View Article Online View Journal
ChemComm Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Zhang, T. Shen, H. Zhang, A. M. Kirillov, H. Cai, J. Wu, W. Liu and Y. Tang, Chem. Commun., 2016, DOI: 10.1039/C6CC00010J.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
www.rsc.org/chemcomm
Please do not adjust margins ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C6CC00010J
ChemComm
Received 00th January 20xx, Accepted 00th January 20xx
Published on 15 February 2016. Downloaded on 15/02/2016 18:35:57.
DOI: 10.1039/x0xx00000x
Multifunctional Nanocomposite for Luminescence Resonance Energy Transfer-Guided Synergistic Monitoring and Therapy under Single Near Infrared Light Yu Zhang,a Ting-Ting Shen,a Hao-Li Zhang,a Alexander M. Kirillov,b Hui-Juan Cai,a Jiang Wu,a WeiSheng Liu,a and Yu Tang*a
www.rsc.org/ 3+
By utilizing drug coordinated to Eu as blocker of luminescence 3+ resonance energy transfer from Eu complex to gold nanotriangles, we successfully implemented multiple functions into one nanocomposite; it operates under single near infrared light and is efficient for the temperature/luminescence monitoring of drug release and synergistic turning-on of photothermal chemotherapy. The demand for precision medicine has set new requirements for drug delivery systems, including the target drug delivery, controlled drug release and its real-time 1 monitoring, and synergistic therapy. Recently, the near infrared (NIR)-triggered photothermal therapy (PTT) has received considerable attention because of deep noninvasive 2 tissue penetration and easy operation. However, PTT alone is unlikely to completely eradicate the malignant cells because of the local heterogeneous distribution of heat in tumor.3 Therefore, chemotherapy, a traditional and direct-damage anticancer treatment, still has an irreplaceable role in synergistic photothermal chemotherapy. However, chemotherapy represents some severe problems, such as strong toxicity and various side effects due to the nonspecific distribution of anti-cancer drugs.4 Thus, a method for the real-time feedback on the local drug distribution or concentration is urgently needed to reduce the side toxicity. The most common strategy for the real-time drug release monitoring consists of using an optical imaging agent, which is highly sensitive, relatively simple, and provides a real-time detection.5 Another widely adapted strategy is based on the magnetic resonance imaging (MRI) technique, which produces noninvasive and tissue-depth-independent images with a high spatial and temporal resolution.6 Each imaging modality has its own unique advantages along with intrinsic limitations, such as
an insufficient spatial resolution for optical imaging and a low sensitivity for MRI, thus making difficult to gather an accurate 7 and reliable information at the disease site. Therefore, the combination of multimodal monitoring techniques is urgently needed to overcome the disadvantages of single monitoring methods. Most importantly, the integration of multiple functions into a single nanoplatform can allow the precise diagnosis and therapy of disease, including an individualized selection of treatment modality, multimodal real-time monitoring of drug release, and assessment of therapeutic outcomes. Despite being conceptually impressive for clinical applications, it is still a major challenge to assemble and explore a highly efficient theranostic nanoplatform via a controllable fabrication of an ideal multifunction relying on a single stimulus such as light or heat. In this report, we propose a novel, smart, and highly efficient strategy to assemble an ‘all-in-one’ theranostic nanocomposite for the luminescence resonance energy transfer (LRET)-guided and simultaneous light-triggered drug release, dual-mode in-vivo monitoring of drug release, and synergistic photothermal chemotherapy under single NIR light (Scheme 1). For such a multifunctional nanocomposite, we have chosen a two-photon-sensitized Eu3+ complex [Eu(THA)3(phen)] (HTHA = 4,4,4-trifluoro-1-(9-hexylcarbazole3-yl)-1,3-butanedione, phen = 1,10-phenanthroline) as a LRET donor, gold nanotriangles (AuNTs) as an acceptor, and a model doxorubicin (DOX) drug as a LRET blocker. Thus, the NIR light can be used to trigger the energy transfer between the donor and acceptor. To the best of our knowledge, this is the first theranostic nanoplatform that enables the dual-mode realtime monitoring of drug release using photothermal imaging (PTI) and two-photon luminescence (TPL) imaging techniques. Most importantly, the logical design of our theranostic nanocomposite can achieve the drug release monitoring together with the synergistic photothermal chemotherapy, which are based on one nanoplatform using a single NIR excitation light (808 nm). This new strategy reveals a great potential for different biomedical applications, especially for precision medicine.
Chem. Commun., 2015, 00, 1-4 | 1
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins
ChemComm Accepted Manuscript
COMMUNICATION
Please do not adjust margins ChemComm
Page 2 of 4 View Article Online
DOI: 10.1039/C6CC00010J
Journal Name
Scheme 1. Simplified representation for the assembling process of the multifunctional theranostic nanocomposite (top). Mechanism of the dual-mode monitoring of drug release and synergistic photothermal chemotherapy under single NIR light (bottom). 3+
In our design, the Eu complex is an excellent donor for achieving two-photon luminescent properties and attracting drug molecules, since it is easier to optimize the complex than 8 organic dye molecules and upconversion nanoparticles (NPs). Previous LRET-based drug delivery systems generally required the drug to exhibit certain optical absorption properties in 5b order to be involved into the LRET. In contrast, to achieve a wider drug applicability, our system uses the drug molecule as a spatial blocker that does not require to possess any special absorption properties. When the drug molecules have strong interactions with the donor or acceptor, the drug loading and release will affect the donor-acceptor separation, thereby inducing a change in the LRET efficiency. Therefore, by monitoring the parameters associated to the LRET efficiency, it is possible to control the drug release process. A detailed description of the design idea is given in Section S2 (ESI). The synthetic route for the nanocomposite formulated as [Au-phMSNs@P(NIPAm-co-MAA)-cRGD@Eu(THA)3(phen)] is shown in Scheme 1. The phenyl-modified mesoporous silica coated AuNTs (Au-phMSNs) were designed and synthesized by 9 a sol-gel method. As shown in Fig. 1a, the average size of the AuNTs is approximately 52 nm along the length of edges, being consistent with the result of dynamic light scattering (DLS) experiments (Fig. S1). After coating a layer of phMSNs with an average thickness of 10 nm, the as-obtained Au-phMSNs have a mean edge length of 60 nm (Fig. 1b). To achieve the smart drug release and targeted cancer therapy, the surface of the Au-phMSNs was modified with pH/thermo-coupling sensitive polymer brushes, poly[(N-isopropylacrylamide)-co(methacrylic acid)] (P(NIPAm-co-MAA)), to form the AuphMSNs@P(NIPAm-co-MAA) precursor (named as AMP), followed by further conjugation with a targeting peptide cyclic(Arg-Gly-Asp-D-Phe-Lys) (cRGD) to generate the AuphMSNs@P(NIPAm-co-MAA)-cRGD material (named as AMPC). The successful modification of Au-phMSNs by P(NIPAm-coMAA) and cRGD was achieved and the obtained AMPC was fully characterized as described in Section S3 (ESI).
AMPC was further loaded with the [Eu(THA)3(phen)] complex to form the basic nanocomposite, AMPC@Eu(THA)3(phen). Transmission electron microscopy (TEM), high-angle annular dark-field scanning TEM technique (HAADF-STEM), and energy dispersive spectrometry (EDS) (Fig. 1d-f) confirm the presence of Au, Eu, O, F, Si, and C elements in the as-prepared sample. Additionally, the elemental mappings obtained from the HAADF-STEM measurements 3+ confirm a uniform distribution of the Eu complex in the 10 nanocomposite (Fig. 1g–k). Besides, powder X-ray diffraction (PXRD) patterns of the nanocomposite (Fig. S4) exhibit very 3+ weak diffraction peaks of the Eu complex, thus confirming that most of the complex was successfully encapsulated into the mesopores; this process was facilitated by strong hydrophobicity and π-π stacking. Doxorubicin (DOX) was chosen as a model drug to evaluate the drug loading and release properties. After loading DOX onto AMPC@Eu(THA)3(phen), the DOX-containing nanocomposite (abbreviated as Nanocom-DOX) was obtained and fully characterized. The DOX loading onto the nanocomposite causes the absorbance to red shift from 480 to 530 nm (Fig. S5), thus supporting an interaction between the drug molecules and the Eu3+ ions.5a,11 Furthermore, the change of the I(5D0/7F2)/I(5D0/7F1) intensity ratios of the Eu3+ emission indicates a modification of the coordination environment of Eu3+ ions upon DOX loading.12 As discussed in the Section S4 (ESI), after the DOX loading into the pores of the phenylmodified mesoporous silica, most of the DOX molecules are located at the outer coordination sphere of Eu3+ ions by electrostatic interactions and π-π stacking; a minor amount of DOX may replace water ligands in the first coordination sphere of Eu3+. Thus, after the DOX loading, most of its molecules are directly gathered around the Eu3+ complex moieties.
Figure 1. (a-d) TEM images of (a) AuNTs, (b) Au-phMSNs, (c) AMPC, and (d) nanocomposite. (e) High-magnified HAADF-STEM image of nanocomposite. (f) EDS of nanocomposite. (g–k) Elemental (Au, Si, O, F, Eu) mappings of nanocomposite.
As expected, based on the well-matched wavelength (Fig. 2a) between the TPL signal of [Eu(THA)3(phen)] and the localized surface plasmon resonance (LSPR) peak of AuNTs (500-750 nm), the LRET process between [Eu(THA)3(phen)] and AuNTs was explored by exposure to an 808 nm NIR laser, 13 which permits a high transmissivity to biological tissues. Then, we evaluated the potential of the nanocomposite for
2 | Chem. Commun., 2015, 00, 1-4
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins
ChemComm Accepted Manuscript
Published on 15 February 2016. Downloaded on 15/02/2016 18:35:57.
COMMUNICATION
Please do not adjust margins ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C6CC00010J
COMMUNICATION
monitoring the drug release by measuring the TPL and temperature signals in real time. It is known that the LRET efficiency is diminished on extending the distance between the donors and acceptors. Hence, the LRET effect is expected to weaken upon DOX loading into the mesopores. DOX can behave as a blocker and give rise to an increased distance between [Eu(THA)3(phen)] and the AuNT core. As shown in Fig. S10a, the addition of DOX into the mesopores of AMP induced 3+ a recovery of the emission intensities of the Eu ions. Moreover, we calculated the distance between the donor and acceptor and discussed the ET efficiency (Section S4, ESI). The obtained results indicate that in AMPC the distance between [Eu(THA)3(phen)] and the AuNT core is 1.85 nm. This distance increases to 3.55 nm upon addition of the drug; such an increase of 1.70 nm exactly matches the size of DOX (~1.55 nm, as estimated from Chem 3D). These data suggest the presence of one or two DOX molecules in between [Eu(THA)3(phen)] and the AuNT core after the DOX loading into the mesopores. Meanwhile, the NIR photothermal heating efficiency diminished upon the DOX loading into the nanocomposite (Fig. S12). Thus, the NIR photothermal heating efficiency represents an additional piece of evidence of the DOX loading into the mesopores. A reverse trend is observed upon the DOX release from the mesopores, resulting in the shortening of the distance between [Eu(THA)3(phen)] and the AuNT core, which substantially heightens the LRET effect. As depicted in Fig. S14a, the drug release from the Nanocom-DOX is stimulated by the NIR irradiation, since the temperature increased above the low critical solution temperature (37 °C) of P(NIPAm-coMAA).14 As a consequence, the polymer chain is forced to shrink and open the porous channels, thus enabling the entrapped drug molecules to leak out. Very low concentrations of the Eu3+ ions observed in the solutions at different time points indicate that only a negligible amount of Eu3+ (
ChemComm Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Zhang, T. Shen, H. Zhang, A. M. Kirillov, H. Cai, J. Wu, W. Liu and Y. Tang, Chem. Commun., 2016, DOI: 10.1039/C6CC00010J.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
www.rsc.org/chemcomm
Please do not adjust margins ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C6CC00010J
ChemComm
Received 00th January 20xx, Accepted 00th January 20xx
Published on 15 February 2016. Downloaded on 15/02/2016 18:35:57.
DOI: 10.1039/x0xx00000x
Multifunctional Nanocomposite for Luminescence Resonance Energy Transfer-Guided Synergistic Monitoring and Therapy under Single Near Infrared Light Yu Zhang,a Ting-Ting Shen,a Hao-Li Zhang,a Alexander M. Kirillov,b Hui-Juan Cai,a Jiang Wu,a WeiSheng Liu,a and Yu Tang*a
www.rsc.org/ 3+
By utilizing drug coordinated to Eu as blocker of luminescence 3+ resonance energy transfer from Eu complex to gold nanotriangles, we successfully implemented multiple functions into one nanocomposite; it operates under single near infrared light and is efficient for the temperature/luminescence monitoring of drug release and synergistic turning-on of photothermal chemotherapy. The demand for precision medicine has set new requirements for drug delivery systems, including the target drug delivery, controlled drug release and its real-time 1 monitoring, and synergistic therapy. Recently, the near infrared (NIR)-triggered photothermal therapy (PTT) has received considerable attention because of deep noninvasive 2 tissue penetration and easy operation. However, PTT alone is unlikely to completely eradicate the malignant cells because of the local heterogeneous distribution of heat in tumor.3 Therefore, chemotherapy, a traditional and direct-damage anticancer treatment, still has an irreplaceable role in synergistic photothermal chemotherapy. However, chemotherapy represents some severe problems, such as strong toxicity and various side effects due to the nonspecific distribution of anti-cancer drugs.4 Thus, a method for the real-time feedback on the local drug distribution or concentration is urgently needed to reduce the side toxicity. The most common strategy for the real-time drug release monitoring consists of using an optical imaging agent, which is highly sensitive, relatively simple, and provides a real-time detection.5 Another widely adapted strategy is based on the magnetic resonance imaging (MRI) technique, which produces noninvasive and tissue-depth-independent images with a high spatial and temporal resolution.6 Each imaging modality has its own unique advantages along with intrinsic limitations, such as
an insufficient spatial resolution for optical imaging and a low sensitivity for MRI, thus making difficult to gather an accurate 7 and reliable information at the disease site. Therefore, the combination of multimodal monitoring techniques is urgently needed to overcome the disadvantages of single monitoring methods. Most importantly, the integration of multiple functions into a single nanoplatform can allow the precise diagnosis and therapy of disease, including an individualized selection of treatment modality, multimodal real-time monitoring of drug release, and assessment of therapeutic outcomes. Despite being conceptually impressive for clinical applications, it is still a major challenge to assemble and explore a highly efficient theranostic nanoplatform via a controllable fabrication of an ideal multifunction relying on a single stimulus such as light or heat. In this report, we propose a novel, smart, and highly efficient strategy to assemble an ‘all-in-one’ theranostic nanocomposite for the luminescence resonance energy transfer (LRET)-guided and simultaneous light-triggered drug release, dual-mode in-vivo monitoring of drug release, and synergistic photothermal chemotherapy under single NIR light (Scheme 1). For such a multifunctional nanocomposite, we have chosen a two-photon-sensitized Eu3+ complex [Eu(THA)3(phen)] (HTHA = 4,4,4-trifluoro-1-(9-hexylcarbazole3-yl)-1,3-butanedione, phen = 1,10-phenanthroline) as a LRET donor, gold nanotriangles (AuNTs) as an acceptor, and a model doxorubicin (DOX) drug as a LRET blocker. Thus, the NIR light can be used to trigger the energy transfer between the donor and acceptor. To the best of our knowledge, this is the first theranostic nanoplatform that enables the dual-mode realtime monitoring of drug release using photothermal imaging (PTI) and two-photon luminescence (TPL) imaging techniques. Most importantly, the logical design of our theranostic nanocomposite can achieve the drug release monitoring together with the synergistic photothermal chemotherapy, which are based on one nanoplatform using a single NIR excitation light (808 nm). This new strategy reveals a great potential for different biomedical applications, especially for precision medicine.
Chem. Commun., 2015, 00, 1-4 | 1
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins
ChemComm Accepted Manuscript
COMMUNICATION
Please do not adjust margins ChemComm
Page 2 of 4 View Article Online
DOI: 10.1039/C6CC00010J
Journal Name
Scheme 1. Simplified representation for the assembling process of the multifunctional theranostic nanocomposite (top). Mechanism of the dual-mode monitoring of drug release and synergistic photothermal chemotherapy under single NIR light (bottom). 3+
In our design, the Eu complex is an excellent donor for achieving two-photon luminescent properties and attracting drug molecules, since it is easier to optimize the complex than 8 organic dye molecules and upconversion nanoparticles (NPs). Previous LRET-based drug delivery systems generally required the drug to exhibit certain optical absorption properties in 5b order to be involved into the LRET. In contrast, to achieve a wider drug applicability, our system uses the drug molecule as a spatial blocker that does not require to possess any special absorption properties. When the drug molecules have strong interactions with the donor or acceptor, the drug loading and release will affect the donor-acceptor separation, thereby inducing a change in the LRET efficiency. Therefore, by monitoring the parameters associated to the LRET efficiency, it is possible to control the drug release process. A detailed description of the design idea is given in Section S2 (ESI). The synthetic route for the nanocomposite formulated as [Au-phMSNs@P(NIPAm-co-MAA)-cRGD@Eu(THA)3(phen)] is shown in Scheme 1. The phenyl-modified mesoporous silica coated AuNTs (Au-phMSNs) were designed and synthesized by 9 a sol-gel method. As shown in Fig. 1a, the average size of the AuNTs is approximately 52 nm along the length of edges, being consistent with the result of dynamic light scattering (DLS) experiments (Fig. S1). After coating a layer of phMSNs with an average thickness of 10 nm, the as-obtained Au-phMSNs have a mean edge length of 60 nm (Fig. 1b). To achieve the smart drug release and targeted cancer therapy, the surface of the Au-phMSNs was modified with pH/thermo-coupling sensitive polymer brushes, poly[(N-isopropylacrylamide)-co(methacrylic acid)] (P(NIPAm-co-MAA)), to form the AuphMSNs@P(NIPAm-co-MAA) precursor (named as AMP), followed by further conjugation with a targeting peptide cyclic(Arg-Gly-Asp-D-Phe-Lys) (cRGD) to generate the AuphMSNs@P(NIPAm-co-MAA)-cRGD material (named as AMPC). The successful modification of Au-phMSNs by P(NIPAm-coMAA) and cRGD was achieved and the obtained AMPC was fully characterized as described in Section S3 (ESI).
AMPC was further loaded with the [Eu(THA)3(phen)] complex to form the basic nanocomposite, AMPC@Eu(THA)3(phen). Transmission electron microscopy (TEM), high-angle annular dark-field scanning TEM technique (HAADF-STEM), and energy dispersive spectrometry (EDS) (Fig. 1d-f) confirm the presence of Au, Eu, O, F, Si, and C elements in the as-prepared sample. Additionally, the elemental mappings obtained from the HAADF-STEM measurements 3+ confirm a uniform distribution of the Eu complex in the 10 nanocomposite (Fig. 1g–k). Besides, powder X-ray diffraction (PXRD) patterns of the nanocomposite (Fig. S4) exhibit very 3+ weak diffraction peaks of the Eu complex, thus confirming that most of the complex was successfully encapsulated into the mesopores; this process was facilitated by strong hydrophobicity and π-π stacking. Doxorubicin (DOX) was chosen as a model drug to evaluate the drug loading and release properties. After loading DOX onto AMPC@Eu(THA)3(phen), the DOX-containing nanocomposite (abbreviated as Nanocom-DOX) was obtained and fully characterized. The DOX loading onto the nanocomposite causes the absorbance to red shift from 480 to 530 nm (Fig. S5), thus supporting an interaction between the drug molecules and the Eu3+ ions.5a,11 Furthermore, the change of the I(5D0/7F2)/I(5D0/7F1) intensity ratios of the Eu3+ emission indicates a modification of the coordination environment of Eu3+ ions upon DOX loading.12 As discussed in the Section S4 (ESI), after the DOX loading into the pores of the phenylmodified mesoporous silica, most of the DOX molecules are located at the outer coordination sphere of Eu3+ ions by electrostatic interactions and π-π stacking; a minor amount of DOX may replace water ligands in the first coordination sphere of Eu3+. Thus, after the DOX loading, most of its molecules are directly gathered around the Eu3+ complex moieties.
Figure 1. (a-d) TEM images of (a) AuNTs, (b) Au-phMSNs, (c) AMPC, and (d) nanocomposite. (e) High-magnified HAADF-STEM image of nanocomposite. (f) EDS of nanocomposite. (g–k) Elemental (Au, Si, O, F, Eu) mappings of nanocomposite.
As expected, based on the well-matched wavelength (Fig. 2a) between the TPL signal of [Eu(THA)3(phen)] and the localized surface plasmon resonance (LSPR) peak of AuNTs (500-750 nm), the LRET process between [Eu(THA)3(phen)] and AuNTs was explored by exposure to an 808 nm NIR laser, 13 which permits a high transmissivity to biological tissues. Then, we evaluated the potential of the nanocomposite for
2 | Chem. Commun., 2015, 00, 1-4
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins
ChemComm Accepted Manuscript
Published on 15 February 2016. Downloaded on 15/02/2016 18:35:57.
COMMUNICATION
Please do not adjust margins ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C6CC00010J
COMMUNICATION
monitoring the drug release by measuring the TPL and temperature signals in real time. It is known that the LRET efficiency is diminished on extending the distance between the donors and acceptors. Hence, the LRET effect is expected to weaken upon DOX loading into the mesopores. DOX can behave as a blocker and give rise to an increased distance between [Eu(THA)3(phen)] and the AuNT core. As shown in Fig. S10a, the addition of DOX into the mesopores of AMP induced 3+ a recovery of the emission intensities of the Eu ions. Moreover, we calculated the distance between the donor and acceptor and discussed the ET efficiency (Section S4, ESI). The obtained results indicate that in AMPC the distance between [Eu(THA)3(phen)] and the AuNT core is 1.85 nm. This distance increases to 3.55 nm upon addition of the drug; such an increase of 1.70 nm exactly matches the size of DOX (~1.55 nm, as estimated from Chem 3D). These data suggest the presence of one or two DOX molecules in between [Eu(THA)3(phen)] and the AuNT core after the DOX loading into the mesopores. Meanwhile, the NIR photothermal heating efficiency diminished upon the DOX loading into the nanocomposite (Fig. S12). Thus, the NIR photothermal heating efficiency represents an additional piece of evidence of the DOX loading into the mesopores. A reverse trend is observed upon the DOX release from the mesopores, resulting in the shortening of the distance between [Eu(THA)3(phen)] and the AuNT core, which substantially heightens the LRET effect. As depicted in Fig. S14a, the drug release from the Nanocom-DOX is stimulated by the NIR irradiation, since the temperature increased above the low critical solution temperature (37 °C) of P(NIPAm-coMAA).14 As a consequence, the polymer chain is forced to shrink and open the porous channels, thus enabling the entrapped drug molecules to leak out. Very low concentrations of the Eu3+ ions observed in the solutions at different time points indicate that only a negligible amount of Eu3+ (
