A site-specific, stimuli-responsive nanocarrier has been synthesized by conjugating folate, magnetic particles and doxorubicin to the backbone of norbornene polymer. Monomers, namely, cis-5-norbornene-6-(diethoxyphosphoryl)hexanote (mono 1), norbornene grafted poly(ethyleneglycol)-folate (mono 2), and norbornene derived doxorubicin (mono 3) are carefully designed to demonstrate the smart nanorcarrier capabilities. The synthesis and complete characterization of all three monomers are elaborately discussed. Their copolymerization is done by controlled/living ring-opening metathesis polymerization (ROMP) to get the triblock copolymer PHOS-FOL-DOX. NMR spectroscopy and gel permeation chromatography confirm the formation of the triblock copolymer, while FT-IR spectroscopy, thermogravimetric analysis, along with transmission electron microscope confirm the anchoring of iron particle (Fe3O4) to the PHOS-FOL-DOX. Drug release profile shows the importance of having the hydrazone linker that helps to release the drug exactly at the mild acidic conditions resembling the pH of the cancerous cells. The newly designed nanocarrier shows greater internalization (about 8 times) due to magnetic field. Also, increased intracellular DOX release is observed due to the folate receptor. From these results, it is clear that PHOS-FOL-DOX has the potential to act as a smart nanoreservoir with the magnetic field guidance, folate receptor targeting, and finally pH stimulation.

A unique polymersome from amphiphilic, norbornene-derived thiobarbiturate homopolymers (NDTH) and its application as nanocarrier for cancer therapy are elaborately discussed. Various experiments like structural characterizations, control studies, cell viability studies, encapsulation studies, and MTT assay against 4T cancer cells are performed on these NDTH polymersomes to substantiate our claims. All of these results demonstrate that these self-assembled NDTH vesicles have great scope in the world of medicine, and they also symbolize promising carriers for the stimuli-triggered intracellular delivery of hydrophobic drugs. ■ INTRODUCTIONThe field of polymer vesicles (polymersomes) has the phenomenal record of consistent development over the last ten years. 1−3 The ability of amphiphilic block copolymers to self-assemble in selective solvents has been widely studied. 4 The self-assembled polymersomes are at the forefront of this nanotechnological revolution. 5−10 The current research theme of soft-nanotechnology is using polymersomes in the medical applications as nontoxic and targeted drug-delivery agents. 11 Though several types of nanocarriers have been proposed for biomedical purposes, 12,13 polymersomes (structures similar to lipid vesicles) represent an excellent candidate for medical applications. 14−16 These structures are more stable than liposomes but retain their low immunogenicity. But, we are here very specific among the polymersomes formed by the self-assembly of amphiphilic homopolymers, 17−21 for their fundamental perspectives along with their potential applications in drug delivery, nanotechnology and as model systems of biomembranes. 22−27 Self-assembly due to the strong hydrogen bonding nature, remains a subject of interest in the field of supramolecular chemistry. 28 Pioneering work in recognition-induced polymersomes (RIPs) are well-known in the literature. These RIPs are spontaneously formed from a threepoint hydrogen bonding recognition dyads. However, these recognition sensitive structures cannot be used in biomedical applications, due to the complex synthesis and the use of nonpolar media.Living ring-opening metathesis polymerization (ROMP) is more attractive due to the exceptional functional group tolerance of the Grubbs' catalyst employed in the polymerization process. 29−37 Here we have come up with a pH-and lipidsensitive polymersomes from a new molecular architecture, an amphiphilic, norbornene-derived thiobarbiturate homopolymers, NDTH. On the basis of the hydrophobicity and hydrophilicity of the solvent, the molecular orientation of NDTH is systematically modified. The role of hydrophilic headgroup is enacted by the thiobarbiturate functionality of each monomer unit in NDTH while the norbornene backbone behaves as a hydrophobic moiety. Polymersomes formed by the hydrophilic thiobarbiturate head groups attached to each repeating unit of the hydrophobic norbornene backbone will have greater stability and also are capable of spontaneously responding to their environmental conditions, s...

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 ...

Biocompatible nanocarriers conjugated with magnetic nanoparticle, doxorubicin and poly(ethylene oxide) (PEG) motif have been designed (PVLPEG-PVLDOXI-PCL-PHOS) to create a magnetic vector under magnetic field. Acylhydrazine linker is used to release the drug exactly at the mild acidic conditions resembling the pH of the cancerous cells. All the monomers and polymers are characterized carefully by the routine analytical techniques. Thermogravimetric analysis (TGA), FT-IR spectroscopy and scanning electron microscope (SEM) techniques are employed to confirm the anchoring of iron particle (Fe 3 O 4 ) to the PVLPEG-PVLDOXI-PCL-PHOS. Reservoir capabilities of the newly designed biodegradable nanocarrier are tested by both dynamic light scattering (DLS) and transmission electron microscopy (TEM). Drug release profile from nanocarrier is monitored by fluorimeter. The release profile shows the importance of having the acylhydrazine linker that helps to release the drug at the mild acidic conditions similar to cancerous cells. Confocal laser scanning microscopy (CLSM) and flow cytometry studies on 4T cells indicate that nanocarriers from PVLPEG-PVLDOXI-PCL-PHOS polymer are internalized efficiently. It is very interesting to note that the nanocarriers have exhibited both biologically and magnetically targeting abilities toward 4T cells in vitro.

Pendent functionalization of biodegradable polymers provides unique importance in biological applications. In this work, we have synthesized a polymeric nanocarrier for the controlled release of the anticancer drug doxorubicin (DOXI). Inspired by the pH responsiveness of acylhydrazine bonds along with the interesting self-assembly behavior of amphiphilic copolymers, this report delineates the development of a PEG-SS-PCL-DOXI copolymer consisting of DOXI, PEG, and a caprolactone backbone. First, the inclusion of a PEG moiety in the copolymer helps to achieve biocompatibility and aqueous solubility as well as a prolonged circulation time of the nanocarrier. Second, an acid-sensitive acylhydrazine-based linkage is chosen to attach DOXI to trigger sustained drug release, whereas the inclusion of an enzymatically cleavable disulfide linkage in the backbone adds to the advantage of backbone biodegradability at the intracellular level.

The newly developed polymeric nanocarrier could open a new avenue for cancer therapy, due to its unique design as well as, most importantly, its biocompatible and biodegradable nature.

Molecular imaging along with combinations of imaging modalities can provide a thorough understanding of disease, in particular, tumors. Magnetic resonance imaging (MRI) offers exceptional tissue contrast and resolution; whereas optical imaging provides high sensitivity. Hence a norbornene based copolymer (Nor-Cob-Py-Fol) is reported in this paper as a dual-imaging agent. Nor-Cob-Py-Fol having Co2+ complex, pyrene and poly­(ethylene glycol) derived folate, have been synthesized using ring-opening metathesis polymerization (ROMP). All the monomers and polymers are characterized by 1H NMR, IR, GPC, and TGA techniques. The morphology of the copolymer nanoaggregates has been evaluated with DLS, TEM, and SEM techniques. The functionalization of Co2+ to the polymer is monitored by FTIR, 1H NMR, and 13C NMR spectroscopy. Furthermore, the presence of Co2+ in the nanoaggregates is confirmed by the EDX (SEM) technique. To prove the MRI capabilities nature of copolymer nanoaggregates, NMR experiment is performed at room temperature. Cell viability studies suggest the biocompatibility nature of the copolymer. Flow cytometry as well as epifluoroscence microscope experiments clearly demonstrate the dual-imaging ability of the newly designed copolymer. The much higher relaxivity ratio (r 2/r 1) of the present method clearly establishes the superiority of our system as one of the best contrast agents known to the practitioners of magnetic resonance imaging.

A multifunctional stimuli-responsive nanotheranostic agent provides huge benefits in nanomedicine by combining both the diagnostic agent and the drug molecule in a single system. This nanosystem is capable of doing multiple tasks, for example, diagnosis, drug delivery, and monitoring the therapeutic response. Hence, theranostic agents are expected to play a significant role in personalized medicine. Herein, a new class of nanotheranostic agents, Pnr-Cbt-Cpt-Pg-Bn, is proposed for the effective delivery of camptothecin. This new class of polymer has been functionalized with a superparamagnetic norbornene cobalt unit for its use in magnetic resonance imaging (MRI). The NMR one-dimensional image confirms the MRI capability of this nanotheranostic agent. This is further modified with the poly(ethylene glycol)–biotin moiety for biocompatibility and site-specificity. The uniqueness of the design is confirmed by an in vitro study where a greater uptake of the nanotheranostic agent is observed when compared with free drugs. Hence, this new class of copolymer shows improved potential as nanotheranostic agents in drug delivery.