.
Angewandte
Communications
Nanomaterials
A Multifunctional Subphthalocyanine Nanosphere for Targeting,
Labeling, and Killing of Antibiotic-Resistant Bacteria
Indranil Roy, Dinesh Shetty, Raghunandan Hota, Kangkyun Baek, Jeesu Kim, Chulhong Kim,
Sandro Kappert, and Kimoon Kim*
Dedicated to Professor Nagao Kobayashi
Abstract: Developing a material that can combat antibiotic-
resistant bacteria, a major global health threat, is an urgent
requirement. To tackle this challenge, we synthesized a multi-
functional subphthalocyanine (SubPc) polymer nanosphere
that has the ability to target, label, and photoinactivate
antibiotic-resistant bacteria in a single treatment with more
than 99% efficiency, even with a dose as low as 4.2 JcmÀ2 and
a loading concentration of 10 nm. The positively charged
nanosphere shell composed of covalently linked SubPc units
can increase the local concentration of photosensitizers at
therapeutic sites. The nanosphere shows superior performance
compared to corresponding monomers presumably because of
their enhanced water dispersibility, higher efficiency of singlet-
oxygen generation, and phototoxicity. In addition, this material
is useful in fluorescence labeling of living cells and shows
promise in photoacoustic imaging of bacteria in vivo.
(ROS) and has been proposed as an alternative to controlling
bacterial infections.[3] In most cases, although Gram-positive
bacteria are susceptible to the photosensitizing action of
a variety of sensitizers, Gram-negative bacteria exhibit
a remarkable resistance to negatively charged or neutral
agents.[4] However, studies shown that cationic photosensi-
tizers can cause direct photoinactivation of Gram-negative
bacteria even in the absence of additives.[5] Another promis-
ing approach to combating such bacteria is based on nano-
materials, in which the higher number of functional sites
compared to any given small molecule enhances the inter-
action with a given microbe.[6] In spite of progress in this field,
however, existing materials have several shortcomings, such
as poor water dispersibility and/or nonspecific accumulation
of photosensitizers.[7,8] Selective targeting of photosensitizers
in microorganisms may solve the problem of nonspecific
accumulation and may also reduce the dosage required for
PDT. Considering all these aspects, developing a material that
possesses the above-mentioned critical criteria would be
a great addition to the ongoing fight against the major medical
problem of antiobiotic-resistant bacteria.
Subphthalocyanines (SubPcs) have interesting photophys-
ical features, such as intense fluorescence and photosensitiz-
ing properties, stemming from their cone-shaped structure
and 14-p-electron aromatic conjugated system.[9] In partic-
ular, SubPcs have a longer triplet excited-state lifetime
compared to other well-known classes of photosensitizers,
including porphyrins (Ps) and phthalocyanines (Pcs), which
results in a higher quantum yield for the generation of singlet
oxygen (0.67 for SubPcs, 0.44 for Ps, and 0.52 for Pcs).[9,10,11b]
Additionally, SubPcs show more intense fluorescence signals
compared to Ps or Pcs, which may be exploited in efficient
fluorescent labeling of living cells. As a result of these merits
along with their high phototoxicity and intense light absorp-
tion in the therapeutic window (l = 600–900 nm), SubPcs
have been explored as photosensitizers in PDT.[9] However,
these molecules have some serious limitations including
limited photostability as well as poor dispersibility in water
or phosphate-buffered saline (PBS).[8] To overcome these
limitations, we decided to develop well-defined, water-
dispersible SubPc-based nanomaterials that can target,
label, and photoinactivate antibiotic-resistant bacterial cells.
Our strategy involves: 1) synthesis of a hollow nanosphere
composed of covalently linked SubPc molecules utilizing the
template-free, covalent self-assembly method recently devel-
oped by us,[11] which can increase the local concentration of
R
esistance of bacteria to multiple antibiotics has increased
dramatically over the past few years and is currently
recognized as a major medical challenge in most healthcare
settings.[1] The Center for Disease Control and Prevention has
recently issued an assessment that we are very close to
entering the “post-antibiotic era”,[2] which highlights the need
to find innovative and creative solutions to inhibit bacterial
growth. Photodynamic therapy (PDT) combines three intrins-
ically nontoxic components, namely a photosensitizer, light,
and oxygen, to generate cytotoxic reactive oxygen species
[*] I. Roy, Dr. D. Shetty, Dr. K. Baek, S. Kappert, Prof. Dr. K. Kim
Center for Self-assembly and Complexity (CSC)
Institute for Basic Science (IBS)
Pohang, 790-784 (Republic of Korea)
E-mail: kkim@postech.ac.kr
I. Roy, Dr. R. Hota, Prof. Dr. K. Kim
Department of Chemistry, Pohang University of Science and
Technology, Pohang, 790-784 (Republic of Korea)
Prof. Dr. K. Kim
Division of Advanced Materials Science
Pohang University of Science and Technology
Pohang, 790-784 (Republic of Korea)
J. Kim, Prof. Dr. C. Kim
Department of Creative IT Engineering and Electrical Engineering
Pohang University of Science and Technology
Pohang, 790-784 (Republic of Korea)
Supporting information for this article is available on the WWW
15152
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 15152 –15155