Renal Clearable Theranostic Nanoplatforms for Gastrointestinal Stromal Tumors

Abstract

tumors. [2] Despite advances in imaging techniques and the development of new localization procedures, tumors less than 1 cm in size remain difficult to localize by conventional means [3] because of the difficulty in specific delivery of contrast agents to the tumor site and a low tumorto-background ratio (TBR) resulting from high nonspecific uptake and background retention. Chemotherapeutic agents such as imatinib (IM) can be used to treat GIST with locally advanced, recurrent, primary unresectable, and metastasized tumors. [4] IM is the first approved selective tyrosine kinase inhibitor for KIT (also known as mast/stem cell growth factor receptor Kit, receptor tyrosine kinase Kit, proto-oncogene c-Kit, or CD117) and platelet derived growth factor receptor alpha (PDGFRA) in GIST. [5] Importantly, IM continuation is crucial for long-term survival of advanced GIST patients since IM typically suppresses GIST growth but does not eradicate the tumors. IM can occasionally cause serious adverse effects including myelosuppression, tumor bleeding, gastrointestinal perforation, interstitial pneumonia, and severe skin symptoms. [6] Recently, drug delivery technology has advanced, making it possible for small molecules to be delivered to target tumors with the use of nanoparticles (NPs). [7] This development has Advances in molecular imaging modalities have accelerated the diagnosis and treatment of human diseases. However, tumors less than 1 cm in size still remain difficult to localize by conventional means because of the difficulty in specific targeting/delivery to the tumor site. Furthermore, high nonspecific uptake in the major organs and persistent background retention results in low tumor-to-background ratio. The targeting and therapy of gastrointestinal stromal tumors (GIST) using nonsticky and renal clearable theranostic nanoparticles (a.k.a. H-Dots) are demonstrated. H-Dots not only target GIST for image-guided surgery, but also tailor the fate of anticancer drugs such as imatinib (IM) to the tumor site resulting in efficient treatment of unresectable GIST. In addition, H-Dots can monitor targetability, pharmacokinetics, and drug delivery, while also showing therapeutic efficacy in GIST-bearing xenograft mice following surgical resection. More importantly, IM loaded H-Dots exhibit lower uptake into the immune system, improved tumor selectivity, and increased tumor suppression compared to free IM, which accumulates in the spleen/liver. Precisely designed H-Dots can be used as a promising theranostic nanoplatform that can potentially reduce the side effects of conventional chemotherapies.Gastrointestinal stromal tumors (GIST) are the most common mesenchymal malignancies of the gastrointestinal tract. Surgical resection with negative margins is the standard for GIST therapy, which allows most patients with operable GIST to be cured by primary surgery. [1] However, a critical clinical challenge with GIST surgery lies in its localization of small

Rapid and Selective Targeting of Heterogeneous Pancreatic Neuroendocrine Tumors

“…The most common tumor targeting strategy is to conjugate a targeting ligand (e.g., small molecule, peptide, peptidomimetic, or protein) to a contrast agent . Targeted delivery of a specific agent to the cancerous tissue is significant for oncologists to plan a treatment strategy as well as for surgeons to decide the surgical margin based on image guidance (Kang et al, 2016(Kang et al, , 2020.…”

Image-guided drug delivery of nanotheranostics for targeted lung cancer therapy

“…2) The size of the H-dot is smaller than the kidney filtration threshold which allows it to be excreted through the kidneys to the urinary bladder, 3) but is large enough to maintain tumor targetability via the small size enhanced permeability and retention (EPR) effect 29 . 4) H-dots include a NIR fluorescent moiety which enables real-time intraoperative imaging, monitoring of tumor targeting, pharmacokinetics, and drug delivery following precise surgical resection 25 , 30 . H-dots were synthesized following a previously reported synthetic route 25 , 31 which is detailed in Supporting Information .…”

“…4) H-dots include a NIR fluorescent moiety which enables real-time intraoperative imaging, monitoring of tumor targeting, pharmacokinetics, and drug delivery following precise surgical resection 25 , 30 . H-dots were synthesized following a previously reported synthetic route 25 , 31 which is detailed in Supporting Information . To confirm the structure, the H-dots were characterized thoroughly using several techniques.…”

“…Known for its superior renal clearable ability, H-dot has proved to be the ideal drug nanocarrier for tumor targeting and drug delivery for gastrointestinal stromal tumors (GIST) 25 , 31 . In this section, we evaluated the possibility of using H-dot as a carrier for Gef and Gen co-deliveries aiming to increase tumor accumulation/therapeutic efficacy and reduce the adverse effects of the drugs (Figure 3 A).…”

“…Incomplete dissection or positive surgical margins results in recurrence and metastases in patients 25 , 26 . Although endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and positron emission tomography (PET)/computed tomography (CT) have been used for the preoperative evaluation of tumors 27 , it is difficult to localize and determine a safe margin for tumors and/or lymph node metastasis (LNM) that may not be visible to the naked eye during surgery.…”