Reversible cell-specific drug delivery with aptamer-functionalized liposomes.

cis-Diamminedichloroplatinum(II) (cisplatin) is a potent chemotherapeutic agent for the treatment of a broad range of cancerous tumors. 2] Despite its excellent antitumor efficacy, the major drawbacks of cisplatin include its lack of tumor specificity and severe side effects. In addition, certain tumor-cell types develop resistance to cisplatin from exposure to the drug. Strategies that allow the delivery of cisplatin specifically to tumor cells are highly desirable. Several strategies have been reported for the delivery of cisplatin specifically to tumor sites, the most common of which is to use antibody (Ab) recognition against different cell-surface targets. The binding of Abs to the cell-membrane receptors triggers receptor-mediated endocytosis, with the result of improved therapeutic efficacy. Despite this success, the use of Abs as cell-specific homing agents poses significant challenges. Ab conjugations are difficult to control and typically show poor site specificity for the conjugation and inconsistent binding affinity. The antibody-based drugdelivery system also tends to be immunogenic, so it requires extra humanization steps, which make it more difficult for clinical application. Nucleic acid based aptamers provide excellent alternatives to antibodies as cell-specific agents. They are singlestranded oligonucleotides identified through an in vitro selection process, termed system evolution of ligands by exponential enrichment (SELEX), to bind the target molecules selectively. 12] Many aptamers identified by SELEX have nearly identical binding affinity and specificity to those of Abs. Aptamers are much easier to prepare and to scale up. They are generally considered nonimmunogenic and can be gradually degraded by nucleases and cleared from the blood to cause minimal system toxicity. Functionalizations of aptamers to facilitate site-specific conjugation are also straightforward. Thus, aptamers are promising targeting ligands and have been used in targeted drug-delivery systems, most of which are block-copolymer nanoparticles. Although these new nanotechnology-based platforms look promising, the clinical benefit of nanoparticles for targeted cancer therapy is yet to be demonstrated. Liposomes are by far the most successful drug-delivery systems; a number of liposome-based systems have been approved by the US Food and Drug Administration for disease treatment in the clinic. Liposomes have been shown to increase the plasma residence time of aptamers. Previous efforts on liposomal drug delivery have focused on developing long-circulating liposomes that target cancerous tumor tissues through the enhanced permeation and retention (EPR) effect, 34] a passive targeting mechanism. However, cancer targeting entirely based on EPR still has undesirable systemic side effects and suboptimal antitumor efficacy: clinical studies of a cisplatin-containing liposome showed only poor to moderate therapeutic efficacy. 38] Delivery vehicles with active tumor-targeting capability could, in principle, improve this significantly. Personalized chemotherapy is an unmet challenge in cancer treatment. Despite the existence of rough empirical dosage guidelines, the individual patient response can deviate strongly from average behavior. This problem is especially acute for chemotherapy agents, for which drug overdosage can have severe consequences. At present, once an initial dosage is administered, the side effects and drug effectiveness can no longer be modulated if there are no “antidotes” to the treatment. However, the discovery of good antidotes or neutralizers for each individual drug molecule is not an easy task, if even practical. Moreover, there are no known ways to “multiplex” different antidotes to control complex treatment profiles with multiple drugs. We report here the controlled formulation of aptamerconjugated, cisplatin-encapsulating multifunctional liposomes. Cancer-cell-specific targeting and drug delivery are demonstrated by using this delivery platform. Furthermore, we also show for the first time that a complementary DNA (cDNA) of the aptamer can function as an antidote to disrupt [*] R. Tong, A. Mishra, Prof. G. C. L. Wong, Prof. J. Cheng, Prof. Y. Lu Department of Materials Science and Engineering University of Illinois at Urbana-Champaign 1304 W. Green Street, Urbana, IL 61801 (USA) Fax: (+ 1)217-333-2736 E-mail: gclwong@illinois.edu jianjunc@illinois.edu Homepage: http://www.matse. illinois.edu/faculty/wong/profile.html http://www.matse. illinois.edu/faculty/cheng/profile.html Dr. Z. Cao, W. Xu, Prof. Y. Lu Department of Chemistry University of Illinois at Urbana-Champaign 600 S. Mathews Avenue, Urbana, IL 61801 (USA) Fax: (+ 1)217-244-3186 E-mail: yi-lu@illinois.eduyi-lu@illinois.edu Homepage: http://www.chemistry. illinois.edu/faculty/Yi_Lu. html [] Z.C. and R.T. contributed equally to this work.