Novel SN-38–Incorporating Polymeric Micelles, NK012, Eradicate Vascular Endothelial Growth Factor–Secreting Bulky Tumors

Abstract

7-Ethyl-10-hydroxy-camptothecin (SN-38), a biological active metabolite of irinotecan hydrochloride (CPT-11), has potent antitumor activity but has not been used clinically because it is a water-insoluble drug. For delivery by i.v. injection, we have successfully developed NK012, a SN-38-releasing nanodevice. The purpose of this study is to investigate the pharmacologic character of NK012 as an anticancer agent, especially in a vascular endothelial growth factor (VEGF)-secreting tumor model. The particle size of NK012 was f20 nm with a narrow size distribution. NK012 exhibited a much higher cytotoxic effect against lung and colon cancer cell lines as compared with CPT-11. NK012 showed significantly potent antitumor activity against a human colorectal cancer HT-29 xenograft as compared with CPT-11. Enhanced and prolonged distribution of free SN-38 in the tumor was observed after the injection of NK012. NK012 also had significant antitumor activity against bulky SBC-3/Neo (1,533

Structure‐Based Rational Design of Prodrugs To Enable Their Combination with Polymeric Nanoparticle Delivery Platforms for Enhanced Antitumor Efficacy

“…Although animal experiments with higher doses of prodrugloaded NPs were not conducted, elevated doses should be expected to improve cancer therapy. [15] In summary, as a proof of principle, we presented a drug reform strategy for constructing a small library of lipophilic SN-38 derivatives and screened their ability to be incorporated into amphiphilic NP formulations. Compared to the …”

“…b) Structures of a small library of SN-38 prodrugs. A variety of hydrophobic moieties were conjugated to the 10-hydroxy group through the formation of phenyl ether (1) or ester (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) bonds. c) Assessment of the stability of the prodrug-encapsulated, self-assembled PEG-PLA nanoparticles (PEG-PLA/prodrug weight ratios fixed at 20:1).…”

A phase I and pharmacokinetic study of NK105, a paclitaxel-incorporating micellar nanoparticle formulation

“…We speculate that NK105 accumulates more in tumour tissues than free PTX, since NK105 is very stable in the circulation and exhibits a markedly higher plasma AUC than free PTX. Moreover, a polymeric micelle carrier system for a drug has the potential to enable the sustained release of the drug inside a tumour following the accumulation of micelles in the tumour tissue (Hamaguchi et al, 2005;Uchino et al, 2005;Koizumi et al, 2006). Regarding NK105 in particular, this sustained release may begin at a PTX-equivalent dose of o1 mg ml À1 (data not shown).…”

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“…[49] NK105, [50] SP1049C, [51] DTXL-TNP, [52] NC6004, [53] NK012, [54] and NK911 [55] are other polymeric micelle-based formulations which have evaluated in clinical studies.…”