Editorial For reprint orders, please contact: [email protected]

Molecular machines drive smart drug delivery

Yue Bing Zheng “With nanoparticles already functioning at the subcellular level, the possibility of Department of Engineering Science incorporating different molecular machineries onto their surfaces opens the door & Mechanics, The Pennsylvania to a wide variety of intracellular possibilities.” State University University Park, PA 16802, USA

KEYWORDS: azobenzenes n drug delivery n mesoporous n molecular machines Brian Kiraly n nanoimpellers n nanoparticles n nanovalves n rotaxanes Department of Engineering Science & Mechanics, The Pennsylvania State University University Park, In his historic lecture to the American Physical mechanical stress. The diameters of the pores PA 16802, USA Society in 1959, ‘There is plenty of room at the can be tuned between 2 and 10 nm to allow bottom’, Richard Feynman, one of the greatest for different drug loadings. Compared with scientists of the 20th Century, shared a futur­ traditional oral or injectable drugs, these meso­ istic vision with his audience using molecular porous nanoparticles can enhance bioavailabil­ machines in medicine. He contemplated, “What ity, improve therapeutic efficacy and minimize would be the utility of such (molecular-scale) side effects [4]. At present, the key challenge machines? … Although it is a very wild idea, in developing mesoporous nanoparticle-based it would be interesting in surgery if you could DDS is designing the structure and surface swallow the surgeon. You put the mechanical properties of these nanoparticles to enable the Tony Jun Huang surgeon inside the blood vessel and it goes into targeted, on-demand release of drug molecules. Author for correspondence: the heart and ‘looks’ around. It finds out which Molecular machines (e.g., rotaxanes, pseu­ Department of Engineering Science & Mechanics, The Pennsylvania valve is the faulty one and takes a little knife and dorotaxanes and azobenzenes) are capable of State University University Park, slices it out. Other small machines might be per­ delivering efficient actuations at dramatically PA 16802, USA manently incorporated in the body to assist some reduced length scales when compared with tra­ [email protected] inadequately functioning organ” [1]. As of today, ditional microscale actuators [5–10]. Their ability the small machine-powered surgeon predicted by to precisely and cooperatively control mechani­ Feynman has yet to be realized; however, the idea cal motions at the molecular level, in addition of using molecular-level machines in nanomedi­ to their comparable sizes to the mesopores of cine is burgeoning just as predicted [2,3]. Thus far, nanoparticles, makes molecular machines prime scientists have made significant progress in devel­ candidates for controlled release systems in oping molecular-machine-driven, mesoporous mesoporous nanoparticle-based drug delivery. nanoparticle-based smart drug delivery systems Molecular machines are enabling timed and (DDS) that are capable of timely, on-demand controlled release of therapeutic compounds drug release. By combining the robustness of from the mesoporous nanoparticles upon vari­ mesoporous nanoparticles and the preciseness ous forms of external stimuli, such as chemi­ of molecular machines, these smart DDS hold cal reduction/oxidation, light, magnetic fields, great promise for future nanotechnology-based enzymes and changes in the surrounding pH [11]. medical therapy and treatment. This area of research is swiftly maturing with the progress in synthesis, surface function­ Functionalizing mesoporous alization, operation and characterizations of nanoparticles with molecular machines. molecular machines To fulfill their potential in DDS, molecular Mesoporous nanoparticles have long been rec­ machines must retain the switching capabil­ ognized as appealing materials for DDS, as ity and full range of mechanical motion when they have the ability to encapsulate a payload transferred from solution to nanoparticle sur­ of therapeutic compounds and transport them faces. Extensive research on molecular machines to specific locations throughout the body. The assembled on metallic nanoparticles reveals stable, rigid frame of mesoporous nanoparticles multiple effects of surface confinement on the allows for resistance to pH, degradation and switching and motions of molecular machines,

10.2217/NNM.10.111 © 2010 Future Medicine Ltd Nanomedicine (2010) 5(9), 1309–1312 ISSN 1743-5889 1309 Editorial Zheng, Kiraly & Huang Molecular machines drive smart drug delivery Editorial

including steric effects, excitation quenching direction has demonstrated molecular-machine- and altered redox potentials [11]. While much powered DDS with a series of external stimuli can be gleaned from these results, further (e.g., optical, chemical and electrochemical) [11]. research on the effects of immobilization to non­ Compared with chemical and electrochemi­ metallic, porous nanoparticles should be under­ cal stimuli, light has several advantages as an taken to systematically evaluate all alterations, external and noninvasive method for actuating so that proper designs can be used to permit the nanovalves in DDS [12]. Light is abundant, and enhance switching properties. Plasmonic clean and can be transmitted to molecules with­ quenching is perhaps the most significant issue out physically contacting them, in contrast to facing metallic nanoparticle systems; however, chemical stimuli that require the addition of most molecular-machine-powered DDS gener­ fresh reactants at every step of the working cycle, ally involve nonmetallic particles that do not and result in the concomitant formation of waste support plasmon resonance, so the quenching products. With light, the energy input can be effect will be of diminished consequence. The carefully controlled with the wavelength and effects of ligands and surface conditions on intensity of the exciting photons to regulate the redox potentials will be of greater importance, as drug release. Brinker and coworkers have used they can alter the switching conditions for both cis–trans photoisomerization properties of azo­ rotaxanes and pseudorotaxanes, two widely benzenes to make such light-switchable nano­ used molecular machines in nanoparticle-based valves [13]. In the cis form, produced under ultra­ DDS. The modifications to the functionalities violet (UV) radiation, the pendant molecules of molecular machines at nonmetallic mesopo­ on the internal walls of the pores are shorter rous nanoparticle surfaces must be thoroughly and leave an open channel. Upon restoration understood and designed around before the to the trans form using heat or green light, the molecular-machine-powered DDS can fulfill molecules revert back to a pore-blocking state. its potential. In another important work, Stoddart, Zink and coworkers have devised switchable molecular Operating molecular-machine- valves based on pseudorotaxanes for nano­particle powered DDS in abiotic conditions drug delivery. The pores in these nanoparticles Abiotic demonstration is often the first step in are closed by the ring-like components of the the development of novel biomedical technolo­ pseudorotaxanes at the pore openings; drug gies. With the recent progress in the synthesis release is accomplished by the light-triggered of molecular machines, control of surface chem­ removal of the ring-like component [11]. istries and surface characterization, research­ ers have demonstrated a series of molecular- “Recently, much effort has been dedicated to machine-powered smart DDS under abiotic moving research on molecular-machine- conditions. These systems have proven capable of powered drug delivery systems from abiotic on-demand drug delivery by employing molecu­ demonstrations to biological uses.” lar machines as nanovalves, n­anoimpellers, or both, in organic solvents. Nanovalves have proven effective in regulat­ Nanovalves represent an important develop­ ing the release of drug molecules that naturally ment along the path to smart drug delivery; they diffuse out of the mesopores; however, some present the opportunity to transport materials drug molecules have a larger affinity with the without loss and release them on demand. In pores that prevent their natural diffusion. In acting as nanovalves, molecular machines gener­ this case, forces are needed to drive the drug ally make use of the combination between a stalk out of the mesopores. The nanoimpeller is a and a capping agent [2]. Generally, the stalks molecular device that can provide just this type are covalently attached to the pore openings, of force. Zink and coworkers developed molecu­ with the pores themselves being large enough lar nanoimpellers based on azobenzene deriva­ to contain common drug molecules, yet small tives tethered to the mesopore interiors [3]. By enough to be blocked by the capping agents irradiating the system at the isosbestic point, the (e.g., the macrocyclic organic molecules, such cis–trans photoisomerizations result in continual as the cyclodextrins). Under various forms of motion of the molecules, making them work like external stimuli, the capping agents experience an impeller to propel the drug molecules out mechanical motions, effectively opening and of the pores. By controlling the arrangement of closing the pores and regulating the release of the azobenzenes, switching efficiency and switch­ encapsulated drug. Development in this research ing dynamics, the drug releasing process can

1310 Nanomedicine (2010) 5(9) future science group Editorial Zheng, Kiraly & Huang Molecular machines drive smart drug delivery Editorial

be regulated. Furthermore, nanovalves can be the catalytic action of an enzyme, causing the added into the nanoimpeller system at the meso­ dethreading of the tori and release of the guest pore openings to provide an additional indepen­ molecules from the pores of the nanoparticles. dent mechanism for control over drug delivery. The flexibility in choosing the stoppering unit, The dual-controlled nanoparticles operate with incorporated in the final step of the synthesis, an AND logic and allow refined control of the makes it possible for the system to target any release dynamics [14]. number of hydrolytic enzymes. One of the most common obstacles in the appli­ Another biologically inclined DDS is based cation of photoresponsive molecular machines on the operation of molecular nanovalves that in biomedical applications is the requirement of are tightly closed at physiological pH (7.4), but UV stimulation. UV radiation is limited to use capable of opening in acidifying cellular com­ in peripheral tissues where penetration depth partments. In the system, b-cyclodextrin rings and lack of transparency are not as significant. (as capping agents) encircle aromatic amines (as To circumvent this limitation, next-generation stalks) as a result of noncovalent bonding inter­ nanovalves and nanoimpellers must be triggered actions under neutral pH conditions, effectively by near-infrared light that penetrates deeper into blocking the mesopore openings. A decrease in human tissue and thus increases the potential the pH leads to protonation of the aromatic working area for the new delivery systems [15,16]. amines, followed by b-cyclodextrin cap release Furthermore, near-infrared radiation can avoid and drug molecule diffusion from the meso­ the cytotoxic effects of UV light due to the low- pores. The operation of this autonomous nano­ power photoirradiation under b­iocompatible system was demonstrated successfully in human and physiological conditions. differentiated myeloid (THP-1) and squamous carcinoma (KB-31) cell lines [18]. Moving the research from abiotic demonstrations to biological uses Prospects, challenges Although significant progress has been made in & opportunities molecular-machine-powered DDS that operate In the past decade, the developments in molec­ in abiotic conditions, in vivo applications of these ular-machine-powered DDS mark substantial systems remain the ultimate goal. The complex­ steps in the progression toward biological and ity of biological systems and their response to clinical use. Flexibility in molecular design and the molecular-machine-functionalized nano­ synthesis has helped produce various molecu­ particles present great challenges to the devel­ lar machines for DDS applications with a wide opment of molecular-machine-powered DDS range of stimuli. Advanced tools in surface func­ for biological uses. To develop such systems, tionalization and characterization are enabling collaborated research efforts are required from researchers to engineer the switching dynamics multiple disciplines, including biology, medi­ of molecular machines on nanoparticle surfaces cine, chemistry, physics and engineering, to gain for specific release profiles of drugs in response insights into a range of issues from molecular to biological conditions [11]. Despite these recent synthesis to s­ystem design. developments, several major obstacles need to Recently, much effort has been dedicated to be overcome before molecular-machine-powered moving research on molecular-machine-powered DDS is fit for clinical applications. For exam­ DDS from abiotic demonstrations to biological ple, biocompatibility of both the nanoparticles uses. The use of cellular stimuli, which exploit and molecular machines is of primary concern the physiological processes within a cell to in these delivery systems. Work has been car­ affect the motion of molecular machines and ried out with biocompatible stalks and caps in ultimately the release of a drug, constitutes a pseudo­rotaxanes, and the formation of biocom­ significant milestone in molecular-machine- patible complexes in molecular machines holds powered DDS. This process allows the DDS great promise for future development in total to operate autonomously, requiring no external system biocompatibility. The ultimate utility stimuli. The rotaxanes, which consist of tri­ of these systems will be proven as the research ethylene glycol chains threaded by a-cyclodex­ moves in vivo and the pharmacology of the sys­ trin tori, have been attached to mesopore open­ tems is thoroughly examined. It will also be ings of nano­particles for enzyme-controlled important to control the dynamics of the drug drug delivery [2,17]. The bulky stoppers, which delivery. While it has been characterized for serve to hold the tori in place, are stable under most current systems, control over the release physiological conditions, but are cleaved by rates remain fairly novice. To effectively deliver

future science group www.futuremedicine.com 1311 Editorial Zheng, Kiraly & Huang

a wide variety of drugs, it will be necessary to to a wide variety of intracellular possibilities have variable release rates from impulses to slow, (e.g., gene therapy, proteomics and individual steady release. In addition to dynamic control organelle treatment). Molecular machines seem over a full range of delivery times, further dem­ to be driving smart drug delivery toward bio­ onstrations and refinements in logical control, logical and clinical viability with a full head of which utilize multiple inputs to control deliv­ steam, but this research must rely on the con­ ery, will result in greater efficiency with reduced tinued efforts and harmonic collaboration of c­ollateral damage. the bright minds in all related fields to achieve The beauty of molecular nanotechnology complete success. resides in its promise to manipulate materials at the atomic level. While individual atom-by-atom Financial & competing interests disclosure manipulation does not yet exist, it is possible The authors have no relevant affiliations or financial to work at the molecular and nanoscopic lev­ involvement with any organization or entity with a finan- els to create the precisely controlled molecular cial interest in or financial conflict with the subject matter machines for DDS with unprecedented timed/ or materials discussed in the manuscript. This includes controlled drug release, therapeutic efficiency employment, consultancies, honoraria, stock ownership or and biocompatibility. With nanoparticles options, expert testimony, grants or patents received or already functioning at the subcellular level, the p­ending, or royalties. possibility of incorporating different molecular No writing assistance was utilized in the production of machineries onto their surfaces opens the door this manuscript.

8 Huang TJ, Juluri BK: Biological and 14 Angelos S, Yang Y-W, Khashab NM, Bibliography biomimetic molecular machines. Stoddart JF, Zink JI: Dual-controlled 1 Feynman RP: There is plenty of room at the Nanomedicine 3(1), 107–124 (2008). nanoparticles exhibiting AND logic. bottom. Eng. Sci. 23, 22–36 (1960). 9 Juluri BK, Kumar AS, Liu Y et al.: J. Am. Chem. Soc. 131(32), 11344–11346 2 Coti KK, Belowich ME, Liong M et al.: A mechanical actuator driven (2009). Mechanised nanoparticles for drug delivery. electrochemically by artificial molecular 15 Lin Q, Huang Q, Li C, Bao C, Liu Z, Li F, Nanoscale 1, 16–39 (2009). muscles. ACS Nano 3(2), 291–300 Zhu L: Anticancer drug release from a 3 Lu J, Choi E, Tamanoi F, Zink JI: Light- (2009). mesoporous silica based nanophotocage activated nanoimpeller-controlled drug release 10 Zheng YB, Yang YW, Jensen L et al.: Active regulated by either a one- or two-photon in cancer cells. Small 4(4), 421–426 (2008). molecular plasmonics: controlling plasmon process. J. Am. Chem. Soc. 132(31), 10645–10647 (2010). 4 Emerich DF, Thanos CG: The pinpoint resonances with molecular switches. Nano promise of nanoparticle-based drug delivery Lett. 9(2), 819–825 (2009). 16 Yavuz MS, Cheng Y, Chen J et al.: Gold and molecular diagnosis. Biomol. Eng. 23(4), 11 Klajn R, Stoddart JF, Grzybowski BA: nanocages covered by smart polymers for 171–184 (2006). Nanoparticles functionalised with reversible controlled release with near-infrared light. Nat. Mater. 8(12), 935–939 (2009). 5 Balzani V, Credi A, Raymo FM, Stoddart JF: molecular and supramolecular switches. Artificial molecular machines.Angew. Chem. Chem. Soc. Rev. 39(6), 2203–2237 17 Patel K, Angelos S, Dichtel WR et al.: Int. Edit. 39(19), 3349–3391 (2000). (2010). Enzyme-responsive snap-top covered silica nanocontainers. J. Am. Chem. Soc. 130(8), 6 Huang TJ, Tseng HR, Sha L et al.: 12 Zheng YB, Hao Q, Yang Y-W, Kiraly B, 2382–2383 (2008). Mechanical shuttling of linear motor- Chiang I-K, Huang TJ: Light-driven artificial molecules in condensed phases on solid molecular machines. J. Nanophotonics 4, 18 Meng H, Xue M, Xia T et al.: Autonomous substrates. Nano Lett. 4(11), 2065–2071 042501 (2010). in vitro anticancer drug release from (2004). 13 Liu N, Dunphy DR, Atanassov P et al.: mesoporous silica nanoparticles by pH- sensitive nanovalves. J. Am. Chem. Soc. 7 Huang TJ: Recent developments in artificial Photoregulation of mass transport through a 132(36), 12690–12697 (2010). molecular-machine-based active photoresponsive azobenzene-modified nanomaterials and nanosystems. MRS Bull. nanoporous membrane. Nano. Lett. 4, 33, 226–231 (2008). 551–554 (2004).

1312 Nanomedicine (2010) 5(9) future science group