Synthesis and Evaluation of 177Lu-DOTA-DN(PTX)-BN for Selective and Concomitant Radio and Drug—Therapeutic Effect on Breast Cancer Cells

Abstract

The peptide-receptor radionuclide therapy (PRRT) is a successful approach for selectively delivering radiation within tumor sites through specific recognition of radiolabeled peptides by overexpressed receptors on cancer cell surfaces. The efficacy of PRRT could be improved by using polymeric radio- and drug- therapy nanoparticles for a concomitant therapeutic effect on malignant cells. This research aimed to prepare and evaluate, a novel drug and radiation delivery nanosystem based on the 177Lu-labeled polyamidoamine (PAMAM) dendrimer (DN) loaded with paclitaxel (PTX) and functionalized on the surface with the Lys1Lys3(DOTA)-bombesin (BN) peptide for specific targeting to gastrin-releasing peptide receptors (GRPr) overexpressed on breast cancer cells. DN was first conjugated covalently to BN and DOTA (chemical moiety for lutetium-177 complexing) and subsequently loaded with PTX. The characterization by microscopic and spectroscopic techniques, in-vitro drug delivery tests as well as in in-vitro and in-vivo cellular uptake of 177Lu-DOTA-DN(PTX)-BN by T47D breast cancer cells (GRPr-positive), indicated the formation of an improved delivery nanosystem with target-specific recognition by GRPr. Results of the 177Lu-DOTA-DN(PTX)-BN effect on T47D cell viability (1.3%, compared with 10.9% of 177Lu-DOTA-DN-BN and 14.0% of DOTA-DN-(PTX)-BN) demonstrated the concomitant radiotherapeutic and chemotherapeutic properties of the polymeric nanosystem as a potential agent for the treatment of GRPr-positive tumors.

Characterization and Therapeutic Effect of a pH Stimuli Responsive Polymeric Nanoformulation for Controlled Drug Release

“…Doxil ® , the first nanopharmaceutical approved by the U.S. Food and Drug Administration (FDA) in 1995, takes advantage of the EPR effect and moves passively to the tumors where the encapsulated doxorubicin is released [16]. Recently, many nanotechnology-based drug delivery systems have been reported for the selective release of doxorubicin [17][18][19].…”

Drug Delivery Systems‐Based Dendrimers and Polymer Micelles for Nuclear Diagnosis and Therapy

“…The radiopharmaceutical showed suitable characteristics for targeted therapy applications in GRPr‐positive tumors. [ 67 ]…”

Preclinical Advances in Theranostics for the Different Molecular Subtypes of Breast Cancer

“…To increase the stability of the targeting peptide, nanoparticles have been increasingly used as drug delivery vehicles. A nanosystem based on the 177 Lu-labeled polyamidoamine (PAMAM) dendrimer (DN) loaded with paclitaxel (PTX) and functionalized on the surface with the DOTA-BBN peptide was designed for specific targeting to GRPR in T47D breast cancer xenografts ( Gibbens-Bandala et al, 2019a ). The 177 Lu-DOTA-DN(PTX)-BBN nanoconjugate had significant uptake and internalization in T47D cells, with an estimated absorbed radiation dose of 3.0 Gy/MBq at infinite time.…”

“… Intratumoral administration of 177 Lu-DOTA-DN(PTX)-BN after 1.5 h (A) , 9 h (B) , 10 h (C) , 24 h (D) , and 120 h (E) in T47D xenograft model ( Gibbens-Bandala et al, 2019a ). The general structure of 177 Lu-DOTA-DN(PTX)-BN was shown in Figure 2I .…”