Preparation of quantum dot/drug nanoparticle formulations for traceable targeted delivery and therapy

Abstract

Quantum dots (QDs) are luminescent nanocrystals with rich surface chemistry and unique optical properties that make them useful as probes or carriers for traceable targeted delivery and therapy applications. QDs can be functionalized to target specific cells or tissues by conjugating them with targeting ligands. Recent advancement in making biocompatible QD formulations has made these nanocrystals suitable for in vivo applications. This review provides an overview of the preparation of QDs and their use as probes or carriers for traceable, targeted therapy of diseases in vitro and in vivo. More specifically, recent advances in the integration of QDs with drug formulations for therapy and their potential toxicity in vitro and in vivo are highlighted. The current findings and challenges for optimizing QD/drug formulations with respect to optimal size and stability, short-term and long-term toxicity, and in vivo applications are described. Lastly, we attempt to predict key trends in QD/drug formulation development over the next few years and highlight areas of therapy where their use may provide breakthrough results in the near future.

Keywords: Drug Nanoparticle Formulations; Quantum dots; Targeted Delivery.

Figure 1

Time-dependent in vivo luminescence imaging of Panc-1 tumor bearing mice (left shoulder, indicated by white arrows) injected with silicon quantum dots conjugated with (A−E) and without (K−O) RGD peptide. All images were acquired under the same conditions. Autofluorescence and the unmixed SiQD signal are coded in green and red, respectively. Panels F−J and panels P−T correspond to the luminescence images in panels A−E and K−O, respectively. Reprinted with permission from (Erogbogbo F, Yong KT, Roy I, Hu R, Law CW, Zhao W, Ding H, Wu F, Kumar R, Swihart MT, and Prasad PN et al. In Vivo Targeted Cancer Imaging, Sentinel Lymph Node Mapping and Multi-Channel Imaging with Biocompatible Silicon Nanocrystals. ACS Nano. 2011; 5: 413-423.). Copyright (2011) American Chemical Society.

Figure 2

(a) Absorption and emission of rhodamine red, a common organic dye, and genetically-encoded DsRed2 protein. (b) Absorption and emission of different QD dispersions. The black line shows the absorption of the 510-nm-emitting QDs. (c) Photo demonstrating the size-tunable luminescence properties and spectral range of the six QD dispersions plotted in b versus CdSe core size. All samples were excited at 365 nm. Reprinted by permission from Macmillan Publishers Ltd: Nature Materials (Medintz IL, Uyeda HT, Goldman ER, Mattoussi H. Quantum dot bioconjugates for imaging, labelling and sensing. Nat Mater. 2005; 4: 435-46., http://www.nature.com), copyright 2005.

Figure 3

Functionalization and bioconjugation chemistry for QDs. Reprinted by permission from Macmillan Publishers Ltd: Nature Materials (Medintz IL, Uyeda HT, Goldman ER, Mattoussi H. Quantum dot bioconjugates for imaging, labelling and sensing. Nat Mater. 2005; 4: 435-46., http://www.nature.com), copyright 2005.

Figure 4

(a) Schematic illustration of QD−Apt(Dox) Bi-FRET system. In the first step, the QD are surface functionalized with the A10 PSMA aptamer. The intercalation of Dox within the A10 PSMA aptamer on the surface of QDs results in the formation of the QD−Apt(Dox) and quenching of both QD and Dox fluorescence through a Bi-FRET mechanism. (b) Schematic illustration of specific uptake of QD−Apt(Dox) conjugates into target cancer cell through PSMA mediated endocytosis. The release of Dox from the QD−Apt(Dox) conjugates induces the recovery of fluorescence from both QD and Dox, thereby sensing the intracellular delivery of Dox and enabling the synchronous fluorescent localization and killing of cancer cells. Reprinted with permission from (Bagalkot V, Zhang L, Levy-Nissenbaum E, Jon S, Kantoff PW, Langer R, et al. Quantum Dotâˆ'Aptamer Conjugates for Synchronous Cancer Imaging, Therapy, and Sensing of Drug Delivery Based on Bi-Fluorescence Resonance Energy Transfer. Nano Letters. 2007; 7: 3065-70.). Copyright (2007) American Chemical Society.

Figure 5

MMP-9 gene silencing in BMVEC by QD-siRNAMMP-9 nanoplexes: BMVECs were transfected with QD-siRNAMMP-9 or Xtreme-siRNAMMP-9 or Xtreme siRNAscrambled for 48 h. RNA was extracted, reverse transcribed, cDNA amplified and MMP-9 gene expression was determined by real-time, quantitative PCR. Relative expression of mRNA species was calculated using the comparative CT method. Data are the mean ± SD of 3 separate experiments done in duplicate. Statistical significance was determined using ANOVA based comparing QD-siRNAMMP-9 nanoplexes to the negative control samples. Reprinted from Brain Research, 1282, Adela Bonoiu, Supriya D. Mahajan, Ling Ye, Rajiv Kumar, Hong Ding, Ken-Tye Yong, Indrajit Roy, Ravikumar Aalinkeel, Bindukumar Nair, Jessica L. Reynolds, Donald E. Sykes, Marco A. Imperiale, Earl J. Bergey, Stanley A. Schwartz, Paras N. Prasad, MMP-9 gene silencing by a quantum dot-siRNA nanoplex delivery to maintain the integrity of the blood brain barrier, 142-155, Copyright (2009), with permission from Elsevier.