| Cancer is one of the major disease worldwide and taking millions of lives every year.Researcher are focusing on the development of new techniques for cancer treatment that can target specific kind of tumor cells.The common available treatments for cancer treatment are,radiation therapy,surgery,and chemotherapy.Chemotherapy is most widely used for cancer treatment and to deliver the chemotherapeutics drug,various drug delivery systems have been reported such as polymeric supramolecular,biomolecular drug carriers etc.The conventional systems to site specific drug delivery are limited by their non-targeted properties,metabolism of cargo during circulation,solubility of drug molecules,and cytotoxic nature of drug carriers.To overcome this problem,we designed the new drug carriers from supramolecules in combination with biomolecules.Cyclodextrin is one of the well-known enzymatically degraded product of carbohydrate(starch).CDs belong to the family of cage molecules;the core structure is composed of a dimensionally stable hydrophobic cavity that can trap or encapsulate the small molecules.Besides the hydrophilic nature of the outer surface,the cavity is relatively apolar that creates a hydrophobic microenvironment and make them suitable for interaction with guest molecules.The nomenclature of parent CD compounds has been given on the basis of numbers of glucose units present in their structure such as 6 glucose units containing CD referred as ?-CD,the 7-glucose ring containing CD is known as ?-CD,and ?-CD contains 8 glucose units.In the pharmaceutical industry,CDs offer a good deal for more functionality,stabilization,and solubilization.Besides conventional applications,CDs play an active role in advanced drug delivery systems.Supramolecular cross-linking with biomolecules is an interesting area for advance research for various purposes of drug deliveries.The conjugation with target moieties can use for targeting specific kind of cells(particularly cancer)and site-specific drug diseases.Moreover,CD based supramolecular biomaterials have been used in biomedical engineering,tissue regeneration and controlled drug delivery systems.To utilize the drug encapsulation properties of CDs and targeting properties of biomolecules inspires us to design this research.In conventional way,we firstly designed the surface modification of NSPs for biomedical and site-specific applications.Furthermore,we designed the crosslinked copolymers which contains supramolecular section along with covalently attached biomolecules.The purpose of these experiments was to develop advanced drug delivery carriers for pharmaceutical and biomedical applications.Three kinds of drug carriers have been reported in this research by three different methods,namely,surface modification,copolymer formation,and branched polymer fabrication,for site specific drug delivery applications.1.Biofunctionalization of Cyclodextrin NanospongesThe cyclodextrin nanosponges(CD-NSPs)are highly porous crosslinked polymers with potential applications in the delivery of small and macro-molecular therapeutic agents,unfortunately the inherent lack of cellular binding ability of CD-NSPs had limited applications in drug delivery.The incorporation of drugs within the structure either as inclusion complexes or as non-inclusion is a characteristic feature of NSPs.Interestingly,the encapsulation properties of NSPs could be used to treat specific diseases such as cancer,cardiovascular disorders by direct delivery of the drug into the site of action,but the applications are unfortunately hampered in many cases by their non-binding nature and lack of interactions with specific proteins or cell membranes.The post/pre-modification of polymers with biomolecules or targeting moiety is widely applied to improve the interaction with cells or receptors.Meanwhile,surface modification of drug carriers can alter the cellular uptake and the therapeutic properties of nanocarrier systems.CHS was selected which is a universal biomolecule that plays various important roles in the mammalian cellular process with both hydrophilic and lipophilic properties.As a starting step,CDs crosslinked polymer,namely CD-NSP was synthesized and the surface of NSP particles was functionalized by using cholesterol(CHS).The spectroscopic,microscopic,thermogravimetric,and chromatographic techniques were used for confirmation of successful synthesis and changes in physicochemical properties.Moreover,?-CD-NSP was found to be safe in cytotoxicity assay.Doxorubicin(Dox)was selected as a model drug for drug adsorption and drug release properties determination of CHS grafted ?-CD-NSP.The cellular uptake of ?-CD-NSP was found to be enhanced after CHS modification confirmed by confocal laser scanning microscopy(CLSM).Thus,proposed CHS modified ?-CD-NSP system could be used as a site-specific drug delivery carrier.In conclusion,the ?-CD-NSP has been successfully synthesized and surface biofunctionalized with CHS for improvement in the therapeutic and drug delivery efficacy of CD-NSP.The CHS expression on CD-NSP has been confirmed by various spectroscopic and thermal analytical techniques.The CHS modification has changed the surface properties of ?-CD-NSP in many ways.The results have demonstrated that CHS grafting can enhance the Dox adsorption because of hydrophobic charge on surface.In addition,the biofriendly nature of surface modified CD-NSP was verified with cell viability assay.The cellular uptake of the Dox loaded ?-CD-NSP showed better internalization in cells due to the interaction between CHS and cell membrane.It is very much of interest that surface engineered CD-NSP could be used as a carrier for low water soluble small drug molecules to improve the solubility and bioavailability in site specific drug delivery systems.The research published in Carbohydrate Polymers Carbohydrate Polymers,2018,(190): 23-30(IF=4.881).2.Fabrication of ?-CD-SA copolymerCopolymerization of CDs is an interesting area to fabricate sophisticated and advanced drug carriers with advanced properties for site specific drug delivery applications.The functionalization of CDs by crosslinking with bioactive moiety improves the therapeutic properties.5-acetyl neuraminic acid or specially called sialic acid(SA)was selected as a biomolecule for copolymerization.SA is well known for effectively block improvement in the antigenic site or recognition marker on the cell surface and protection them from degradation by surrounding immune system.SA is anionic monosaccharide 9-carbon sugar commonly located at the cell surface and can be used as a ligand to target and detection of various type cancer cells.The role of SA in the cells is participant in carbohydrate-protein interaction to medicate recognition phenomenon.SA has properties to bind with sialic acid binding immunoglobulin like lectin(Siglic)family which are immunomodulatory receptor expressed by immune cells.Moreover,SA has been previously used for biochemical engineering purpose of cell surface.Subsequently,the CDs with biomolecules were crosslinked directly with diphenyl carbonate(DPC)as a crosslinker by single step chemical crosslinking reaction for targeted drug delivery applications,instead of using conventional method of surface modification.The as-synthesized copolymer has complexation properties,which could cover the drug within the structure and deliver to the site of action.The well-known inclusion capability of ?-CD and targeted efficacy of SA made it more appropriate for targeted drug delivery.The copolymer was characterized using a wide range of spectroscopic and microscopic techniques such as synchrotron radiation based FTIR spectroscopy,differential scanning calorimetry,thermogravimetric analysis,and powder X-ray diffraction.The surface area and porosity were calculated by using Nitrogen adsorption method.Doxorubicin(Dox)was selected as a model drug to evaluate the loading efficiency and cellular penetration ability of the copolymer.The copolymer showed high adsorption towards Dox with no significant cytotoxic effects on He La cells as proved by cell viability assay.High cellular penetration of Dox loaded copolymer was also recorded by confocal microscopy when compared with free Dox in He La cells at 4 h of exposure.The synthesis of the ?-CD-SA copolymer was inspired by the high drug encapsulation and inclusion efficiency of ?-CD for drug molecules and site-specific targeting properties of SA.The copolymer possesses the amorphous nature and better thermal stability when compared with ?-CD or SA.Cell viability assay demonstrates that ?-CD-SA copolymer does not have a significant cytotoxic effect on He La cells.What's more,the obtained copolymer has good drug loading capacity for Dox and high cellular penetration ability as compare to ?-CD.In summary,integrated with both of,the loading capacity of CDs and the targeting function of SA,the resultant copolymer can be a novel effective carrier for targeted drug delivery.Thus,?-CD-SA copolymer could be a useful carrier for targeted drug delivery of cancer and has the potential for further investigation in viral and nervous disease due to the targeting ability of SA.The research published in Arabian Journal of Chemistry,2017,https://doi.org/10.1016/j.arabjc.2017.11.011(IF=4.551).3.Branched Polymer of Hyaluronic Acid and ?-cyclodextrinThe water solubility is an important concern with CD based crosslinked drug carriers.To overcome this problem,the polymer of CD molecules and hyaluronic acid(HA)biomolecule was fabricated by chemical crosslinking.The well-known biomolecules Hyaluronic Acid(HA),composed of D-glucuronic acid and D-glucosamine,remains as a major constituent of extracellular matrix.Along with drug carrier,HA is essential for tissue organization,proper cell growth,regulation of cell adhesion,cell proliferation, migration,differentiation and,organ structure stability.Besides these functions,many types of tumor cells overexpress CD44 and RHAMM receptors which are specific to bind with HA for regulation of angiogenesis.As an important combination of molecules as a copolymer,researchers are attracted to develop a new way to treat the disease with smarter drug carriers.For modification,HA has multiple functional groups to interact with other chemical moieties,drugs or genes and ?-CD also has free hydroxyl group for combination with various molecules.The combination of these molecules could be a new area to produce advance drug carriers,especially if CD cavity can function as independent host sites with target-oriented biomolecules.In the polymer,HA functioned as a backbone while CD molecules were attached over the long chain via ester bonding.The hyaluronic acid-?-cyclodextrin branched polymer(HA-?-BP)was water soluble in nature and characterized by various analytical techniques.Additionally,polymer exhibited high cell viability,cellular binding ability and cellular uptake.Moreover,the HA-?-CD-BP showed high encapsulation capacities of vitamin E(VE)and the inclusion supramolecular complexes changed insoluble VE into water soluble.The surface of ?-CD-NSP was functionalized for high cellular binding and site-specific drug delivery,which can open new directions for ?-CD-NSP for targeted or sitespecific drug delivery applications.While,two novel CD biomolecules polymer have been fabricated by covalent crosslinking instead of surface modification and validated for their advance properties for drug deliveries.Alternation of polymer has grown to be productive area in biomedicine and pharmaceutical industry to produce advanced functional polymers.In summary,we have successfully prepared HA-?-CD-BP which contains supramolecular host with biomolecules.This polymer can be dissolved into water with hydrophilic HA block and low water soluble ?-CD block.The effects of building block on morphology,thermal nature,drug encapsulation,and drug loading have been systematically studied.The CDs units were grafted on long chain biomolecules which was confirmed with HPGPC.It has been demonstrated that this HA-?-CD branched polymer is biocompatible and have high tendency to attach on cells.This supramolecular complex can be useful as biodegradable,and cell-specific targetable carrier for intracellular delivery of hydrophobic drugs for treatment of disease like cancers.The aim of this study was to synthesize CD based drug carriers and biofunctionalization of previous reported carriers for pharmaceutical and biomedical applications.Firstly,we biofunctionalised the ?-CD NSP which was previously reported by our lab.We developed single step techniques to functionalized the surface of ?-CD-NSP using CHS.After the surface modification,the physicochemical properties of ?-CD-NSP changed significantly and became target-oriented drug carriers.Moreover,?-CD-NSP showed high cell viability and high cellular binding affinity of ?-CD-NSP.In future this system can be explored for solubility enhancement of small drug molecules and their sitespecific drug delivery applications.In biomaterial development,supramolecular polymer in combination with biomolecules could lead major role for advancement of drug carriers with high drug payload and target specific tissues.So,we tried to develop new kind of drug carrier which contain supramolecular properties along with biological functions.To do so,SA and HA were selected as biomolecules for fabrication with CD.For characterization part,new chromatographic methods were developed for detection and quantification of biomolecules attached overt the CDs.These supramolecular copolymers successfully characterized by spectroscopic,microscopic,thermogravimetric,and crystallographic techniques.Interestingly,the supramolecular biomaterials were found safe for biomedical applications in cell viability assay.The cellular experiments showed high cellular penetration which was confirmed with CLSM.These supramolecular biomolecules could be a new direction for targeted drug delivery applications,especially in case of cancer.Moreover,these materials explored in both directions such as biomolecular part used for targeting applications and supramolecular part was explored for solubility enhancement study of poorly water-soluble drugs.For this purpose,VE was selected as ideal drug molecules and host-gust inclusion was formed in different ratio to optimize the solubility of VE.HA-?-CD inclusion complexes significantly enhanced the water solubility of VE.Interestingly,HA as biomolecules in the polymer enhance the biocompatibility and make it more suitable for biomedical and cosmetic applications.In summary,we have modified the CDs with surface modification as a conventional technique.In second part,SA was linked with CDs in form of copolymer,and finally CD was grafted on long chain HA biomolecules to develop new drug carriers.After successful characterization,the drug carriers found safe for drug delivery applications.As a preliminary part,cellular uptake studies have been conducted and validated for targeted drug carriers.These obtained carriers could be new direction in site specific drug delivery. |
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