Karaciğer kanseri tedavisine yönelik aktif hedefli nanopartikül ilaç taşıyıcı sistemin hazırlanması, in vitro-in vivo değerlendirilmesi üzerine çalışmalar
Küçük Resim Yok
Tarih
2022
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Ege Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
Günümüzde karaciğer kanser tedavisinde, kanser evrelerine ve lokalizasyonuna bağlı olarak çeşitli tedavi yöntemleri kullanılmaktadır. Karaciğer kanseri tedavisinde; Doksorubisin Hidroklorür, Sorafenib, Floksuridin, Sisplatin, 5-florurasil gibi ilaçlar klasik kemoterapi uygulamalarında yaygın olarak kullanılmaktadır. Ancak, bu ilaçlar ile uygulanan geleneksel tedavi sonrasında, sağlıklı hücreler üzerine de toksik etki sıklıkla görülmektedir. Yaygın olarak kullanılan Doksorubisin Hidroklorür etkin maddesinin başta kardiyotoksisite olmak üzere, myelosupresyon, nöropati, el-ayak sendromu, kusma, bulantı, saç dökülmesi gibi birçok yan etkisi olduğu bilinmektedir. Bu nedenle Doksorubisin Hidroklorür'ün bu yan etkilerini ortadan kaldırabilecek ve aynı zamanda da karaciğer kanserine yönelik etkin bir tedavi sağlayabilecek ilaç taşıyıcı sistem geliştirilmesi oldukça önemlidir. Kanser tedavilerinde aktif hedeflemenin, ilaçların spesifik hücre tiplerine taşınmasını sağlayarak terapötik etkiyi arttırdığı bilinmektedir. Bu mekanizmada ilaç hücre içerisine yüksek konsantrasyonda ulaşabilmekte, bunun aksine hedef olmayan bölgelere minimum düzeyde ulaşarak düşük toksisite yaratmaktadır. Aktif hedefleyici molekül olan Glisirretinik asit'in hepatoselüler karsinomaya karşı hücre döngüsünü durdurduğu, otofajini indüklediği ve immünosupresyonun apoptozunu azalttığı yapılan çalışmalarca gösterilmiştir. Bununla birlikte, Glisirretinik asit ile modifiye edilmiş nano taşıyıcıların karaciğer hedefleme verimliliğini önemli ölçüde artırabileceği ve karaciğer kanseri gelişimini inhibe edebileceği de çalışmalarda bildirilmiştir. Bu nedenle aktif hedefli molekül olan Glisirretinik asit konjügasyonu ile sağlıklı dokuların etkin madde ile etkileşmesinin önüne geçilerek tedavi etkinliğinin artması ve yan etkilerin azaltılması sağlanmıştır. İlaç taşıyıcı sistemlerden lipozomal sistemler, vücudun temel bileşeni olan fosfolipitlerden oluşan, vücutta immünojenik ve toksik etki göstermeyen taşıyıcı sistemlerdir. Bir diğer üstünlükleri ise enkapsüle ilacın absorpsiyon, biyodağılım ve klerensini değiştirerek ilacın farmakokinetiğini değiştirebilmeleridir. Lipozomal sistemler gibi veziküler nanotaşıyıcıların vücuda uygulanmalarına takiben Retikoendoteriyal sistem (RES) organları tarafından tutulmaları nedeniyle, hedef dokuya ulaşılabilirlikleri ve hedef hücreler tarafından tutulumları azalmaktadır. Fakat nanopartiküllerin yüzey özellikleri modifiye edilerek kan dolaşımındaki stabiliteleri ve kalış süreleri arttırılabilmektedir. Bu amaçla tez çalışmamızda, 1,2-distearol-sn-glisero-3-fosfoetanolamin-N-[amino(polietilen glikol)-2000] (DSPE-PEG 2000) kullanılarak pegilasyon yöntemi ile sterik stabilizasyon sağlanmış ve antijenler marofaj ve nötrofiller tarafından fagositozunu engelleyerek lipozomal ilaç taşıyıcı sistemin dolaşımda kalış süresi arttırılmıştır. Lipozomların raf ömrünü sınırlayan fiziksel ve kimyasal stabilite problemleri; fosfolipit hidrolizi, fosfolipit oksidasyonu ve bunlara bağlı olarak agregasyondur. Lipozomal ilaç taşıyıcı sistemlerin stabilite problemlerinin üstesinden gelebilmek adına disperse edildiğinde lipozomal kolloidal sistem oluşturan prolipozomal ilaç taşıyıcı sistemler geliştirilmiştir. Karaciğer kanseri tedavisinde geleneksel kemoterapide gözlenen olumsuzlukları elimine etmek ya da en aza indirgemek amacıyla, karaciğer hücrelerine aktif hedeflendirilmiş Doksorubisin Hidroklorür içeren liyofilize pegile prolipozom formülasyonu tasarlamak; hücresel düzeylere ilaç taşınmasının artması, düşük dozlarda etkin ve güvenli tedavinin sağlanması, ilacın toksik ve immunojenik özelliklerinin en aza indirilerek sağlıklı dokulara zarar vermeden hedef bölgede istenilen düzeyde farmakolojik etkiyi elde etmek adına oldukça önemlidir. Ayrıca geliştirilmiş Doksorubisin Hidroklorür içeren aktif hedefli pegile prolipozomal ilaç taşıyıcı sistemlerle, ticari formülasyona göre raf ömrünün uzatılması da söz konusu olabilecektir
Recently, various treatment methods have been used in the treatment of liver cancer, depending on the cancer stages and localization. In the treatment of liver cancer, drugs such as Doxorubicin, Sorafenib, Floxoridine, Cisplatin, 5-fluorouracil are widely used in traditional chemotherapy applications. However, after traditional treatment with these drugs, toxic effects on healthy cells are frequently observed. It is known that the active ingredient of Doxorubicin Hydrochloride, which is widely used, has many side effects such as cardiotoxicity, myelosuppression, neuropathy, hand-foot syndrome, vomiting, nausea, hair loss. For this reason, it is very important to develop a drug delivery system that can eliminate these side effects of Doxorubicin Hydrochloride and at the same time provide an effective treatment for liver cancer. It is known that these systems with active targeting have a greater therapeutic effect compared to the free drug molecule, which enables the transport of active targeting drugs to specific cell types in cancer treatments. In this mechanism, the drug is able to reach the cell in high concentration, on the contrary, it reaches the non-target regions at a minimum level, creating low toxicity. Studies have shown that Glycyrretinic acid, which is an active targeting molecule, stops cell cycle against hepatocellular carcinoma, induces autophagy and reduces apoptosis of immunosuppression. However, studies have also reported that Glycyrretinic acid-modified nanocarriers can significantly increase liver targeting efficiency and inhibit liver cancer development. For this reason, the interaction of healthy tissues with the active substance is prevented by conjugation of glycyrrhizic acid, which is an active target molecule, thus increasing the effectiveness of the treatment and reducing the side effects. Among the drug delivery systems, liposomal systems are carrier systems that are composed of phospholipits, which are the main components of the body, and that do not show immunogenic and toxic effects in the body. Another advantage is that it can change the pharmacokinetics of the encapsulated drug by changing its absorption, biodistribution and clearance. Since vesicular nanocarriers such as liposomal systems are retained by the RES (Reticoendotherial system) organs following their application to the body, their accessibility to the target tissue and their uptake by target cells decrease. However, by modifying the surface properties of nanoparticles, their stability and residence time in the blood circulation can be increased. For this purpose, in our thesis study, steric stabilization will be achieved by pegylation method using DSPE-PEG 2000 and the residence time of the liposomal drug delivery system in the circulation is increased by preventing the phagocytosis of antigens by marophages and neutrophils. Physical and chemical stability problems that limit the shelf life of liposomes; phospholipit hydrolysis and aggregation. In order to overcome the stability problems of liposomal drug delivery systems, proliposomal drug carrier systems that form a liposomal colloidal system when dispersed have been developed. In the treatment of liver cancer, to design a lyophilized pegylated proliposome formulation containing active targeted doxorubicin to liver cells in order to eliminate or minimize the adverse effects observed in conventional chemotherapy; Increasing drug transport to cellular levels, providing effective and safe treatment at low doses, minimizing the toxic and immunogenic properties of the drug are very important in order to obtain the desired pharmacological effect in the target area without effecting healthy tissues. In addition, it may be possible to extend the shelf life with the developed Doxorubicin Hydrochloride-containing active-targeted pegylated proliposomal drug delivery systems compared to the commercial formulation.
Recently, various treatment methods have been used in the treatment of liver cancer, depending on the cancer stages and localization. In the treatment of liver cancer, drugs such as Doxorubicin, Sorafenib, Floxoridine, Cisplatin, 5-fluorouracil are widely used in traditional chemotherapy applications. However, after traditional treatment with these drugs, toxic effects on healthy cells are frequently observed. It is known that the active ingredient of Doxorubicin Hydrochloride, which is widely used, has many side effects such as cardiotoxicity, myelosuppression, neuropathy, hand-foot syndrome, vomiting, nausea, hair loss. For this reason, it is very important to develop a drug delivery system that can eliminate these side effects of Doxorubicin Hydrochloride and at the same time provide an effective treatment for liver cancer. It is known that these systems with active targeting have a greater therapeutic effect compared to the free drug molecule, which enables the transport of active targeting drugs to specific cell types in cancer treatments. In this mechanism, the drug is able to reach the cell in high concentration, on the contrary, it reaches the non-target regions at a minimum level, creating low toxicity. Studies have shown that Glycyrretinic acid, which is an active targeting molecule, stops cell cycle against hepatocellular carcinoma, induces autophagy and reduces apoptosis of immunosuppression. However, studies have also reported that Glycyrretinic acid-modified nanocarriers can significantly increase liver targeting efficiency and inhibit liver cancer development. For this reason, the interaction of healthy tissues with the active substance is prevented by conjugation of glycyrrhizic acid, which is an active target molecule, thus increasing the effectiveness of the treatment and reducing the side effects. Among the drug delivery systems, liposomal systems are carrier systems that are composed of phospholipits, which are the main components of the body, and that do not show immunogenic and toxic effects in the body. Another advantage is that it can change the pharmacokinetics of the encapsulated drug by changing its absorption, biodistribution and clearance. Since vesicular nanocarriers such as liposomal systems are retained by the RES (Reticoendotherial system) organs following their application to the body, their accessibility to the target tissue and their uptake by target cells decrease. However, by modifying the surface properties of nanoparticles, their stability and residence time in the blood circulation can be increased. For this purpose, in our thesis study, steric stabilization will be achieved by pegylation method using DSPE-PEG 2000 and the residence time of the liposomal drug delivery system in the circulation is increased by preventing the phagocytosis of antigens by marophages and neutrophils. Physical and chemical stability problems that limit the shelf life of liposomes; phospholipit hydrolysis and aggregation. In order to overcome the stability problems of liposomal drug delivery systems, proliposomal drug carrier systems that form a liposomal colloidal system when dispersed have been developed. In the treatment of liver cancer, to design a lyophilized pegylated proliposome formulation containing active targeted doxorubicin to liver cells in order to eliminate or minimize the adverse effects observed in conventional chemotherapy; Increasing drug transport to cellular levels, providing effective and safe treatment at low doses, minimizing the toxic and immunogenic properties of the drug are very important in order to obtain the desired pharmacological effect in the target area without effecting healthy tissues. In addition, it may be possible to extend the shelf life with the developed Doxorubicin Hydrochloride-containing active-targeted pegylated proliposomal drug delivery systems compared to the commercial formulation.
Açıklama
18.10.2024 tarihine kadar kullanımı yazar tarafından kısıtlanmıştır
Anahtar Kelimeler
Eczacılık ve Farmakoloji, Pharmacy and Pharmacology
