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Near-Infrared Cyanine Loaded Liposome-Like Nanocapsules of Camptothecin-Floxuridine Conjugate for Enhanced Chemophotothermal Combination Cancer therapy Chuang Gao, Xiaolong Liang, Shanyan Mo, Nisi Zhang, Desheng Sun, and Zhifei Dai ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b14125 • Publication Date (Web): 04 Jan 2018 Downloaded from http://pubs.acs.org on January 4, 2018
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ACS Applied Materials & Interfaces
Near-Infrared Cyanine Loaded Liposome-Like Nanocapsules
of
Conjugate
Enhanced
for
Camptothecin-Floxuridine Chemophotothermal
Combination Cancer therapy Chuang Gao1, ‡, Xiaolong Liang2, ‡, Shanyan Mo1, ‡, Nisi Zhang1, Desheng Sun3* and Zhifei Dai1,* 1
Department of Biomedical Engineering, College of Engineering, Peking University, Beijing,
100871, China 2
Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China
3
Peking University Shenzhen Hospital, Shenzhen 518036, China
‡ These authors contributed equally to this work.
* Corresponding author, E-mail:
[email protected],
[email protected] Homepage: http://www.mimit-pku.org
ABSTRACT
A dual-in-dual synergistic strategy was proposed based on the self-assembly of combinatorial nanocapsules (NCs) from Janus camptothecin-floxuridine (CF) conjugate and near infrared absorber of
1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine
1 ACS Paragon Plus Environment
iodide
(DiR) by
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introducing PEGylated phospholipid of DSPE-PEG2000 to increase the blood circulation time of NCs. Due to the use of amphiphilic CF and DiR themselves to form liposome-like nanocapsules, the obtained CF-DiR NCs owned significantly high loading content, stable codelivery drug combinations, no premature release and excellent photothermal conversion efficiency. In vivo fluorescence imaging indicated that CF-DiR NCs could achieve high tumor accumulation after intravenous injection. The dual drugs of camptothecin and floxuridine could coordinately release due to the hydrolysis of the ester bond by the esterase in tumor. The in vivo experiments showed that more cytotoxicity of the CF-DiR NCs mediated chemoand photothermal dual therapy to tumor cells could be clearly observed than the chemotherapy or photothermal therapy alone due to the synergistic effect, leading to no recurrence in the entire treatment. All results highlighted that CF-DiR NCs were highly effective
theranostic
agent
which
could
be
used
for
imaging
guided
cancer
chemophotothermal therapy to conquer intrinsic resistance to chemotherapeutics.
Keywords: Nanocapsule, Camptothecin, Foxuridine, Photothermal therapy, Combined therapy 1. Introduction The drug resistance issue has been a long-standing challenge in cancer treatment.1-4 In order to improve therapeutic efficacy for cancer, drugs acting in different modality have long been combined together with precisely controlled release behaviors and adopted as clinical treatment against many types of cancer since it would be difficult for cancer cells to develop compensatory resistance mechanism in comparison with single or sequentially administered drugs.5-8 The development of combinatorial nanoparticles have initiated many unprecedented options to overcome tumor drug resistance due to the capability to deliver drug combinations uniformly and concurrently, and control drug exposure.9-16 Presently, a dual-drug liposomal formulation of a 1:1 irinotecan and floxuridine has been demonstrated to be more effective 2 ACS Paragon Plus Environment
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ACS Applied Materials & Interfaces
than the free drugs with cocktail administration during traditional combination therapy for colorectal cancer treatment.17 Nevertheless, efficient and stable encapsulation of two drugs with fixed ratio and high loading contents inside a single nanoparticle remains one of the key challenges for combinatorial nanoparticles. In addition, nonspecific delivery often results in obvious side effect for normal tissue and limits dosages of anticancer drugs to levels far below those required to remove cancerous tissue.9-16 Heat treatment (hyperthermia) has been demonstrated to increase the cellular metabolism and membrane permeability, thus promote drug uptake for augmenting the cytotoxicity of chemotherapeutic drugs, resulting in requirement of lower drug doses for the same therapeutic results.18-21 Thus, hyperthermia is often used to combine with chemotherapy (termed chemothermal therapy).22-24 Among hyperthermia, photothermal therapy (PTT) convert light energy into heat with the assistance of near-infrared (NIR) light absorbers, has attracted recent interest in chemophotothermal therapy due to its minimal invasiveness and potential effectiveness.25-33
The
nanoparticles
loading
1,1'-dioctadecyl-3,3,3',3'-
tetramethylindotricarbocyanine iodide (DiR) have been applied in PTT owing to strong lightabsorption and negligible cytotoxicity both in vitro and in vivo.34-37 Yet, their application in chemophotothermal therapy is often limited due to limited drug loading content (often less than 10%) and premature leakage.38-40
Especially, the combinatorial nanoparticles co-
encapsulating DiR and two drugs have not yet been reported for imaging guided PTT and combined therapy to the best of our knowledge. Thus, more versatile nanoplatform was urgently needed for chemophotothermal therapy to achieve better synergistic therapeutic effect. As a proof-of-concept, a new type of combinatorial nanocapsules (NCs) were constructed from a highly symmetric Janus camptothecin-floxuridine (CF) conjugate, an NIR absorber of DiR and a PEGylated phospholipid of DSPE-PEG2000 with a fixed molar ratio of camptothecin (CPT)/floxuridine (FUDR) (1:1) and designated molar ratios of CF/DiR to 3 ACS Paragon Plus Environment
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optimize
synergistic
antitumor activity
of
CPT
and
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FUDR,
and
improve
the
chemophotothermal therapeutic efficacy of cancer (Scheme 1). Through conjugation of two hydrophobic CPT molecules and two hydrophilic FUDR molecules to multivalent pentaerythritol by a hydrolyzable ester linkage, we synthesized the CF conjugate with a phospholipid-mimic structure according to the literature. 40-42 The amphiphilic features of CF and DiR facilitated their self-assembly into liposome-like nanocapsules. Because of the employment of CF and DiR themselves as nanocarriers, the obtained CF-DiR NCs own significantly high loading content, highly stable co-delivery drug combinations and no premature release. Upon intravenous (i.v.) injection, CF-DiR NCs could passively accumulate in tumor tissues and internalize into tumor cells. Both CPT and FUDR could coordinately release when the ester bond was hydrolyzed by the esterase and acid environment of tumor cells. Because of the strong NIR absorbance of DiR, it can be used for PTT and further exploited to enhance the chemotherapy effect synergistically. Furthermore, by using the DiR fluorescence for NIR fluorescence (NIRF) imaging, the biodistribution of CF-DiR NCs could be easily monitored for precise chemophotothermal therapy avoiding damage to surrounding normal tissues. In a word, this study highlights that CF-DiR NCs could be used as a promising novel nanomaterials for imaging guided cancer chemophotothermal therapy.
2. Results and Discussion: 2.1. Preparation and Characterization of CF-DiR NCs The combinatorial CF-DiR NCs were self-assembled by injecting the mixture of CF conjugate, DiR and DSPE-PEG2000 in dimethyl sulfoxide (DMSO) into deionized water, followed by homogenization with probe sonication, then dialysis (MWCO 8000–14000) against deionized water for complete removal of DMSO. To study the effect of doping DiR on the formation of NCs, the DiR loading content was varied while the molar ratio of CF to DSPE-PEG2000 was fixed at 8:2. The dynamic light scattering measurements (DLS) 4 ACS Paragon Plus Environment
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ACS Applied Materials & Interfaces
indicated that all the resulting NCs exhibted mean diameters of ≈130 nm with a remarkably narrow distribution (PDI
