Polymer-based nanosystems have been extensively explored either as therapeutic agents or bioimaging probes in the cancer diagnosis. However, very few systems are successful in combining both therapy and imaging. Herein, a new class of norbornene based copolymer, Nor-Dox-Cob-Btn is proposed as potential theranostics agent for tumor diagonosis. The copolymer (Nor-Dox-Cob-Btn) with doxorubicin, cobalt carbonyl complex, and biotin as pendent functionalized group is synthesized, using ring opening metathesis polymerization (ROMP). The cell viability, drug release, NMR relaxation, NMR 1-D image and Epi fluorescence microscopy studies on Nor-Dox-Cob-Btn nanocarrier are thoroughly studied. The effect of nanocarrier on transverse relaxation (T 2 ) of water molecule and NMR 1-D image suggest that the nanocarrier has the potential application in magnetic resonance imaging agent. The T 2 -weighted MRI agent, along with biotin receptor assisted pH responsive doxorubicin release from Nor-Dox-Cob-Btn, prompts us to envision this newly developed polymer for future application in theranostics. ■ INTRODUCTIONDoxorubicin is a well-known frontline anticancer drug, however due to cardiotoxic effect of doxorubicin, it is always necessary to protect this drug from other healthy cells and tissues inside body. 1 There are several different models available to guide this drug more precisely into the tumor cells, for example, polymer, nanoparticle, liposome. 3 However, polymer based delivery vehicle emerged as a superior over all other existing systems due to its pharmacokinetics and biodistribution profiles via the enhanced permeability as well as retention (EPR) effect. 4 These systems also help to maintain the therapeutic concentration over long periods of time. 2−4 There are mainly two approaches to deliver drugs site-specifically to the tumor cells, namely, covalent and non covalent approaches. 5,8 Drugs encapsulated inside the polymeric aggregates can be placed inside the body for using it localized delivery following the burst mechanism. 3,5,6,8 On contrast, in stimuli responsive covalently attached drug (e.g., pH sensitive, light sensitive, etc.) to the polymeric system gives the sustained release of drug to the tumor cells over long period. 11 There are several reports available in literature based on the pH sensitivity linker, for example hydrazone, ester, and amide, in which hydrazone linker is the most commonly used for the sustained release. 11 The medical application of polymeric nanocarrier has enormous potential to improve the therapeutic efficacy, particularly in cancer therapy. The attachment of folate or biotin functionality to the same polymeric prodrug makes the system more site-specific via receptor mediated drug delivery. 5,7,9 This also improves the survival rates of healthy tissues and cells. The attachment of magnetic particles helps the drug-carrier system further, as this magnetic particle can be utilized as MR imaging agent. 11 Magnetic as well as drug containing polymersomes have a great potential for both ...
Theranostic-based nanomedicine plays a crucial role in the field of cancer therapy. This is due to having the capability to combine both therapy and diagnosis together in a single system. Herein a new class of metal–ligand-based nanocarrier in a norbornene backbone has been designed as a theranostic system. Fe3+-terpyridine complex (Fe-Tpy) has been used here as T1 contrast agent for high-resolution MR imaging, and hydrazone-linked doxorubicin is used for effective pH-responsive delivery. Polyethylene glycol functionalized with a folic acid (peg folate) motif is used to make the entire polymeric system dispersible in water for longer retention and site-specific therapy. All these specialty functional groups are anchored in a single system by using the ring-opening metathesis polymerization (ROMP) technique under the norbornene backbone. Relaxivity study and 1D image experiments have shown the utility of Fe-Tpy complex as an effective T1 contrast agent. In vitro studies are performed to confirm the promising potentiality of the nanocarrier as the efficient nanotheranostic system in prostate cancer.
Mercury (Hg 2+ )-triggered desulfurization of 1,3dithiolane to the formyl group formation process has been utilized here to develop a norbornene-based reaction-triggered ESIPT active probe (NT). Mercury (Hg 2+ ) activated the excited-state proton transfer (ESIPT) process of both NT and its water-soluble polymer Poly-PEG-NT to change the emission from colorless to cyan-green. Due to the Hg 2+ -sensitive reaction site, NT and Poly-PEG-NT serve as highly selective and ultrafast detection systems with a limit of detection (LOD) of 8.2 nM and 107 nM, respectively. Additionally, NT can detect the organic mercury species (CH 3 Hg + ) with a quick response time and an impressive LOD of 1.1 μM. Due to the water-soluble nature of Poly-PEG-NT, it has the capability of detecting Hg 2+ in pure aqueous meda. Both these probes are capable of detecting Hg 2+ in both environmental and biological systems with excellent efficiency. Overall, the easy synthesis, cost-effectiveness, ultrafast detection, high selectivity, and sensitivity of NT and Poly-PEG-NT toward Hg 2+ /CH 3 Hg + can be used for practical purposes with efficiency to counter mercury toxicity.
Magnetic resonance imaging-aided real-time diagnosis along with enhanced chemotherapeutic efficacy using a sequential receptor and mitochondria dual-targeting polymer theranostic has become a promising strategy for the effective and precise treatment of cancer. Toward the accomplishment of this goal, chlorambucil (chemotherapeutic agent), biotin (receptor targeting agent), a triphenylphosphonium segment (mitochondriotropic agent), and an iron rhodamine complex (integrated fluorescence-MR imaging agent) were tethered under a single polymer. Owing to the polymer's (RD CH PG BN TP Fe) amphiphilic character, it spontaneously self-assembled into nanospheres, which exhibited a remarkable effect on the relaxation of the water proton. Further, the qualitative estimation of the change in intensity for the water-proton signal reflected its potential as a T 1 contrast theranostic polymer. The mitochondria targeting competency of positively charged nanospheres was displayed using fluorescence microscopy in human cervical, HeLa, and breast, MCF-7, carcinoma cell lines. Furthermore, cytotoxicity experiments demonstrated the enhanced anticancer efficacy in both cancer cell lines. Therefore, effective and precise chemotherapy through sequential receptor-mitochondria targeting and integrated fluorescence-MR imaging would have attractive potential for decisive dose-determination by constantly monitoring the subject area of interest.
The combination therapy where a single delivery agent codelivers multiple drugs at the targeted site has become a promising strategy to achieve synergistic chemotherapeutic effect leading to the suppression of cancer cell drug resistance capability. Herein, we developed a theranostic polymer CP PG MT Gd that can sequentially target folate receptors (FR) onto cancer cell apical membrane at an early phase and exhibited late phase combinational chemotherapy through topoisomerase-I (TOPO-I) and dihydrofolate reductase (DHFR) inhibition synergistically, which resulted in inhibition of nucleic acid biosynthesis. This dual-acting self-targeted CP PG MT Gd polymer could effectively track the loaded chemotherapeutic agents (camptothecin–methotrexate) through MRI-tomography and eventually played a decisive role for subsequent dose-determination in real-time.A thorough comparative investigation on FR-targeting competence of CP PG MT Gd was executed with a folic acid (FOL) conjugated CP PG FL Gd (targeted system) and a nontargeted CP PG Gd polymers using human cervical cancer, HeLa (high FR-expression), and breast cancer MCF-7 (low FR-expression) cell lines. The incorporated Gd(III) chelate-complex in the CP PG MT Gd theranostic polymer displayed remarkable T 1 weighted MRI-proficiency with longitudinal specific relaxivity constant, r 1 = 21.85 mM–1 S–1. Therefore, the MRI-tracking proficiency and sequential targeting–chemotherapy switchable CP PG MT Gd theranostic system opened the way for precise multidrug codelivery at cancer site that might have attractive potential for diagnosis and decisive dose-determination in clinical implication.
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