Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications

Abstract

Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely 131I-hypericin (131I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications.

Exaggerated hypertensive response to combretastatin A-4 phosphate in hypertensive rats: Effective pharmacological inhibition by diltiazem

“…This selective tumor vascular targeting action has been demonstrated both in animal models [11,16,31,32] and human cancer patients [15,17,26,33]. Thus, tubulin depolymerizing class of medication represents novel chemotherapeutic agents that could be effective in the treatment of various forms of cancer.…”

“…Further study is needed to fully define the mechanism behind this weaker effect of nitroglycerin in our hypertensive rat model. CA4P therapy has been shown to have promise in various clinical trials to treat advance cancers [4][5][6]26,32]. Previous study showed that CA4P significantly improved tumor response to radiation or thermoradiation, neither of which was influenced by the addition of anti-hypertensive agent, hydralazine [14].…”

Synthesis and Cytotoxic Activity of a New Group of Heterocyclic Analogues of the Combretastatins

“…Chemicals used-TsCl, Ti(O-iPr) 4 , n-BuLi, CuI, PPh 3 , Lindlar's catalysts and (trimethylsilyl)acetylene 30-were purchased from Sigma-Aldrich (St. Louis, MO, USA) or Alfa Aesar (GmbH, Karlsruhe, Germany). Dichlorobis(triphenylphosphine)palladium(II) was obtained as described in [31].…”

“…CA-4 (1) shows strong cytotoxic activity against a wide variety of human cancer cell lines, including those that are multidrug resistant [2]. A water soluble disodium phosphate derivative of CA-4 (CA-4P, fosbretabulin) has shown promising results in human cancer clinical trials [3,4], thus stimulating significant interest in a variety of CA-4 analogues [5]. Different analogs of combretastatins are obtained, including heterocombretastatins containing heterocyclic fragments as rings A or B [6][7][8][9][10][11][12].…”

Biliary and duodenal drainage for reducing the radiotoxic risk of antineoplastic 131I-hypericin in rat models

“…As 131 I-Hyp preferentially accumulates in necrotic tissues, it delivers its radioactive energy to the adjacent living tumor remnants. 1,6,12 The b-particles emitted by 131 I-Hyp can kill living cells within 2.0 mm, and the g-rays produced by 131 IHyp aid in the detection of necrotic primary and metastatic tumors by means of nuclear imaging. Additionally, each treatment cycle may achieve long-term therapeutic efficacy and allow monitoring for weeks to months due to the eightday decay half-life of 131 I.…”