RDC Peptide/radionuclide drug conjugates

To date, the main clinical use of octreotide or lanreotide has been for the symptomatic control of hypersecretory syndromes. Nevertheless, it has been used in various trials with the aim of testing its antiproliferative efficacy. In an Italian multicentre trial focussing on neuroendocrine tumours of various origin, the use of octreotide (0.5–1 mg t.i.d.) yielded symptomatic and biochemical responses in 73% and 77% of patients, respectively, with only 3% objective responses in patients with carcinoids. The use of high-dose lanreotide (up to 12 mg/day) gave similar biochemical and symptomatic responses, as well as similar tumour responses (5%). As regards the medical treatment of solid tumours such as metastatic breast cancer, octreotide and vapreotide have proven to be useful in reducing breast growth factors, such as IGF-1 and prolactin, though they lack efficacy against the tumour itself. The same effect is encountered in the medical treatment of advanced small-cell lung cancer, where both octreotide and lanreotide failed to show any anti-tumour effect. In most of the other solid tumours, the antiproliferative effect of somatostatin analogues has been found to be virtually negligible, while growth factor inhibition has frequently been registered.
Once octreotide had been radiolabelled for diagnostic imaging in order to localise tumour lesions over-expressing SSRs, the next logical step was to develop radiopeptide therapy. The theoretical basis of such therapy is principally the delivery of radioactivity within the tumour cell owing to the internalisation of the SSR and radiolabelled analogue complex. The first attempts to perform receptor radionuclide therapy with radiolabelled octreotide were made in the 1990s in a multicentre trial using high activities of the molecule already used in diagnostic imaging, 111In-[DTPA]0-D-Phe1-octreotide or 111In-pentetreotide. The results obtained to date, in terms of clinical benefit and overall responses, are ascribable to the Auger and conversion electrons emitted by 111In decaying in close proximity to the cell nucleus, once the peptide/receptor complex has been internalised. Partial remissions, however, have been observed only exceptionally [17]. Higher-energy and longer-range emitters such as the pure beta emitter 90Y (E max 2.27 MeV, R max 11 mm) seem more suitable for therapeutic purposes. Therefore a new analogue, Tyr3-octreotide, with a similar pattern of affinity for SSRs, was developed for its high hydrophilicity, simple labelling with 111In and 90Y, and tight binding to the bifunctional chelator DOTA (1,4,7,10-tetra-azacyclododecane-N,N′,N″,N‴-tetra-acetic acid). To date, experiences with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in large series of patients have been obtained at Rotterdam, Louvain University, Basel University and the European Institute of Oncology in Milan. This paper reports on the state of the art of receptor radionuclide therapy, as regards safety, efficacy and new perspectives [1].

[1]. Receptor radionuclide therapy with 90Y-DOTA0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2004 Jul;31(7):1038-46.

Somatostatin receptors are overexpressed in many tumors, primarily neuroendocrine tumors, and therefore can be treated with somatostatin analogs. Currently, some centers of excellence have accumulated nearly a decade of clinical experience in receptor radionuclide therapy using the somatostatin analog (90)Y-[DOTA](0)-Tyr(3)-octreotide [(90)Y-DOTATOC]. This article reviews the latest advances in receptor radionuclide therapy and explores new research directions. [1]

C67H93F3N14O19S2

1519.66

1518.613493

DOTA-Octreotide;209277-09-8

172677216

DOTA-{d-Phe}-Cys-Phe-{d-Trp}-Lys-Thr-Cys-{Threoninol} (Disulfide bridge: Cys2-Cys7)

DOTA-{d-Phe}-CF-{d-Trp}-KTC-{Threoninol} (Disulfide bridge: Cys2-Cys7)

White to off-white Solid powder

17

29

26

105

2660

10

C[C@H]([C@H]1C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=CC=C4)NC(=O)[C@@H](CC5=CC=CC=C5)NC(=O)CN6CCN(CCN(CCN(CC6)CC(=O)O)CC(=O)O)CC(=O)O)C(=O)N[C@H](CO)[C@@H](C)O)O.C(=O)(C(F)(F)F)O

QZKKFXOJBYSQTI-VXEZFZBVSA-N

InChI=1S/C65H92N14O17S2.C2HF3O2/c1-40(81)51(37-80)72-64(95)53-39-98-97-38-52(73-60(91)48(29-42-13-5-3-6-14-42)68-54(83)33-76-21-23-77(34-55(84)85)25-27-79(36-57(88)89)28-26-78(24-22-76)35-56(86)87)63(94)70-49(30-43-15-7-4-8-16-43)61(92)71-50(31-44-32-67-46-18-10-9-17-45(44)46)62(93)69-47(19-11-12-20-66)59(90)75-58(41(2)82)65(96)74-53;3-2(4,5)1(6)7/h3-10,13-18,32,40-41,47-53,58,67,80-82H,11-12,19-31,33-39,66H2,1-2H3,(H,68,83)(H,69,93)(H,70,94)(H,71,92)(H,72,95)(H,73,91)(H,74,96)(H,75,90)(H,84,85)(H,86,87)(H,88,89);(H,6,7)/t40-,41-,47+,48-,49+,50-,51-,52+,53+,58+;/m1./s1

2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-16-benzyl-4-[[(2R,3R)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid;2,2,2-trifluoroacetic acid

DOTA-Octreotide (TFA);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ≥ 50 mg/mL (~32.90 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)