Sri Aguswarini
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Studi Dosimetri Internal Radiofarmaka Terapi Kanker Payudara 177Lu-DOTA-Trastuzumab Susyati, Susyati; Mutalib, Abdul; Muchtaridi, Muchtaridi; Ramli, Martalena; Aguswarini, Sri; Karyadi, Karyadi; Hidayat, Basuki; Massora, Stepanus
Jurnal Keselamatan Radiasi dan Lingkungan Vol 1, No 1 (2016): Juni 2016
Publisher : Pusat Teknologi Keselamatan dan Metrologi Radisasi - BATAN

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Abstract

Pengobatan terarah berbasis imunologik (Imunoterapi) kanker payudara dengan mekanisme pengikatan reseptor HER2/neu oleh antibodi spesifik telah dikembangkan oleh para peneliti sejak tahun 80-an. Trastuzumab adalah antibodi yang pertama disetujui oleh Badan Pengawas Obat dan Makanan Amerika. Dari pemantauan diketahui bahwa pengobatan dengan trastuzumab selain berbiaya tinggi juga terjadi kardiotoksisitas dan resistensi obat. Mengantisipasi hal ini, para peneliti mulai mengembangkan trastuzumab dalam bentuk konjugat dengan suatu radionuklida (salah satunya adalah 177Lutesium), sebagai farmaka Radioimunoterapi (RIT) baru. Sebagai penerapan aspek keselamatan untuk tujuan melakukan proteksi terhadap pasien dari efek samping pemberian dosis radiasi internal yang tidak akurat, studi dosimetri internal perlu dilakukan sejak awal pengembangan farmaka RIT baru. Tujuan studi dosimetri internal pada RIT adalah memastikan pemberian dosis radiasi internal yang akurat dan aman untuk setiap individu pasien/memaksimalkan dosis radiasi ke sel-sel kanker dan meminimalkan dosis radiasi ke sel-sel normal. Radiofarmaka baru (177Lu)m-(DOTA)n-trastuzumab telah berhasil dipreparasi oleh para peneliti BATAN. Uji praklinik in vivo/uji biokinetik pada hewan coba mencit betina normal inbred substrain BALB/c paska pemberian dosis tunggal 100 µCi bolus intravena injeksi radiofarmaka 177Lu-DOTA-trastuzumab juga telah dilakukan. Ruang lingkup studi dosimetri internal yang dilakukan ini adalah melakukan penghitungan perkiraan dosis terabsorb oleh berbagai organ hewan coba berdasarkan data biokinetik hasil uji praklinik in vivo. Dari hasil penghitungan perkiraan dosis terabsorb menggunakan persamaan MIRD dengan bantuan data Fraksi absorbsi spesifik dari pustaka diketahui bahwa dosis terabsorb organ paru-paru paling tinggi diantara organ-organ lainnya, yaitu 1,5X10-2 µGy. Dengan memperhitungkan faktor bobot tipe radiasi dan faktor bobot tipe jaringan/organ (sebagaimana tercantum pada Publikasi ICRP No.103 tahun 2007), diperoleh dosis ekivalen dan dosis efektif organ paru-paru berturut-turut adalah 1,5 X 10-2 µSv dan 1,8 X 10-3 µSv. Dosis efektif seluruh tubuh hewan coba adalah 4,2 X 10-3 µSv. Data biokinetik berbagai organ hewan coba dapat juga dipakai sebagai masukan (input) pada penghitungan perkiraan dosis terabsorb berbagai organ phantom manusia menggunakan software dosimetri internal tertentu, seperti OLINDA/EXM software. Breast cancer targeted therapy which mechanism is the binding of HER2/neu receptor with specific antibodies have been developed by researchers since the 80’s. Trastuzumab is the first antibody approved by the US Food & Drug Administration. From monitoring known that treatment with trastuzumab also occur cardiotoxity and drug resistance in addition to high costs. Anticipating this, the researchers began developing trastuzumab in the conjugate form with a radionuclide (one of which is 177Lutesium) as a new pharmaceutical of Radioimmunotherapy (RIT). As the implementation of safety aspects in order to protect the patients from adverse effects of inaccurate internal radiation dose administration, internal dosimetry studies / assessment need to be done since the beginning of a new RIT pharmaceutical development. The objective of internal dosimetry study at RIT is to ensure accurate and safe internal radiation dose administration for each individual patients / to maximize the radiation dose to the cancer cells and minimize the radiation dose to the normal cells. The new RIT pharmaceutical 177Lu-DOTA-trastuzumab has been successfully prepared by BATAN researchers.  In vivo preclinical trials/biokinetic testing in normal female mice inbred substrain BALB/c after administration of a single dose 100 μCi of bolus intravenous 177Lu-DOTA-trastuzumab radiopharmaceutical injection also been conducted. The scope of internal dosimetry studies conducted was absorbed dose calculation estimation of the various experimental animals organs based on biokinetic data of in vivo preclinical trials. Calculation estimation of Absorbed Dose using the MIRD (Medical Internal Radiation Dose) equation with the aid of SAFs (Specific absorbed fractions) data from reference known that Absorbed Dose of lungs organ is highest among other organs ie. 1,5 X 10-2µGy. Taking into account of recommended radiation weighting factors and tissue / organ weighting factors (as stated in ICRP Publication #103, 2007) obtained equivalent dose and effective dose of lungs organ is 1,5 X 10-2 μSv and 1,8 X 10-3μSv respectively. The whole body effective dose of experimental animal is 4,2 X 10-3 μSv. The biokinetic-test results data of the various experimental animal organs can also be used as an input on the Absorbed dose calculation estimation of the various human phantom organs using certain internal dosimetry software (one example is OLINDA/EXM software).
Uji Preklinis 177Lu-DOTA-Trastuzumab: Radiofarmaseutika Potensial untuk Terapi Kanker Payudara HER-2 Positif RAMLI, MARTALENA; HIDAYAT, BASUKI; AGUSWARINI, SRI; KARYADI, KARYADI; ARDIYATNO, CAHYA NOVA; SUBUR, HAMMAD; HUMANI, TITIS SEKAR; RITAWIDYA, RIEN; MUTALIB, ABDUL; MASJHUR, JOHAN
JURNAL ILMU KEFARMASIAN INDONESIA Vol 11 No 2 (2013): JIFI
Publisher : Fakultas Farmasi Universitas Indonesia

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Abstract

Radiofarmaka 177Lu-(1,4,7,10-tetraazacyclododecane-N,N’,N”,N”’-tetra acetic acid)-trastuzumab (177Lu-DOTA-trastuzumab), berbasis antihuman epithelial receptor type 2 (HER-2) antibodi monoklonal, yang diharapkan potensial untuk diagnosis dan terapi kanker payudara positif HER-2, dengan kemurnian radiokimia besar dari 99% telah berhasil dipreparasi. Uji preklinis yang dimaksudkan untuk mendapatkan data dasar sebelum pelaksanaan uji klinis dan khususnya untuk melihat efektifitas 177Lu-DOTA-trastuzumab dalam membunuh sel kanker yang mengekspresikan HER-2, telah berhasil dilakukan. Data dasar tersebut diantaranya adalah data clearance, citra dengan gamma kamera dan data hasil uji sitoksisitas. Hasil uji clearance memperlihatkan bahwa ekskresi radioaktif setelah pemberian 177Lu-DOTA-trastuzumab pada tikus sehat lebih cepat melalui urin dibandingkan dengan eksresi melalui feses. Hasil pencitraan dengan kamera gamma pada tikus normal 144 jam setelah pemberian 177Lu-DOTA-trastuzumab memperlihat adanya residu radioaktif di daerah hati (< 5%, berdasarkan hasil uji biodistribusi). Residu ini lebih rendah jika dibandingkan dengan residu radioaktif pada hati yang dilaporkan untuk 111In-NSL-trastuzumab. Walaupun residu radioaktif ini relatif rendah, tetapi harus tetap menjadi perhatian yang serius pada saat 177Lu-DOTA-trastuzumab akan digunakan pada pasien penderita kanker. Uji sitotoksisitas memperlihatkan 177Lu-DOTA-trastuzumab jauh lebih efektif dalam membunuh sel kanker positif HER-2 (SKOV-3 cell lines) dibandingkan dengan trastuzumab tidak bertanda.
Technetium-99m-Human IgG Radiopharmaceuticals: Preparation, Biodistribution and Infection Imaging in Mice WIDJAKSANA, WIDYASTUTI; ROSELIANA, ANNA; ARIYANTO, AGUS; AGUSWARINI, SRI; MARIALINA, MARIALINA; MONDRIDA, GINA
JURNAL ILMU KEFARMASIAN INDONESIA Vol 6 No 2 (2008): JIFI
Publisher : Fakultas Farmasi Universitas Indonesia

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Abstract

Technetium-99m-Immunoglobulin-G preparation and analysis were carried out using human immunoglobulin-G (IgG) which was conjugated with hydrazinonicotinamide (HYNIC) prior to labeling with technetium-99m (99mTc), and the HYNIC-IgG molecules were stabilized with a co-ligand, tricine. Tricine was prepared both in the form of lyophilized kits and in frozen solutions and their stabilities were compared. The effect of pH on the labeling efhciency was also studied. Characterization of native IgG as well as the radiolabeled IgG were carried out using size exclusion HPLC, whereas the labeling efficiency of 99mTc-HYNIC-IgG was determined using thin layer and paper chromatographic methods. The stability of radiolabeled 99mTc-HYNIC-IgG at room temperature as well as in human serum were investigated by observing the radiochemical purity within 4 hours in vitro. The shelf-life of Lmlabeled HYNIC-IgG stored at -40°C and tricine kits stored at 4°C were determined. Biodistribution of 99mTc- HYNIC-IgG in healthy mice and in infection-induced mice and rats were also studied. The HPLC results showed that the native and radiolabeled IgG had similar retention times, which indicated that conjugation and radiolabeling processes did not affect the integrity of the IgG molecules. The radiochemical purity of 99mTc-HYNIC-IgG was high - more than 90% - without purification step, and the preparation was stable up to 4 hours. Tricine kits prepared at pH 3 was proven to produce clear solution and high labeling yield, while pH 4 produced slight opalescence solution which turned to turbid after a few hours. Biodistribution studies in healthy mice showed an obvious uptake in liver but normal distribution in other tissues, while biodistribution in infection-induced mice showed significantly different uptake between infected tissues, i.e higher than normal tissues. Blood clearance was achieved within 2 hours and excretion via urine and faeces were observed within 24 hours. It is concluded that the preparation using human IgG showed high uptake in the infection site, and the 99mTc-HYNIC-IgG can be a promising radiopharmaceutical for infection or inflammation imaging.