the nanoparticle surface, is necessary to increase circulation times through avoidance of removal by the
reticuloendothelial systems (RES) [12,13

Nanopartiküllerle ilgili çok çalışma var ama FDA onayı alanlar:

****Specifically, the systems that have been approved include liposomal doxorubicin (Myocet™, Elan
Pharmaceuticals), PEGylated liposomal doxorubicin (Doxil®, Ortho Biotech, and Caelyx®, Schering Plough), PEGylated
liposomal daunorubicin (DaunoXome ®, Diatos), and the recently approved albumin-bound paclitaxelloaded
nanoparticles (Abraxane®, Abraxis Bioscience) [2].
1.2. Passive targeting of tumors using nanoparticles

Tüümör hücreleri kontrolsüz çoğalmanın getirdiği difüzyon kısıtlılıklarını anormal damarlar oluşturarak aşarlar.Bu
damarlar güçsüzdür ve gaplaeri fazladır.Dlayısıyla ilaçlar ve nanopartiküller bu damarlardan daha kolay geçerler.Bu
anlattığıma EPR efekt denir.
*****The combination of leaky vasculature and poor lymphatic drainage results in what is known as the Enhanced
Permeation and Retention (EPR) effect.

1.3. Active targeting of cancer(Makale zaten buna odaklandığı için çok genel ileride de eklediğim bilgiler vardı.)

1.4. Type of targeting moiety

Seçtiğimiz parçacığa göre farklı fizyolojik etkiler görürüz.Buna bir örnek;

*****In another study, three targeting moieties (whole mAb, Fab′, and single chain variable fragment (scFv)) were
used to target the same Bcell antigen CD19. The Fab′ immunoliposomes exhibited the most prolonged circulation
times and resulted in higher yet statistically
insignificant numbers of long-term survivors [35]. In a similar B-cell model, the anti-CD19 Fab′ immunoliposomes also
exhibited increased circulation times and higher survival rates for Namalwa-bearing SCID mice as compared to the
anti-CD19 mAb immunoliposome treatment
[36]. The affinity of the targeting moiety is also important, as Adams et al. have shown that high affinity scFV
molecules have impaired tumor penetration properties compared to lower affinity scFV molecules[37].

Antikor fragmanları active targeting stratejisinde sıklıkla nanopartikül olarak kullanılıyor.

****In addition, antibody fragments have a smallersize which can be an important factor in the development of
anactively targeting nanoparticle
*****An important factor in the use of antibodies for therapeuticpurposes is the immunogenicity of these
antibodies

Üretim şekillerine göre de antikorların etkinlikleri değişmektedir:

*****Antibodiesderived from animals are easily recognized as foreign and causestrong immune responses. Chimeric
antibodies, combining humanconstant regions and mouse variable regions, have shown to reducebut not completely
prevent immune reactions [39]. Humanizedantibodies, which contain only the binding regions of the
mouseantibodies fused with a human antibody, have shown reduction inimmunogenicity but sometimes at the
expense of affinity for thetarget [39]. More recently, antibodies which are 100% human havebeen developed in
transgenic animals [40] and through phage displaytechniques [41].

Antikor üretiminde bir de konjugasyon aşaması var.Teknik bir konu.

Tüm bu iyiliklerine rağmen antikorlarla ilgili problemler aşağıda sıralanmş:

******Antibodies and antibody fragments are effective as targetingagents, however, there are innate problems
associated with decreased receptor affinity as a result of conjugation methods, circulating free antigen, insufficient
tumor penetration, binding of antibodies to nonspecific
Fc receptors and possible changes in the antigen over time. For this reason, some researchers have turned to
endogenous transport mechanisms within cells, such as recycling high affinity folate receptor pathways [46–48].
Other targeting moieties include short peptides, RNA aptamers, and small molecules.

1-Angiogenesis-associated targeting

Tümörde yeni gelişen damarlardan aşağıdaki faktörler salınır.:HEPSİ TEDAVİDE HEDEF OLABİLECEĞİ İÇİN ÖNEMLİ
******Tumor and host cells infiltrate the newly developed lumen structure and secrete a
variety of proangiogenic factors, consisting of vascular endothelial growth factor (VEGF), platelet-derived growth
factor (PDGF), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), angiogenin,
angiotropin, platelet-derived endothelial cell growth factor (PD-ECGF), transforming growth factor-α (TGF-α), TGF-β,
epidermal growth factor (EGF), and tumor necrosis factor-α (TNF-α) [50].

Anjiyogenezis metastazda da çok önemli:

*****Angiogenesis appears to be one of the most crucial steps in tumor translation to themetastatic
form, capable of spreading to other parts of the body [49]

Anjiyogenezis neden hedef olarak seçildi?

*****Kumar et al. stated four major advantages of targeting tumor vasculature as compared to conventional
therapies:(1) the physiological barrier that prohibits the dissemination of
nanoparticles through the tumor is overcome by targeting the vasculature, (2) destroying the vasculature decreases
the growth and metastatic capabilities of the tumor, (3) neovascular endothelial cells are less able to undergo
phenotypic variations, diminishing secondarily acquired drug resistance found in conventional cancer therapies, and
(4) the tumor vasculature is not specific for the type of cancer [51,52].

Şimdi tek tek bu başlık altında hedef olarak kullanılan moleküllere bakacağız:
2.1. Vascular endothelial growth factor receptor

VEGF önemli hedeflerden temel özeelikleri ve hedef alınmaları:

*****Tumor hypoxia and oncogenes upregulate VEGF levels in the neoplastic cells, resulting in an
upregulation of VEGF receptor-1 (also known as fms-like tyrosine kinase) and VEGF receptor-2 (fetal liver kinase-1,
flk-1) on tumor endothelial cells [53–55].
*****Two major approaches to targeting angiogenesis via VEGF and VEGFR-2 have been explored: (1) targeting
VEGFR-2 to decrease VEGF binding and induce an endocytotic pathway and (2) targeting VEGF to inhibit ligand
binding to VEGFR-2 [62,63].

2.2. αvβ3 Integrin

Nedir?
****The targeting scheme for the αvβ3 integrin has centered upon the three amino acid sequence Arginine-Glycine-
Aspartic Acid (RGD). The αvβ3 integrin is an endothelial cell receptor for extracellular matrix (ECM) proteins
harboring the RGD sequence, which includes von Willenbrand factor, fibrinogen (fibrin), vitronectin,
thrombospondin, osteopontin, and fibronectin [66]. The αvβ3 integrin is highly expressed on neovascular endothelial
cells and is important in the calcium-dependent signaling pathway leading to endothelial cell migration [67].
Endothelial cells undergoing angiogenesis experience at least three cellular alterations, including an increase in
proliferation,
increase in locomotion, and endothelial cell interaction with the ECM. These alterations are directly related to the
adhesion processes of the αvβ3 integrin [67].

αvβ3 Integrin ve VEGF ilişkisi de şöyle ki;

****An important characteristic of the αvβ3 integrin is that it is intrinsically associated with VEGFR-2 signaling
*****Targeting the αvβ3 integrin with an active targeting nanoparticle system increases the effectiveness of anti-
angiogenic treatments by the downregulation of VEGF

2.3. Vascular cell adhesion molecule

Nedir?
*****Vascular cell adhesion molecule-1 (VCAM-1), an immunoglobulinlike transmembrane glycoprotein, is an
optimal target as it is virtually absent on normal human vasculature, yet readily inducible by angiogenesis.
 2.4. Matrix metalloproteinases

Genel özellikleri:
****Similar to the αvβ3 integrin and VCAM-1, the matrix metalloproteinases (MMPs) are targets that interact with
the ECM. MMPs are a family of structurally related zinc-dependent endopeptidases capable of degrading the ECM
[75]. As an essential physiological component for tissue repair, morphogenesis, and angiogenesis, MMPs also play a
role in the pathological conditions of rheumatoid arthritis, periodontitis, autoimmune blistering of the skin and
tumor invasion and
metastasis [75]

MMP moleküllerinini kullanımları:

****membrane type 1 matrix metalloproteinase (MT1-MMP), an activator of MMP-2. MMP-2, of the MMP family, is
essential for angiogenesis as it hydrolyzes Type IV collagen, a major component of the basement membrane [76].

Özellikle bazı kanserlerde metastazla ilişkileri gösterilmiş:

*****MT1-MMP is associated with metastasis and angiogenesis and is found to be expressed on endothelial cells
and certain types of tumor cells, including malignancies of lung, gastric, colon, breast, cervical carcinomas, gliomas,
and melanomas [78–80].

2-Uncontrolled cell proliferation targeting

Nanopartiküllerle hücre proliferasyonunu inhibe ederken aslında antikor tedavilerindeki yolu izliyoruz:O yol da
aşağıda anlatılmış:
*****Actively targeting nanoparticles have followed the schemes of monoclonal antibodies to target cell
proliferation receptors. The four basic targeting criteria of monoclonal antibodies for cancer
therapeutic application are: (1) the antigen of interest is overexpressed by tumor cells, (2) the antigen participates as
a principle component in the progression of the disease, (3) the antigen is stable in its present form
upon the tumor cell surface, and (4) the antigen is expressed by a large percentage of tumor cells and a large variety
of tumors [82].

Bu Başlıkta da 3 temel hedef var şimdi bunlara bakarsak;

3.1. Human epidermal receptor

HER bir ailedir.Özellikleri de aşağıda verilmiş:
*****The human epidermal receptor (HER) family of receptor tyrosine kinases offers two highly upregulated targets
on tumor cell surfaces. These receptor tyrosine kinases, epidermal growth factor receptor (EGFR) and human
epidermal receptor-2 (HER-2), are known to mediate a cell signaling pathway for growth and proliferation in
response to the binding of the growth factor ligand [83]. As a result, EGFR and HER-2 are the most heavily
researched for cancer therapeutic applications.

3.2. Transferrin receptors

Bu başlığın da temel özellikleri şöyle:

*****Due to the presence of an increased number of transferrin receptors on metastatic and drug resistant cells
compared to normal healthy cells, transferrin is a very pertinent target for cancer therapeutics [95]. Transferrin is a
serum non-heme iron-binding glycoprotein that helps transport iron to proliferating cells [95]. Upon binding to the
transferrin receptors upon the cell surface, the transferrin is endocytosed into acidic compartments where the iron
dissociates. The transferrin receptor is overexpressed in malignant cells due to the increased requirement of iron
[96].
Transferrin reseptörlerini hedefleyen ilaçlarımız:
***** Transferrin receptor targeting for cancer therapeutics has been used in human clinical trials with adriamycin
[97], cisplatin [98], and diphtheria toxin[99].
Bu başlığın nanopartikülli halini çalışan bi araştırmacının çalışmasından bahsedilmiş.İlginç geldi eklemek istedi.
diğerlerinden farklı olarak demir düzeyine göre ilacın efikasisi değişiyor.
******Mark Davis from the California Institute of Technology has recently become the forerunner in transferrin
targeting using self-assembled transferrin–polymer–drug conjugates to treat malignant cells. Transferrin–
PEG–admantane (Tf-PEG-AD) conjugates synthesized for nanoparticle modification have been used to target
malignant tumors including Ewing's sarcoma [4,100]. An important characteristic for transferrin receptor targeting is
the iron-binding efficiency of the transferrin ligand. A low efficiency of iron-binding by the transferrin
ligand resulted in a lower efficiency in binding to the transferrin receptor [4].

3.3. Folate receptors

Folatla ilgili bildiğimiz temel şeyler yine de ekliyorum:

*****The folate receptor, a 38 kDa glycosyl-phosphatidylinositol-anchored glycoprotein, is one of the most highly
researched targets for cancer therapeutics [104–107]. The vitamin, folic acid, is necessary for the synthesis of
purines and pyrimidines. Since folic acid is required for essential cell function, the cargo attached the ligand is
retained within an endocytic vesicle or released into the cytoplasm. On the other hand, antibodies, hormones, and
other related ligands are normally internalized to clear the ligand fromthe receptor, in order to discontinue the
activated signaling scheme, and are shuttled to the lysosome for destruction [108].

Folat reseptörleri kanser hücrelerinde ciddi artmış bulunur.En son cümlede özellikle hangi tümörlerde aşırı olduğu
söylenmiş:
****The folate receptor is significantly upregulated on many cancer cells compared to normal tissue, in some cases
by two orders of magnitude [109]. In addition, normal cells transport a reduced folate across theirmembranes
butwill not transport folate conjugates of any type. Malignant cells transport folate conjugates through the folate
receptor, which is considered the alternative route. Functional folate receptors are largely localized to the apical
surfaces of polarized epithelia [109]. Lastly, the folate receptor has a very high affinity for folic acid, and folic acid-
liposomal conjugates can be administered at low concentrations with a high possibility of folate receptor saturation.
The folate receptor is overexpressed in ovarian, lung, brain, head and neck, renal cell, and breast cancers [110,111].

Folat reseptörlerini kullanmanın avantajları:

****Folate ligands arewidely used for targeting because they are inexpensive, nontoxic, nonimmunogenic,
easy to conjugate to carriers, retain high binding affinity, and are stable in storage and in circulation [109].

3. Tumor cell targeting

Sık görülen kanserleri tek tek ele alırsak;

4.1. Targeting to breast cancer

Meme kanserinde temel hedef bazı meme ca lerinde overexprese olan HER 2 dir .Bununla ilgili ilaç Trastuzumab
****One of the most commonly used strategies for targeted delivery of drug delivery systems to breast cancer
utilizes the HER-2, which is overexpressed in breast cancer. As mentioned previously, Trastuzumab,
a humanized monoclonal antibody against HER-2, was approved by the FDA in 1998 for the treatment of HER-2-
positive metastatic breast cancer.

Diğer hedef folat reseptörü üzerinden geliştirilen tedvi:

*****Targeting to folate receptors has also been used for improved therapy. In vitro studies of folic acid-conjugated
PEGylated magnetite nanoparticles with BT-20 breast cancer cells demonstrated that targeted PEGylated
nanoparticles readily entered the cells in comparison to non-targeted PEGylated nanoparticles or nanoparticles with
folic acid directly conjugated to the surface without a PEG linker [118].
Diğer hedef LH resü.Özellikle metastatik kanserlerde önemli.
******The luteinizing hormone releasing hormone (LHRH) receptor is another target that has been widely
investigated for targeted delivery of imaging agents and drugs for the detection and treatment of localized and
metastasized breast cancer

4.2. Targeting colorectal cancer

Onay almış terapiler şunlar(Tek tek onay süreçlerini açıklamış ihtiyacımız olursa bakarız)
****Recently a number of antibody-based targeted therapies for colorectal cancer have been approved by the FDA.
Some examples include Panitumumab (Amgen, Thousand Oaks, CA), Avastin (Genentech, South San Francisco, CA),
and Cetuximab

Son zamanlarda kolorektal kanserlerde hedef alınan reseptör:

******Recently, a novel targeting approach for the therapy of localized and metastatic colorectal cancer has been
proposed. Waldman et al. have suggested the use of guanylyl cyclase C receptors, which havebeen reported to be
overexpressed in colorectal cancer cells

4.3. Targeting to lung cancer

En çok ölüme neden olan kanser amerikada (türkiyede de böyle) akc kanseri.Şu an tedavisinde cerrahi kemoterapi ve
radyoterapi kullanılıyor.
Önemli bir ilaç Avastin örneği;
*****For example, Avastin® (Genentech, South San Francisco, CA) is a recombinant humanized anti-VEGF
monoclonal antibody that has been approved by the FDA for the treatment of nonsmall cell lung cancer, metastatic
colorectal cancer and metastatic breast cancer [129].

Nanopartiküller akciğer kanserinde kısıtlı çünkü akc kanserine özgü ligand yok.Tek tük yeni çalışmadan bahsedilmiş
eklemedim henüz sadece ligandlar bulunmuş.Tedavi geliştirilmemiş.
*****To date, targeting of systemically-administered drug delivery systems including nanoparticles has been limited
by the lack of ligands specific to lung cancer cells.

4.4. Targeting to prostate cancer

PSMA en popüler hedef:
******Prostate specific membrane antigen (PSMA) is one of the most studied targets for prostate cancer treatment.
PSMA, a class II transmembrane glycoprotein, is known to be overexpressed by cancerous prostate tissue [134].
PSMA expression has been confirmed in the LNCaP prostate cancer cell line

Burada PSMA YA ÖZGÜ GELİŞTİRİLEN APTAMER OLDUĞU SÖYLENMİŞ:

*****The group led by Omid Farokhzad and Robert Langer at Harvard and MIT have investigated
the targeting potential of aptamers specific to PSMA [115,117,135–139]. Specifically, they have
investigated physical
drug/aptamer conjugates and polymeric stealth nanoparticles with surface-conjugated aptamer
for targeting chemotherapeutic agents to prostate cancer [115,117,136–139]

Prostat ca nde yeni hedef:

*****Another approach that has been used for targeting prostate cancer tissue through PSMA involves folate
ligands. PSMA is known to bind folate and can consequently be targeted by folate-modified drug carriers [140].