The dense interstitial structure of tumors often prevents further penetration and internalization into the central region in drug delivery by the enhanced permeability and retention (EPR) effect. In this issue of Chem, Tan et al. report a nucleic-acid-based micelle that undergoes size transformation to resolve the conflict between the EPR effect and spatially uniform tumor penetration. The dense interstitial structure of tumors often prevents further penetration and internalization into the central region in drug delivery by the enhanced permeability and retention (EPR) effect. In this issue of Chem, Tan et al. report a nucleic-acid-based micelle that undergoes size transformation to resolve the conflict between the EPR effect and spatially uniform tumor penetration. Developing strategies to bypass biological barriers and achieve efficient delivery of therapeutic nanoparticles (NPs) is the key to translating promising in vitro studies to positive treatment outcomes in nanomedicine. Avoiding an ultrasmall size, maintaining a neutrally charged surface, and promoting hydrophilicity of the NPs are common strategies for overcoming rapid renal clearance and opsonization by the reticuloendothelial system during circulation.1Abadeer N.S. Murphy C.J. Recent progress in cancer thermal therapy using gold nanoparticles.J. Phys. Chem. C. 2016; 120: 4691-4716Crossref Scopus (715) Google Scholar For NP cancer therapy, there is a wide consensus that material design can be used to take full advantage of abnormalities in the tumor microenvironment to enhance the efficiency of drug delivery.2Dai Y. Xu C. Sun X. Chen X. Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment.Chem. Soc. Rev. 2017; 46: 3830-3852Crossref PubMed Google Scholar, 3Torchilin V.P. Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery.Nat. Rev. Drug Discov. 2014; 13: 813-827Crossref PubMed Scopus (1082) Google Scholar Specifically, vascular abnormalities, as well as a deficiency in lymphatic drainage, exist in cancerous tumors, including fenestrated, leaky, and poorly organized vessel endothelial cells.2Dai Y. Xu C. Sun X. Chen X. Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment.Chem. Soc. Rev. 2017; 46: 3830-3852Crossref PubMed Google Scholar This phenomenon, known as the enhanced permeability and retention (EPR) effect, allows NPs within the size range of 20–200 nm to accumulate at a tumor site. Additionally, the acidic microenvironment of tumors and overexpression of a series of proteins and biomarkers can serve as triggers for the controlled release of therapeutic cargo. However, challenges remain because even after successful accumulation of NPs at the periphery of a tumor, difficulties penetrating the center of the tumor lead to low therapeutic efficacy. Literature precedent points to reducing the overall size to less than 10 nm (i.e., 6 and 2 nm gold NPs) to assist in tumor penetration,4Huang K. Ma H. Liu J. Huo S. Kumar A. Wei T. Zhang X. Jin S. Gan Y. Wang P.C. et al.Size-dependent localization and penetration of ultrasmall gold nanoparticles in cancer cells, multicellular spheroids, and tumors in vivo.ACS Nano. 2012; 6: 4483-4493Crossref PubMed Scopus (644) Google Scholar but ultrasmall NP design does not favor prolonged in vivo circulation. Combining the contradictory design attributes that promote either long circulation time or deep penetration into tumor tissue requires a multistage NP construct. Multistage NPs can initially maximize the circulation in vivo and then transform to adapt to the local microenvironment once they reach the targeted site. For example, Li et al. designed an amphiphilic polymer with an amide bond cleavable at a mildly acidic pH to release PAMAM prodrugs as a smaller entity to enable tumor penetration.5Li H.-J. Du J.-Z. Du X.-J. Xu C.-F. Sun C.-Y. Wang H.-X. Cao Z.-T. Yang X.-Z. Zhu Y.-H. Nie S. Wang J. Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy.Proc. Natl. Acad. Sci. USA. 2016; 113: 4164-4169Crossref PubMed Scopus (551) Google Scholar Chen et al. presented a shell-stacked NP (∼150 nm) that could reduce size to ∼40 nm and reverse surface charge when its dimethylmaleic-anhydride-modified shells “melted” in the tumor microenvionment.6Chen J. Ding J. Wang Y. Cheng J. Ji S. Zhuang X. Chen X. Sequentially responsive shell-stacked nanoparticles for deep penetration into solid tumors.Adv. Mater. 2017; 29: 1701170Crossref Scopus (317) Google Scholar Wong et al. developed matrix-metalloproteinase-cleavable gelation NPs (∼100 nm) that could release <10 nm quantum dots at the tumor site where this protease was highly expressed.7Wong C. Stylianopoulos T. Cui J. Martin J. Chauhan V.P. Jiang W. Popović Z. Jain R.K. Bawendi M.G. Fukumura D. Multistage nanoparticle delivery system for deep penetration into tumor tissue.Proc. Natl. Acad. Sci. USA. 2011; 108: 2426-2431Crossref PubMed Scopus (828) Google Scholar Despite the above advances, scientists still lack precise control over polymeric NP size after the transformation process. In this issue of Chem, Tan et al. exploit the programmability of DNA nanotechnology to present a novel micellar platform assembled with amphiphilic nucleic acids; they call this aptamer-ferrocene assembly (ApFA).9Tan J. Li H. Hu X. Abdullah R. Xie S. Zhang L. Zhao M. Luo Q. Li Y. Sun Z. et al.Size-tunable assemblies based on ferrocene-containing DNA polymers for spatially uniform penetration.Chem. 2019; 5: 1775-1792Abstract Full Text Full Text PDF Scopus (58) Google Scholar DNA nanotechnology employs nucleic acids as bottom-up building blocks to enable precise control over all physiochemical properties, leading to programmable designer biomaterials. The DNA double helix follows the strict Watson-Crick base pairing, offering a fully addressable platform with nanometer resolution and a highly ordered assembly pattern. Moreover, the combination of the automated oligonucleotide synthesis and traditional organic chemistry has enabled a wide variety of convenient modifications to DNA and/or RNA strands. ApFA can effectively accumulate at a tumor site via the EPR effect and then undergo a drastic size shrinkage, consequently achieving deep tumor penetration and elevated antitumor efficacy (Figure 1A). Specifically, Tan et al. introduced a hydrophobic ferrocene moiety to the 5′ prime end of a 16-base DNA aptamer sequence. The ferrocene serves three purposes: (1) The hydrophobicity of the ferrocene assists the formation of the ApFA core via hydrophobic interactions. Additionally, the π-π stacking of ferrocene with G-quadruplexes from the aptamer further stabilizes the entire micelle (Figure 1B). (2) Under acidic condition and H2O2, ferrocene moieties can undergo the Fenton reaction to become hydrophilic ferrocenium salts, raising the hydrophilic/hydrophobic ratio of ApFA, thus leading to size shrinkage (Figure 1C). As an advantageous byproduct of the Fenton reaction, toxic hydroxyl radicals are produced, which can induce cancer cell death. (3) The resulting Fe(III) salt can be used as an MRI negative contrast agent for monitoring the biodistribution of ApFA. Furthermore, the authors strengthened the therapeutic efficacy by first loading extra glucose oxidase inside ApFA (i.e., G-ApFA) to generate more H2O2 and then attaching the S13 aptamer to target cancer cells and promoting the internalization of ApFA. As a proof of concept, the authors examined the size transformation of ApFAs in response to a simulated biochemical tumor microenvironment. They strategically adopted seven ferrocene-modified phosphoramidites in the amphiphilic nucleic acid (Figure 1C) to build ApFAs with a diameter of ∼100 nm, which would theoretically maximize the EPR effect. Under normal physiological pH, uniform spherical micellar assemblies around 80–100 nm were clearly observed by transmission electron microscopy (TEM). The addition of H2O2 alone reduced the size at a very slow pace, indicating low oxidation of H2O2 to ApFA under neutral pH. When the pH was lowered to 6.0–6.5, activation of the Fenton reaction caused a remarkable size reduction from ∼100 to ∼10 nm (Figure 1D), which the authors verified by monitoring hydroxyl radical production. The decreased signal in T2-weighted phantom images of ApFA after the Fenton reaction confirms the additional potential application of MRI to monitoring tumor size. The authors further demonstrated a significantly deeper and brighter signal inside tumor tissue after ex vivo co-incubation with ApFA, indicating improved penetration ability of ApFA after size shrinkage. Finally, the authors systematically verified the in vivo therapeutic efficacy of ApFA and G-ApFA in mice. Strikingly, G-ApFA treatment significantly hindered the tumor growth rate by ∼90% in comparison with the untreated groups. Tan et al. developed tumor xenografts by injecting A549 cancer cells into the right backside of BALB/c nude mice, and the xenografts reached a size of 20–30 mm3 before all experiments. Randomized DNA-Fe oligonucleotides incapable of micellar formation, denoted as G-rDNA-Fe, served as a negative control. The biodistribution of intravenously injected G-rDNA-Fe and G-ApFA was monitored by in vivo fluorescence imaging. Compared with the negative control, G-ApFA exhibited notably higher NP accumulation at the tumor site, which lasted for 24 h. The pharmacokinetic half-life (t1/2) was determined to be 6 h. Next, four treatment groups (PBS, ApFA, G-ApFA, and G-rDNA-Fe) were intratumorally administered in mice and measured for the body weights and tumor volumes on a daily basis for 14 days. The low toxicity of ApFA and G-ApFA was first confirmed by no significant variations in the body weight between therapeutic groups and control groups throughout the therapeutic period. Daily analysis of tumor volumes of all groups showed that G-ApFA treatment significantly inhibited tumor growth (Figure 1E). After dissecting the mice on day 14, the authors imaged the tumors from all groups for size (Figure 1F). Tumors treated with G-ApFA displayed the smallest volume and a ∼90% suppression rate in comparison with tumors from the PBS group. Moreover, Tan et al. detected inhibited hypoxia at the tumor site, as evidenced by downregulation of two nucleic markers, hypoxia-inducible factor-α and vascular epithelial growth factor, as determined by immunostaining. This work presents an exciting application of biocompatible and programmable nucleic acids as a “smart” nanoplatform that can overcome multiple biological barriers, adapt to the tumor microenvironment, and significantly suppress tumor growth. A few challenges remain for the translation of this method. First, the therapeutic cargo that reaches the tumor site is still dependent on the EPR effect and thus limited in the amount that can be delivered.8Wilhelm S. Tavares A.J. Dai Q. Ohta S. Audet J. Dvorak H.F. Chan W.C.W. Analysis of nanoparticle delivery to tumours.Nat. Rev. Mater. 2016; 1: 16014Crossref Scopus (2902) Google Scholar In addition, more in-depth pharmacokinetics and long-term toxicity tests, as well as non-xenograft tumor models, should be explored to reinforce the authors’ conclusions. Overall, the results presented in this article are a major step forward in the area of nanoparticle drug delivery and are a noteworthy application of smart nanomaterials. Size-Tunable Assemblies Based on Ferrocene-Containing DNA Polymers for Spatially Uniform PenetrationTan et al.ChemJune 17, 2019In BriefPolymeric micelles have received increased attention in the field of pharmaceutical exploitation. However, supra-100-nm micelles, suitable for the EPR effect, cannot penetrate through the dense collagen matrix in solid tumor tissues, thus decreasing the efficacy of anticancer agents. In this work, amphiphilic nucleic acid polymers with tunable hydrophobicity were designed, and size-tunable nucleic acid assemblies were developed to resolve the conflict between EPR effect and spatially uniform penetration ability. Full-Text PDF Open Archive
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