Visible Drug Delivery by Supramolecular Nanocarriers Directing to Single-Platformed Diagnosis and Therapy of Pancreatic Tumor Model

Abstract

Nanoparticle therapeutics are promising platforms for cancer therapy. However, it remains a formidable challenge to assess their distribution and clinical efficacy for therapeutic applications. Here, by using multifunctional polymeric micellar nanocarriers incorporating clinically approved gadolinium (Gd)-based magnetic resonance imaging contrast agents and platinum (Pt) anticancer drugs through reversible metal chelation of Pt, simultaneous imaging and therapy of an orthotopic animal model of intractable human pancreatic tumor was successfully performed without any serious toxicity. The strong tumor contrast enhancement achieved by the micelles correlated with the 24 times increase of r 1 of the Gd chelates, the highest for the formulations using clinically approved Gd chelates reported to date. From the microsynchrotron radiation X-ray fluorescence spectrometry scanning of the lesions, we confirmed that both the Gd chelates and Pt drugs delivered by the micelles selectively colocalized in the tumor interior. Our study provides new insights for the design of theranostic micelles with high contrast enhancement and site-specific clinical potential. Cancer Res; 70(18); 7031-41. ©2010 AACR.

MRI-detectable polymeric micelles incorporating platinum anticancer drugs enhance survival in an advanced hepatocellular carcinoma model

“…17 Our results showed that the injection of Gd-DTPA/DACHPtloaded micelles modified the enhancement pattern in the liver. Tumor signal intensity was enhanced from hypointense to markedly hyperintense.…”

“…17 Briefly, Gd-DTPA (SigmaAldrich Japan, Tokyo, Japan) was converted to sodium salt by adjusting the pH to 7 with NaOH, and lyophilized. A 5 mmol/L solution of bis(nitrato) (trans-l-1,2-diaminocyclohexane)platinum(II) [DACHPt(NO 3 ) 2 ; W.C. Heraeus GmbH & Co. KG, Hanau, Germany] in water was mixed with the sodium salt of Gd-DTPA (5 mmol/L), and the solution was maintained for 24 hours at 37°C.…”

“…They are relatively small (10-100 nm), can incorporate various substances with controlled release, exhibit prolonged circulation in the bloodstream, and selectively accumulate in cancerous tissues. [17][18][19][20][21] Several micelle formations with anticancer agents, doxorubicin (NK911), paclitaxel (NK105), SN-38 (NK012), cisplatin (NC6004), and (1,2-diaminocyclohexane)platinum(II) (DACHPt) (NC4016), are undergoing clinical trial and have demonstrated significant anticancer efficacy and fewer adverse reactions than that with the use of free drugs. [22][23][24][25][26][27] Moreover, the integration of tracer functions for clinical imaging, including computed tomography, magnetic resonance imaging (MRI), single-photon emission computed tomography, and positron emission tomography, with anticancer drugs allows the construction of polymeric micelle carriers for simultaneous diagnosis and therapy.…”

“…Earlier characterization of these micelles revealed a relatively small diameter of 33 nm, which allowed high penetration and accumulation even in tumors with poor permeability. 17,30 In this study, we examined the feasibility of using these Gd-DTPA/DACHPt-loaded micelles to simultaneously diagnose and treat a clinically relevant rat model of HCC that was generated using the N1-S1 hepatoma cell line, which exhibits high levels of malignancy and hypervascularization. After injecting the micelles through…”

“…Moreover, Gd-DTPA/DACHPt-loaded micelles induced exceptionally bright contrast not only because of the accumulation of micelles in the tumor via the EPR effect, but also because of the augmentation of Gd-DTPA relaxivity in the cores of the micelles. 17 These features may prove advantageous by improving the sensitivity of clinical HCC diagnoses, particularly in cases of multiple small tumors or satellite tumors in a cirrhotic liver, which may be overlooked by other imaging diagnostic modalities. Moreover, the concomitant incorporation of contrast molecules and anticancer agents in the micelles permits real-time evaluation of drug distribution in the tumors by MRI, thus enabling practitioners to adjust the doses to ensure proper efficacy with minimal adverse reactions and to anticipate treatment response.…”