Immune-stealth VP28-conjugated heparin nanoparticles for enhanced and reversible anticoagulation.

Heparins are a family of sulfated linear negatively charged polysaccharides that have been widely used for their anticoagulant, antithrombotic, antitumor, anti-inflammatory, and antiviral properties. Additionally, it has been used for acute cerebral infarction relief as well as other pharmacological actions. However, heparin's self-aggregated macrocomplex may reduce blood circulation time and induce life-threatening thrombocytopenia (HIT) complicating the use of heparins. Nonetheless, the conjugation of heparin to immuno-stealth biomolecules may overcome these obstacles. An immunostealth recombinant viral capsid protein (VP28) was expressed and conjugated with heparin to form a novel nanoparticle (VP28-heparin). VP28-heparin was characterized and tested to determine its immunogenicity, anticoagulation properties, effects on total platelet count, and risk of inducing HIT in animal models. The synthesized VP28-heparin trimeric nanoparticle was non-immunogenic, possessed an average hydrodynamic size (8.81 ± 0.58 nm) optimal for the evasion renal filtration and reticuloendothelial system uptake (hence prolonging circulating half-life). Additionally, VP28-heparin did not induce mouse death or reduce blood platelet count when administered at a high dosein vivo(hence reducing HIT risks). The VP28-heparin nanoparticle also exhibited superior anticoagulation properties (2.2× higher prothrombin time) and comparable activated partial thromboplastin time, but longer anticoagulation period when compared to unfractionated heparin. The anticoagulative effects of the VP28-heparin can also be reversed using protamine sulfate. Thus, VP28-heparin may be an effective and safe heparin derivative for therapeutic use.

Synthesis and Staphylococcus aureus biofilm inhibitory activity of indolenine-substituted pyrazole and pyrimido[1,2-b]indazole derivatives.

Staphylococcus aureus is a highly adaptable opportunistic pathogen that can form biofilms and generate persister cells, leading to life-threatening infections that are difficult to treat with antibiotics alone. Therefore, there is a need for an effective S. aureus biofilm inhibitor to combat this public health threat. In this study, a small library of indolenine-substituted pyrazoles and pyrimido[1,2-b]indazole derivatives were synthesised, of which the hit compound exhibited promising antibiofilm activities against methicillin-susceptible S. aureus (MSSA ATCC 29213) and methicillin-resistant S. aureus (MRSA ATCC 33591) at concentrations significantly lower than the planktonic growth inhibition. The hit compound could prevent biofilm formation and eradicate mature biofilms of MSSA and MRSA, with a minimum biofilm inhibitory concentration (MBIC50) value as low as 1.56 µg/mL and a minimum biofilm eradication concentration (MBEC50) value as low as 6.25 µg/mL. The minimum inhibitory concentration (MIC) values of the hit compound against MSSA and MRSA were 50 µg/mL and 25 µg/mL, respectively, while the minimum bactericidal concentration (MBC) values against MSSA and MRSA were > 100 µg/mL. Preliminary structure-activity relationship analysis reveals that the fused benzene ring and COOH group of the hit compound are crucial for the antibiofilm activity. Additionally, the compound was not cytotoxic to human alveolar A549 cells, thus highlighting its potential as a suitable candidate for further development as a S. aureus biofilm inhibitor.

Nature-Inspired Surface Structures Design for Antimicrobial Applications.

Surface contamination by microorganisms such as viruses and bacteria may simultaneously aggravate the biofouling of surfaces and infection of wounds and promote cross-species transmission and the rapid evolution of microbes in emerging diseases. In addition, natural surface structures with unique anti-biofouling properties may be used as guide templates for the development of functional antimicrobial surfaces. Further, these structure-related antimicrobial surfaces can be categorized into microbicidal and anti-biofouling surfaces. This review introduces the recent advances in the development of microbicidal and anti-biofouling surfaces inspired by natural structures and discusses the related antimicrobial mechanisms, surface topography design, material application, manufacturing techniques, and antimicrobial efficiencies.

Antibody-dependent cellular phagocytosis of tropomyosin receptor kinase C (TrkC) expressing cancer cells for targeted immunotherapy.

Conventional cancer therapies such as chemotherapy are non-selective and induce immune system anergy, which lead to serious side effects and tumor relapse. It is a challenge to prime the body's immune system in the cancer-bearing subject to produce cancer antigen-targeting antibodies, as most tumor-associated antigens are expressed abundantly in cancer cells and some of normal cells. This study illustrates how hapten-based pre-immunization (for anti-hapten antibodies production) combined with cancer receptor labeling with hapten antigen constructs can elicit antibody-dependent cellular phagocytosis (ADCP). Thus, the hapten antigen 2,4-dinitrophenol (DNP) was covalently combined with a cancer receptor-binding dipeptide (IYIY) to form a dipeptide-hapten construct (IYIY-DNP, MW = 1322.33) that targets the tropomyosin receptor kinase C (TrkC)-expressed on the surface of metastatic cancer cells. IYIY-DNP facilitated selective association of RAW264.7 macrophages to the TrkC expressing 4T1 cancer cells in vitro, forming cell aggregates in the presence of anti-DNP antibodies, suggesting initiation of anti-DNP antibody-dependent cancer cell recognition of macrophages by the IYIY-DNP. In in vivo, IYIY-DNP at 10 mg/kg suppressed growth of 4T1 tumors in DNP-immunized BALB/c mice by 45% (p < 0.05), when comparing the area under the tumor growth curve to that of the saline-treated DNP-immunized mice. Meanwhile, IYIY-DNP at 10 mg/kg had no effect on TrkC-negative 67NR tumor-bearing mice immunized with DNP. Tumor growth suppression activity of IYIY-DNP in DNP-immunized mice was associated with an increase in the anti-DNP IgG (7.3 × 106 ± 1.6 U/mL) and IgM (0.9 × 106 ± 0.07 U/mL) antibodies after five cycles of DNP treatment, demonstrated potential for hapten-based pre-immunization then treatment with IYIY-DNP to elicit ADCP for improved immunotherapy of TrkC expressing cancers.

Recent Emergence of Rhenium(I) Tricarbonyl Complexes as Photosensitisers for Cancer Therapy.

Photodynamic therapy (PDT) is emerging as a significant complementary or alternative approach for cancer treatment. PDT drugs act as photosensitisers, which upon using appropriate wavelength light and in the presence of molecular oxygen, can lead to cell death. Herein, we reviewed the general characteristics of the different generation of photosensitisers. We also outlined the emergence of rhenium (Re) and more specifically, Re(I) tricarbonyl complexes as a new generation of metal-based photosensitisers for photodynamic therapy that are of great interest in multidisciplinary research. The photophysical properties and structures of Re(I) complexes discussed in this review are summarised to determine basic features and similarities among the structures that are important for their phototoxic activity and future investigations. We further examined the in vitro and in vivo efficacies of the Re(I) complexes that have been synthesised for anticancer purposes. We also discussed Re(I) complexes in conjunction with the advancement of two-photon PDT, drug combination study, nanomedicine, and photothermal therapy to overcome the limitation of such complexes, which generally absorb short wavelengths.

Surfactant-Free Direct Access to Porphyrin-Cross-Linked Nanogels for Photodynamic and Photothermal Therapy.

Photosensitizing nanogels were obtained through a surfactant-free single-step protocol by using a porphyrin-based cross-linker for stabilizing self-assembled nanosized aggregates of thermoresponsive copolymers. Nanogels with varying amounts of porphyrin retained the singlet oxygen generation ability of the porphyrin core and were also capable of inducing temperature increase upon irradiation at 635 nm. Photoinduced killing efficiency was tested against three cell lines: human breast adenocarcinoma (MDA-MB-231 and MCF7) and pancreatic adenocarcinoma (AsPC-1) cells, and a predominant photodynamic mechanism at 450 nm and a mixed photodynamic and photothermal effect at 635 nm was observed. This innovative access to photosensitizing nanogels is a proof of concept, and opens new perspectives toward the preparation of optimized nanophotosensitizers.

Near-Infrared Activatable Phthalocyanine-Poly-L-Glutamic Acid Conjugate: Enhanced in Vivo Safety and Antitumor Efficacy toward an Effective Photodynamic Cancer Therapy.

We previously developed a new zinc(II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PG possessed high near-infrared (NIR) light absorptivity (λmax = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that 1-PG accumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose 1-PG (2 mg of Pc 1 equivalent/kg) induced a greater tumor volume reduction (-74 ± 5%) when compared to high dose ZnPc (8 mg/kg, -50 ± 12%). At higher treatment doses (8 mg of Pc 1 equivalent/kg), 1-PG reduced tumor volume maximally (-91 ± 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with 1-PG (both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of 1-PG as a useful photosensitizer candidate for clinical PDT.

Recent strategies to improve boron dipyrromethene (BODIPY) for photodynamic cancer therapy: an updated review.

BODIPYs are photosensitizers activatable by light to generate highly reactive singlet oxygen (1O2) from molecular oxygen, leading to tissue damage in the photoirradiated region. Despite their extraordinary photophysical characteristics, they are not featured in clinical photodynamic therapy. This review discusses the recent advances in the design and/or modifications of BODIPYs since 2013, to improve their potential in photodynamic cancer therapy and related areas.

Preclinical safety assessments of nano-sized constructs on cardiovascular system toxicity: A case for telemetry.

While nano-sized construct (NSC) use in medicine has grown significantly in recent years, reported unwanted side effects have raised safety concerns. However, the toxicity of NSCs to the cardiovascular system (CVS) and the relative merits of the associated evaluation methods have not been thoroughly studied. This review discusses the toxicological profiles of selected NSCs and provides an overview of the assessment methods, including in silico, in vitro, ex vivo and in vivo models and how they are related to CVS toxicity. We conclude the review by outlining the merits of telemetry coupled with spectral analysis, baroreceptor reflex sensitivity analysis and echocardiography as an appropriate integrated strategy for the assessment of the acute and chronic impact of NSCs on the CVS. Copyright © 2017 John Wiley & Sons, Ltd.

Near-infrared activatable phthalocyanine-poly-L-glutamic acid conjugate: increased cellular uptake and light-dark toxicity ratio toward an effective photodynamic cancer therapy.

In photodynamic therapy (PDT), the low absorptivity of photosensitizers in an aqueous environment reduces singlet oxygen generation efficiency and thereby decreases photosensitizing efficacy in biological conditions. To circumvent this problem, we designed a phthalocyanine-poly-L-glutamic acid conjugate (1-PG) made from a new phthalocyanine (Pc 1) monofunctionalized to allow adequate conjugation to PGA. The resulting 1-PG conjugate retained high absorptivity in the near-infrared (NIR) region at its λmax 675nm in an aqueous environment. The 1-PG conjugate demonstrated good singlet oxygen generation efficiency, increased uptake by 4 T1 breast cancer cells via clathrin-mediated endocytosis, and enhanced photocytotoxic efficacy. The conjugate also displayed a high light-dark toxicity ratio, approximately 1.5-fold greater than zinc phthalocyanine at higher concentration (10 µM), an important feature for the reduction of dark toxicity and unwanted side effects. These results suggest that the 1-PG conjugate could be a useful alternative for deep tissue treatment with enhanced anti-cancer (PDT) efficacy.

Secretion of N- and O-linked Glycoproteins from 4T1 Murine Mammary Carcinoma Cells.

Breast cancer is one of the most common cancers that affect women globally and accounts for ~23% of all cancers diagnosed in women. Breast cancer is also one of the leading causes of death primarily due to late stage diagnoses and a lack of effective treatments. Therefore, discovering protein expression biomarkers is mandatory for early detection and thus, critical for successful therapy. Two-dimensional electrophoresis (2D-E) coupled with lectin-based analysis followed by mass spectrometry were applied to identify potential biomarkers in the secretions of a murine mammary carcinoma cell line. Comparisons of the protein profiles of the murine 4T1 mammary carcinoma cell line and a normal murine MM3MG mammary cell line indicated that cadherin-1 (CDH), collagenase 3 (MMP-13), Viral envelope protein G7e (VEP), Gag protein (GAG) and Hypothetical protein LOC433182 (LOC) were uniquely expressed by the 4T1 cells, and pigment epithelium-derived factor (PEDF) was exclusively secreted by the MM3MG cells. Further analysis by a lectin-based study revealed that aberrant O-glycosylated CDH, N-glycosylated MMP-13 and LOC were present in the 4T1 medium. These differentially expressed N- and O-linked glycoprotein candidates, which were identified by combining lectin-based analysis with 2D-E, could serve as potential diagnostic and prognostic markers for breast cancer.

Targeted PDT agent eradicates TrkC expressing tumors via photodynamic therapy (PDT).

This contribution features a small molecule that binds TrkC (tropomyosin receptor kinase C) receptor that tends to be overexpressed in metastatic breast cancer cells but not in other breast cancer cells. A sensitizer for (1)O2 production conjugated to this structure gives 1-PDT for photodynamic therapy. Isomeric 2-PDT does not bind TrkC and was used as a control throughout; similarly, TrkC- cancer cells were used to calibrate enhanced killing of TrkC+ cells. Ex vivo, 1- and 2-PDT where only cytotoxic when illuminated, and 1-PDT, gave higher cell death for TrkC+ breast cancer cells. A 1 h administration-to-illumination delay gave optimal TrkC+/TrkC--photocytotoxicity, and distribution studies showed the same delay was appropriate in vivo. In Balb/c mice, a maximum tolerated dose of 20 mg/kg was determined for 1-PDT. 1- and 2-PDT (single, 2 or 10 mg/kg doses and one illumination, throughout) had similar effects on implanted TrkC- tumors, and like those of 2-PDT on TrkC+ tumors. In contrast, 1-PDT caused dramatic TrkC+ tumor volume reduction (96% from initial) relative to the TrkC- tumors or 2-PDT in TrkC+ models. Moreover, 71% of the mice treated with 10 mg/kg 1-PDT (n = 7) showed full tumor remission and survived until 90 days with no metastasis to key organs.

In vivo studies of nanostructure-based photosensitizers for photodynamic cancer therapy.

Animal models, particularly rodents, are major translational models for evaluating novel anticancer therapeutics. In this review, different types of nanostructure-based photosensitizers that have advanced into the in vivo evaluation stage for the photodynamic therapy (PDT) of cancer are described. This article focuses on the in vivo efficacies of the nanostructures as delivery agents and as energy transducers for photosensitizers in animal models. These materials are useful in overcoming solubility issues, lack of tumor specificity, and access to tumors deep in healthy tissue. At the end of this article, the opportunities made possible by these multiplexed nanostructure-based systems are summarized, as well as the considerable challenges associated with obtaining regulatory approval for such materials. The following questions are also addressed: (1) Is there a pressing demand for more nanoparticle materials? (2) What is the prognosis for regulatory approval of nanoparticles to be used in the clinic?

Comparative secretomic and N-glycoproteomic profiling in human MCF-7 breast cancer and HMEpC normal epithelial cell lines using a gel-based strategy.

BACKGROUND: Concurrent study of secretomic and glycoproteomic profiles in cancer cell lines represents an excellent approach for investigating cancer progression and identifying novel biomarker candidates. In this study, we performed a comparative secretomic and N-glycoprotein profiling from the secretions of normal human mammary epithelial cells (HMEpC) and the MCF-7 human breast cancer cell line. METHOD: We analyzed these cell lines using a combined methodology involving glycan-binding lectins and two-dimensional electrophoresis and identified several differentially secreted factors, including osteonectin and haptoglobin. RESULT: Notably, comparative analyses also revealed that MCF-7 cells produced differentially N-glycosylated forms of haptoglobin. CONCLUSION: The present data suggested that osteonectin and haptoglobin might have potential to be served as potential biomarkers for breast cancer. However, further investigation is needed to validate the findings.

Photodynamic characterization of amino acid conjugated 15(1)-hydroxypurpurin-7-lactone for cancer treatment.

This study aims to improve the photodynamic properties and biological effectiveness of 15(1)-hydroxypurpurin-7-lactone dimethyl ester (G2), a semisynthetic photosensitizer, for the PDT treatment of cancer. The strategy we undertook was by conjugating G2 with aspartic acid and lysine amino acid moieties. The photophysical properties, singlet oxygen generation, distribution coefficiency (Log D in octanol/PBS pH 7.4), and photostability of these analogues and their in vitro bioactivities such as cellular uptake, intracellular localization, and photoinduced cytotoxicity were evaluated. In addition, selected analogues were also investigated for their PDT-induced vasculature occlusion in the chick chorioallantoic membrane model and for their antitumor efficacies in Balb/C mice bearing 4T1 mouse mammary tumor. From the study, conjugation with aspartic acid improved the aqueous solubility of G2 without affecting its photophysical characteristics. G2-Asp showed similar in vitro and in vivo antitumor efficacies compared to the parent compound. Given the hydrophilic nature of G2-Asp, the photosensitizer is a pharmaceutically advantageous candidate as it can be formulated easily for systemic administration and has reduced risk of aggregation in vascular system.

BODIPY dyes in photodynamic therapy.

BODIPY dyes tend to be highly fluorescent, but their emissions can be attenuated by adding substituents with appropriate oxidation potentials. Substituents like these have electrons to feed into photoexcited BODIPYs, quenching their fluorescence, thereby generating relatively long-lived triplet states. Singlet oxygen is formed when these triplet states interact with (3)O(2). In tissues, this causes cell damage in regions that are illuminated, and this is the basis of photodynamic therapy (PDT). The PDT agents that are currently approved for clinical use do not feature BODIPYs, but there are many reasons to believe that this situation will change. This review summarizes the attributes of BODIPY dyes for PDT, and in some related areas.

Inhibition of human cytochrome P450 enzymes by Bacopa monnieri standardized extract and constituents.

Bacopa monnieri and the constituents of this plant, especially bacosides, possess various neuropharmacological properties. Like drugs, some herbal extracts and the constituents of their extracts alter cytochrome P450 (CYP) enzymes, causing potential herb-drug interactions. The effects of Bacopa monnieri standardized extract and the bacosides from the extract on five major CYP isoforms in vitro were analyzed using a luminescent CYP recombinant human enzyme assay. B. monnieri extract exhibited non-competitive inhibition of CYP2C19 (IC50/Ki = 23.67/9.5 µg/mL), CYP2C9 (36.49/12.5 µg/mL), CYP1A2 (52.20/25.1 µg/mL); competitive inhibition of CYP3A4 (83.95/14.5 µg/mL) and weak inhibition of CYP2D6 (IC50 = 2061.50 µg/mL). However, the bacosides showed negligible inhibition of the same isoforms. B. monnieri, which is orally administered, has a higher concentration in the gut than the liver; therefore, this herb could exhibit stronger inhibition of intestinal CYPs than hepatic CYPs. At an estimated gut concentration of 600 µg/mL (based on a daily dosage of 300 mg/day), B. monnieri reduced the catalytic activities of CYP3A4, CYP2C9 and CYP2C19 to less than 10% compared to the total activity (without inhibitor = 100%). These findings suggest that B. monnieri extract could contribute to herb-drug interactions when orally co-administered with drugs metabolized by CYP1A2, CYP3A4, CYP2C9 and CYP2C19.

Ruthenium(II) polypyridyl complexes as emerging photosensitisers for antibacterial photodynamic therapy.

Photodynamic therapy (PDT) has recently emerged as a potential valuable alternative to treat microbial infections. In PDT, singlet oxygen is generated in the presence of photosensitisers and oxygen under light irradiation of a specific wavelength, causing cytotoxic damage to bacteria. This review highlights different generations of photosensitisers and the common characteristics of ideal photosensitisers. It also focuses on the emergence of ruthenium and more specifically on Ru(II) polypyridyl complexes as metal-based photosensitisers used in antimicrobial photodynamic therapy (aPDT). Their photochemical and photophysical properties as well as structures are discussed while relating them to their phototoxicity. The use of Ru(II) complexes with recent advancements such as nanoformulations, combinatory therapy and photothermal therapy to improve on previous shortcomings of the complexes are outlined. Future perspectives of these complexes used in two-photon PDT, photoacoustic imaging and sonotherapy are also discussed. This review covers the literature published from 2017 to 2023.

PDADMAC/Alginate-Coated Gold Nanorod For Eradication of Staphylococcus Aureus Biofilms.

Introduction: Over 75% of clinical microbiological infections are caused by bacterial biofilms that grow on wounds or implantable medical devices. This work describes the development of a new poly(diallyldimethylammonium chloride) (PDADMAC)/alginate-coated gold nanorod (GNR/Alg/PDADMAC) that effectively disintegrates the biofilms of Staphylococcus aureus (S. aureus), a prominent pathogen responsible for hospital-acquired infections. Methods: GNR was synthesised via seed-mediated growth method, and the resulting nanoparticles were coated first with Alg and then PDADMAC. FTIR, zeta potential, transmission electron microscopy, and UV-Vis spectrophotometry analysis were performed to characterise the nanoparticles. The efficacy and speed of the non-coated GNR and GNR/Alg/PDADMAC in disintegrating S. aureus-preformed biofilms, as well as their in vitro biocompatibility (L929 murine fibroblast) were then studied. Results: The synthesised GNR/Alg/PDADMAC (mean length: 55.71 ± 1.15 nm, mean width: 23.70 ± 1.13 nm, aspect ratio: 2.35) was biocompatible and potent in eradicating preformed biofilms of methicillin-resistant (MRSA) and methicillin-susceptible S. aureus (MSSA) when compared to triclosan, an antiseptic used for disinfecting S. aureus colonisation on abiotic surfaces in the hospital. The minimum biofilm eradication concentrations of GNR/Alg/PDADMAC (MBEC50 for MRSA biofilm = 0.029 nM; MBEC50 for MSSA biofilm = 0.032 nM) were significantly lower than those of triclosan (MBEC50 for MRSA biofilm = 10,784 nM; MBEC50 for MRSA biofilm 5967 nM). Moreover, GNR/Alg/PDADMAC was effective in eradicating 50% of MRSA and MSSA biofilms within 17 min when used at a low concentration (0.15 nM), similar to triclosan at a much higher concentration (50 µM). Disintegration of MRSA and MSSA biofilms was confirmed by field emission scanning electron microscopy and confocal laser scanning microscopy. Conclusion: These findings support the potential application of GNR/Alg/PDADMAC as an alternative agent to conventional antiseptics and antibiotics for the eradication of medically important MRSA and MSSA biofilms.

Bispecific antibodies for targeted delivery of anti-cancer therapeutic agents: A review.

Monospecific antibodies have been utilised increasingly for anti-cancer drug targeting owing to their ability to minimise off-target toxicity by binding specifically to a tumour epitope, hence selectively delivering drugs to the tumour cells. Nevertheless, the monospecific antibodies only engage a single cell surface epitope to deliver their drug payload. Hence, their performance is often unsatisfactory in cancers where multiple epitopes need to be engaged for optimal cellular internalisation. In this context, bispecific antibodies (bsAbs) that simultaneously target two distinct antigens or two distinct epitopes of the same antigen offer a promising alternative in antibody-based drug delivery. This review describes the recent advances in developing bsAb-based drug delivery strategies, encompassing the direct conjugation of drug to bsAbs to form bispecific antibody-drug conjugates (bsADCs) and the surface functionalisation of nanoconstructs with bsAbs to form bsAb-coupled nanoconstructs. The article first details the roles of bsAbs in enhancing the internalisation and intracellular trafficking of bsADCs with subsequent release of chemotherapeutic drugs for an augmented therapeutic efficacy, particularly among heterogeneous tumour cell populations. Then, the article discusses the roles of bsAbs in facilitating the delivery of drug-encapsulating nanoconstructs, including organic/inorganic nanoparticles and large bacteria-derived minicells, that provide a larger drug loading capacity and better stability in blood circulation than bsADCs. The limitations of each type of bsAb-based drug delivery strategy and the future prospects of more versatile strategies (e.g., trispecific antibodies, autonomous drug delivery systems, theranostics) are also elaborated.