Improving Drug Delivery of Micellar Paclitaxel against Non‐Small Cell Lung Cancer by Coloading Itraconazole as a Micelle Stabilizer and a Tumor Vascular Manipulator

Abstract

Although polymeric micelles of paclitaxel (PTX) significantly reduce excipient‐induced toxicity compared with Taxol, they exhibit few clinical advantages in tumor inhibition and overall survival. To improve, itraconazole (ITA), an antifungal drug with potent anti‐angiogenesis activity, is co‐encapsulated together with PTX within the PEG‐PLA micelles. The strong intermolecular interactions between the payloads inhibit drug crystallization and prevent drugs from binding with external proteins, render super‐stable micelles upon dilution and exposure to biological environment, and enter the tumor cells through endocytosis. The co‐encapsulated micelles show strong anti‐proliferation potency against non‐small‐cell lung cancer (NSCLC) and even PTX resistant NSCLC cells in vitro and significantly improve the drug accumulation within the tumor in vivo. Compared with PTX monotherapy or combination therapy using individual PTX and ITA micelles, the co‐encapsulated micelle demonstrates strikingly superior efficacy in tumor growth inhibition, recurrence prevention, and reversion of PTX resistance, in Kras mutant patient derived xenografts, orthotropic models, and paclitaxel‐resistance subcutaneous models. Besides the pharmacokinetic improvement, therapeutic benefits are also contributed by angiogenesis inhibition and blood vessel normalization by ITA. Utilizing the pharmaceutical and pharmacological synergies between the therapeutic agents, a simple yet effective design of a combination cancer nanomedicine that is industrially scalable and clinically translatable is achieved.

Surfactant‐Stripped Cabazitaxel Micelles Stabilized by Clotrimazole or Mifepristone

“…This was not examined in detail in this work, but the anti‐tumor results show that any co‐loader impact on anti‐tumor efficacy was modest. This is not always the case, and one of the co‐loaders examined, itraconazole, was shown to enhance efficacy when co‐formulated with PTX and stabilize micelles . In general, benign and inert co‐loaders that are generally recognized as safe (which CLT and MIF are not) would avoid safety concerns and simplify data interpretation.…”

Paclitaxel and Itraconazole Co‐Encapsulated Micelle Prolongs the Survival of Spontaneous LSL‐KrasG12D/+, LSL‐Trp53R172H/+, Pdx‐1‐Cre Genetically Engineered Mouse Model of Pancreatic Cancer

“…[28] The morphology of micelles was characterized by transmission electron microscopy (FEI Tecnai Spirit Bio TWIN TEM D1297, USA) with negative staining with phosphotungstic acid. [28] The morphology of micelles was characterized by transmission electron microscopy (FEI Tecnai Spirit Bio TWIN TEM D1297, USA) with negative staining with phosphotungstic acid.…”

“…[14] Therefore, small molecular inhibitors of Hh, including cyclopamine, arsenic trioxide, [15] vismodegib www.advancedsciencenews.com www.advtherap.com (GDC-0449, Genentech), [16,17] NVPLDE225 (Novartis), [18] IPI-926 (Infinity), [19] and XL-139 (BMS/Exelixis), [20] were exploited to disrupt the Hh-inducing microenvironment, in which GDC-0449 was approved as a first-line therapy for advanced unresectable basal cell carcinoma. [21,[25][26][27] In a previous study, [28] we developed a PTX and ITA co-encapsulated poly (ethylene glycol)-b-poly (d,l-lactide) (PEG-PLA) micelle, termed as "PIM," and has demonstrated remarkably superior efficacy in inhibiting tumor growth, preventing recurrence, and reversing PTX resistance in a variety of clinically relevant NSCLC models. Nevertheless, reprogramming of the stroma by inhibition of the Hh signaling pathway combined with chemotherapy drug has been considered as a useful therapeutic strategy to evaluate for PDAC therapy, [16,[22][23][24] and the previous preclinical study showed that the Hh inhibitors combined with chemotherapy showed prolonged survival compared to GEM monotherapy.…”

“…After four doses, the mice were monitored and recorded until death or characterized by a 20% loss of body weight, severe ascites, or abdominal distension. [28] At the same time, the synergetic therapeutic efficacy between cancer cell inhibition by PTX and deactivation of the Hh pathway by ITA could be another contributing factor. In contrast, PIM treatment significantly prolonged the median survival of KPC mice at 196 days, an increase of 55.6%, 47.4%, 31.5%, 30.7%, relative to physiological saline (126 days), PM (133 days), IM (149 days), and PM/IM (150 days), respectively ( Figure 4B).…”

“…[28] The stable formulation optimizes the systemic pharmacokinetics of both PTX and ITA, improves their tumor accumulation ( Figure 1G,H), thereby increasing the synergistic effect of ITA-induced blood vessel normalization ( Figure 4C,D) and PTX-induced cytotoxicity and improved anti-PDAC efficacy in KPC mice compared to PM or a simple combination of PM/IM therapy. [28] The stable formulation optimizes the systemic pharmacokinetics of both PTX and ITA, improves their tumor accumulation ( Figure 1G,H), thereby increasing the synergistic effect of ITA-induced blood vessel normalization ( Figure 4C,D) and PTX-induced cytotoxicity and improved anti-PDAC efficacy in KPC mice compared to PM or a simple combination of PM/IM therapy.…”