Abstract
Prognosis of patients with HER2+ breast-to-brain-metastasis (BBM) is dismal even after current standard-of-care treatments, including surgical resection, whole-brain radiation, and systemic chemotherapy. Radiation and systemic chemotherapies can also induce cytotoxicity, leading to significant side effects. Studies indicate that donor-derived platelets can serve as immune-compatible drug carriers that interact with and deliver drugs to cancer cells with fewer side effects, making them a promising therapeutic option with enhanced antitumor activity. Moreover, human induced pluripotent stem cells (hiPSCs) provide a potentially renewable source of clinical-grade transfusable platelets that can be drug-loaded to complement the supply of donor-derived platelets. Here, we describe methods for ex vivo generation of megakaryocytes (MKs) and functional platelets from hiPSCs (hiPSC-platelets) in a scalable fashion. We then loaded hiPSC-platelets with lapatinib and infused them into BBM tumor-bearing NOD/SCID mouse models. Such treatment significantly increased intracellular lapatinib accumulation in BBMs in vivo, potentially via tumor cell-induced activation/aggregation. Lapatinib-loaded hiPSC-platelets exhibited normal morphology and function and released lapatinib pH-dependently. Importantly, lapatinib delivery to BBM cells via hiPSC-platelets inhibited tumor growth and prolonged survival of tumor-bearing mice. Overall, use of lapatinib-loaded hiPSC-platelets effectively reduced adverse effects of free lapatinib and enhanced its therapeutic efficacy, suggesting that they represent a novel means to deliver chemotherapeutic drugs as treatment for BBM.
Highlights
The survival of patients with primary breast cancer has increased substantially due to the development of therapies targeting systemic d isease[1,2]
Feeder-free human induced pluripotent stem cells (hiPSCs) can reportedly be differentiated into megakaryocytes and platelets through hemogenic endothelial-like cell and hematopoietic progenitor intermediates[56,57,58,59,60,61]
HiPSC lines used for megakaryocyte and platelet derivation expressed stemness markers, exhibited canonical hiPSC colony morphology (Supplementary Fig. S1B and F), and showed a normal karyotype (Supplementary Fig. S1C)
Summary
The survival of patients with primary breast cancer has increased substantially due to the development of therapies targeting systemic d isease[1,2]. Treatments, including lapatinib, are associated with limited availability and significant cytotoxicity associated with neurological s ymptoms[25], several research groups have developed more targeted therapy using liposomes, polymeric nanoparticles, or polymeric m icelles[26] to deliver chemotherapeutic drugs directly to cancer cells or cancer tissues[20,21,23,24,25,27,28,29,30,31,32] These systems face several limitations, including nanotoxicity, low biodegradability, low clearance, adverse immune responses, and short in vivo circulation time[33]. Finding alternative sources of non-immunogenic, high-quality autologous platelets could reduce these risks
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