Doksorubisin ve elakridar içeren PLGA/silika hibrit nanopartiküllerin formülasyonu ve meme kanserindeki etkinliğinin değerlendirilmesi

Although doxorubicin is efficient alone in cancer treatment, its being a substrate of P-glycoprotein (P-gp) limits its effectiveness. Various approaches have been developed to overcome the growing resistance to these drugs. One of them is the co-administration of P-gp substrate anticancer drugs with another P-gp inhibitor substance. Elacridar which is an inhibitor used for this purpose, has been one of the most studied inhibitors because of the BCRP (breast cancer resistant protein) and P-gp inhibition ability. Another promising approach about overcoming of developed drug resistance is the encapsulation of anticancer drugs into the nanoparticulate drug delivery systems and targeting these systems to the receptors found on cancer cells. In this thesis, folic acid targeted nanoparticles with small size (~50 nm) can penetrate to the cancer cells at a high level were prepared by loading doxorubicin to the mesoporous silica nanoparticles (MSN). Prepared nanoparticles and P-gp inhibitör, elacridar, were co-loaded to the second polymeric system made of PLGA-PEG to ensure the acumulation in desired tissue and extended blood residence time. Developed drug delivery systems were characterized in detail, cytotoxicity, cellular uptake and mechanism of nanoparticles were investigated on T47-D, ZR-5-1 and EMT6/AR1 breast cancer cell lines. The obtained nano-drug delivery system was significantly better than doxorubicin solution and Caelyx® which was the commercially available nano drug.Doksorubisin kanser tedavisinde tek başına etkili olmasına rağmen, P-glikoprotein (P-gp) substratı olması etkinliğini sınırlamaktadır. Gelişen bu ilaç direncinin aşılması amacıyla çeşitli yaklaşımlar geliştirilmiştir. Bunlardan biri P-gp substratı antikanser ilacın, P-gp substratı olan başka bir madde ile birlikte uygulanmasıdır. Bu amaçla kullanılan inhibitörlerden olan Elakridar, BCRP (meme kanseri direnç proteini) ve P-gp'yi inhibe etmesinden dolayı üzerinde en sık araştırma yapılan inhibitörlerden biri olmuştur. Gelişen ilaç direncinin aşılmasında umut vadeden bir diğer yaklaşım ise antikanser ilacın nanopartiküler ilaç taşıyıcı sistemler içerisine yüklenmesi ve bu sistemlerin kanser hücrelerinde bulunan reseptörlere hedeflendirilmesidir. Bu tez kapsamında mezoporlu silika nanopartiküllerine doksorubisin yüklenerek kanser hücrelerine yüksek seviyede penetre olabilen küçük boyutta (~50 nm), folik asit ile aktif olarak hedeflendirilmiş nanopartiküller hazırlanmıştır. Hazırlanan bu nanopartiküller, pasif hedeflendirilme ile istenilen dokuda birikmenin sağlanması ve kanda kalış sürelerinin uzatılması amacıyla P-gp inhibitörü olan elakridar ile birlikte PLGA-PEG’den oluşan ikinci bir polimerik sisteme yüklenmiştir. Geliştirilen bu ilaç taşıyıcı sistem detaylı olarak karakterize edilmiş; sitotoksisiteleri, hücre içine alımları ve mekanizmaları T47-D, ZR-75-1 ve EMT6/AR1(doksorubisine dirençli) meme kanseri hücre hatları kullanılarak değerlendirilmiştir. Elde edilen nano ilaç taşıyıcı sistem doksorubisin çözeltisine ve piyasadaki ticari nanoilaç olan Caelyx®’e göre belirgin derecede daha iyi sonuç vermiştir

Synthesis of Small-Sized Mesoporous Silica Nanoparticles by Experimental Design and Characterization for Further Drug Delivery

Studies on the use of mesoporous silica nanoparticles (MSNs) as a drug delivery system are increasing every year. The present study focused on the synthesis of small-sized MSNs for future drug delivery application. The MSNs with an approximate size of 50 nm with low polydispersity index (PDI) and high synthesis yield were obtained using the technique for order preference by similarity to ideal solution (TOPSIS) based in Taguchi design. The optimized MSN formulation was fully characterized and biocompatibility of this formulation was evaluated. The results demonstrated that optimized MSNs' average particle size was 53.2 nm, PDI was 0.125 and the synthesis yield was 84%. Moreover, obtained nanoparticles had a spherical shape and offer quite high drug loading area. Biocompatibility data also show that obtained MSN's were not reducing cell viability below 80% up to 32 mu g/mL concentration. Results indicated that obtained MSNs might be a promising approach for further drug delivery application

Development of Paclitaxel and Flurbiprofen Co-Loaded PLGA Nanoparticles: Understanding Critical Formulation and Process Parameters Using Plackett–Burman Design

Nano drug co-delivery system is a popular strategy for combined application of two or more anticancer and/or synergistic drugs. Synergistic effects of nonsteroidal anti-inflammatory drugs and anti-cancer drugs in cancer treatment are shown in the literature. This study aimed to screen and understand the critical formulation and process parameters in the preparation of flurbiprofen and paclitaxel co-loaded nanoparticles to develop an anti-cancer nano co-delivery system. With this aim, critical parameters were determined using the Plackett-Burman experimental design (DoE). Flurbiprofen and paclitaxel drug loading amounts were considered as critical quality attributes to control the effective drug loading ratio. Furthermore, average particle size and zeta potential were also defined as critical quality attributes in order to optimize passive drug targeting and colloidal stability. Surfactant type was determined as the most significant factor for the average particle size and zeta potential. For flurbiprofen and paclitaxel drug loading into the nanoparticles, amounts of both flurbiprofen and paclitaxel were determined as critical factors. Consequently, paclitaxel and flurbiprofen were efficiently loaded into nanoparticles, and the impact of the formulation variables was successfully screened by a DoE. By controlling the determined parameters, the therapeutic efficacy of co-loaded drug nanoparticles could be maximized in further studies

Folic acid decoration of mesoporous silica nanoparticles to increase cellular uptake and cytotoxic activity of doxorubicin in human breast cancer cells

© 2021 Elsevier B.V.Breast cancer is the most frequent cancer among women and impacts over two million women each year. Although many different types of anticancer agents are available for breast cancer treatment, doxorubicin is one of the most widely used drug. However, doxorubicin related side effects such as heart failure and arrhythmia limit its usage. To overcome this limitation and improve doxorubicin effectiveness, pegylated liposomal doxorubicin formulation Doxil®/Caelyx® was developed. Although cardiotoxicity related side effects were reduced with liposomal doxorubicin formulations, a superior effect was not obtained and better approaches are still needed. In this study, it was aimed to develop a more effective doxorubicin formulation than Doxil® and to evaluate its anticancer activity. In order to achieve this goal, small sized mesoporous silica nanoparticles (MSNs) (~50 nm) were obtained, actively targeted with folic acid conjugation and loaded with doxorubicin. The obtained nanoparticles were fully characterized, conjugation was verified, and pH dependent drug release profile was shown. The nanoparticles’ anticancer activity was investigated in detail on the ZR-75-1 and T47-D breast cancer cell lines. Fluorescence microscope and flow cytometry studies revealed that the cellular uptake of doxorubicin could be enhanced with small sized MSNs. Moreover, folic acid conjugation made a tangible contribution to this effect. Additionally, similar results were also obtained in cytotoxicity studies on both cell lines. In conclusion, actively targeted small sized MSNs may be a promising approach to potentiate the anticancer effect of doxorubicin