Lipid Drug Conjugates Research Articles

Nanoscale lipid-methylprednisolone conjugates: Effective anti-inflammatory, antioxidant, and analgesic agents

In this study, we have investigated new lipid-drug conjugates (LDCs) of methylprednisolone. Methylprednisolone is a corticosteroid, used for the potential treatment of inflammatory diseases. The LDCs 1–2; methylprednisolone palmitate (1) and methylprednisolone palmityl carbonate (2), were designed by conjugating a C16 aliphatic chain via an ester or carbonate bond, respectively. Their structures were comprehensively characterized using mass spectrometry, nuclear magnetic resonance spectroscopy, and infrared spectroscopy. These LDCs 1–2 were subsequently formulated into nanoscale particles (NPs) using ethanol injection method. Hydrogenated soybean phosphatidylcholine (HSPC) and tween-80 served as excipients in the NPs formulation. Characterization via dynamic light scattering, scanning electron microscopy, and atomic force microscopy confirmed the formation of spherical NPs with a diameter ranging from 100 to 120 nm. The LDCs NPs 1–2 exhibited excellent stability for about a month, with good polydispersity (around 0.2) and a negative zeta potential between −20 mV and −34 mV. Encapsulation efficiency of the LDCs within the LDCs NPs 1–2 surpassed 90 %, as determined by HPLC analysis. In vitro cytotoxicity studies utilizing LPS-activated THP-1 cells demonstrated no adverse effects associated with LDCs NPs 1–2 at concentrations up to 100 μg/mL. Furthermore, the LDCs NPs 1–2 effectively retained the anti-inflammatory activity, as evidenced by the suppression of IL-1β, TNF-α, and MCP-1 secretion in LPS-stimulated THP-1 cells. The therapeutic potential of these LDCs NPs 1–2 was further evaluated in rat intervertebral disc-derived nucleus pulposus cells (NPCs). Curative and preventive treatment regimens with the free drug and LDCs NPs 1–2 were employed. Quantitative PCR analysis revealed a significant downregulation of pain and inflammation markers (Substance P and COX-2) along with a concomitant upregulation of antioxidant markers (GPX1, PRDX1, and SOD1) in NPCs treated with both the drug and LDCs NPs 1–2 compared to oxidative stress-induced and control NPCs. Our novel LDCs NPs 1–2 exhibited promising therapeutic potential for treating inflammatory and pain related complications, (including intervertebral disc degeneration). This promise stems from their multifaceted properties, encompassing anti-inflammatory, antioxidant, and analgesic effects. Further research is warranted to fully explore LDCs NPs 1–2 as potential drug candidates in future pre-clinical and clinical trials.

Drug Delivery System That Self-Emulsify: Transportation of Drug From Gut to Target Organs

Microemulsions are highly popular for their specific uses, including vivid applications and this is due to their special properties, which include very high interfacial interactions with demonstrated stability from a thermodynamics point of view, and on the other hand, also very low interfacial tension, which is required to solubilize highly immiscible dispersions. This review’s goal is to briefly outline potential uses of micro-emulsion systems, their uses, limitations and possible in-vitro and in-vivo techniques. To characterise such dispersion systems, it is commonly known that adding the right surfactant or surfactant mixture can combine large amounts of two non-dissolving-target liquids, such as water and oil, into a single phase that is macroscopically homogeneous but microscopically heterogeneous. Owing to the advantages of lymph drug delivery, the drug-lipid conjugates, when they enter the lymph route, become an ideal approach for enhancing the absorption of such drugs to combat metastatic cancers of the lymph nodes and their drainage to specific organ systems where the cancer is already spread. As the route of lymph delivery is important where a tumor has already been cancerous, this formulation approach has distinct opportunities to transport needy molecules to cancerous sites in various organs, which also includes the lymph nodes. This review, particularly, lays more stress on an overview of microemulsions in general, the in-vivo and in-vitro characterization methods and potential applications related to target drug delivery via the lymphatic circulatory system.

Lipid Drug Conjugates in Pharmaceutical Formulations and Drug Delivery Systems

Abstract: Drugs that have been covalently altered with lipids are known as lipid-drug conjugates. Drug characteristics are altered and their lipophilicity is increased when lipids are conjugated to drug molecules. The conjugates exhibit a number of benefits, including increased oral bioavailability, improved lymphatic targeting, improved tumor targeting, and reduced cytotoxicity. Different conjugation techniques and chemical bridges can be utilized to create lipid-drug conjugates depending on the chemical makeup of medicines and lipids. For lipid-drug conjugates to function at their best, linkers and/or conjugation techniques are essential. They control how medications are released from lipid-drug conjugates. The numerous lipids utilized to make lipid-drug conjugates and the various conjugation techniques are outlined in this article. Although these conjugates can be delivered without a delivery vehicle, many of them are put into suitable delivery techniques. Drug loading into lipophilic parts of vehicles can be considerably improved by the lipid component in the conjugates, leading to combinations with significant drug content and superior stability.

Cysteinylprolyl ester-mediated drug release from a lipid–drug conjugate

For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl ester (CPE) system used in peptide thioester synthesis, which normally requires basic conditions, for use as an self-immolative linker and release device for a lipid-gemcitabine conjugate. To improve release under physiological conditions for medical application, a methyl group at the α-position of cysteine on the CPE unit was incorporated in anticipation of the Thorpe-Ingold effect. As a result, Ac-Gly-(α-Me)Cys(SH)-Pro-gemcitabine 11 drastically promoted the release of gemcitabine in comparison with Ac-Gly-Cys(SH)-Pro-gemcitabine 10. Furthermore, in the presence of bovine serum albumin and/or 2-mercaptoethanesulfonic acid, the gentle and continuous release of gemcitabine from the lipid–gemcitabine conjugate 16 was achieved. In addition to gemcitabine, this method could allow high clearance drugs, including nucleic acid and prostacyclin derivatives, to maintain their biological activity long enough to become effective.

Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth.

Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib's angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.

"In-silico Design and Development of Novel Hydroxyurea Lipid Drug Conjugates for Breast Cancer Therapy Targeting PI3K/AKT/mTOR Pathway".

Hydroxyurea (HU) has shown promise in breast cancer treatment, but its hydrophilic nature limits its efficacy. Therefore, conjugating HU with lipids could increase its liphophilicity and improve its cellular uptake, leading to increased efficacy and reduced toxicity. The PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer not only because it is the second most frequently altered pathway after p53, but also because it serves as a convergence point for many stimuli. The aim of this study is to design and develop novel hydroxyurea lipid drug conjugates for breast cancer therapy targeting the PI3K/Akt/mTOR pathway using in-silico and in-vitro approaches. The conjugates are designed and docked with the proteins selected for each target like PI3K (PDB ID;2JDO), AKT (PDB ID;3APF), mTOR (PDB ID;4JST). The conjugates with higher docking scores are taken for ADME studies and molecular dynamics. Stearic, lauric, palmitic, myristic and linolenic acids have been used for the conjugation. The conjugates are synthesized and characterized. The HLB calculation and partition coefficient are carried out to find the improvement in liphophilicity of the conjugates compared to hydroxyurea. Finally, the in-vitro cytotoxicity studies are performed with MCF -7 cell lines and the compound HU-MA (hydroxyurea with myristic acid) with low IC50 is considered as the compound having good activity with compound code. These conjugates have been shown to have improved drug solubility and better cellular uptake compared to free hydroxyurea, which can increase drug efficacy.

Developing nanosize carrier systems for Amphotericin-B: A review on the biomedical application of nanoparticles for the treatment of leishmaniasis and fungal infections.

New formulations of Amphotericin-B (Am-B), the most popular therapeutic drug for many human infections such as parasitic and fungal pathogens, are safe, economical, and effective in the world. Several newly designed carrier systems for Am-B can also be considered orally with sufficient gastrointestinal permeability and good solubility. However, the clinical application of several new formulations of Am-B with organ cytotoxicity, low bioavailability, high costs, and technical problems have caused some issues. Therefore, more attention and scientific design are required to progress safe and effective drug delivery systems. Currently, the application of nano-based technology and nanomaterials in the advancement of drug delivery systems exhibits promising outcomes to cure many human systemic infections. Designing novel drug delivery systems including solid lipid nanostructured materials, lipo-polymersomes, drug conjugates and microneedles, liposomes, polymer and protein-based nanostructured materials, dendrimers, emulsions, mixed micelles, polymeric micelles, cyclodextrins, nanocapsules, and nanocochleate for Am-B has many advantages to reducing several related issues. The unique properties of nanostructured particles such as proper morphology, small size, surface coatings, and, electrical charge, permit scientists to design new nanocomposite materials against microorganisms for application in various human diseases. These features have made these nanoparticles an ideal candidate for drug delivery systems in clinical approaches to cure a number of human disorders and currently, several therapeutic nanostructured material formulations are under different stages of clinical tests. Hence, this scientific paper mainly discussed the advances in new formulations of Am-B for the treatment of human systemic infections and related clinical tests.

Apolipoprotein E3 functionalized lipid-drug conjugated nanoparticles of Levetiracetam for enhanced delivery to the brain: In-vitro cell line studies and in-vivo study

A significant portion of brain-tumor patients suffer from ‘brain-tumor-related epilepsy (BTE)’ which results in depression, anxiety and hampered quality of life. Conventional anti-epileptic drugs indicate negative interaction with other drugs augmenting the poor outcome of overall therapy. Levetiracetam (LVM) has evidenced effectiveness for BTE but its hydrophilicity restricts the passage into blood-brain barrier. The majority of lipid nanoparticles fails to load hydrophilic drug sufficiently. Therefore, lipid-drug conjugates (LDC) were synthesized using stearic acid via amide bond formation confirmed by FTIR and NMR. The nanoparticles of synthesized LDC were prepared by solvent injection method followed by functionalization with Apolipoprotein E3 (ApoE3@LDC-NP). The nanoparticles were characterized by DSC, XRD, particle size (131.6 ± 1.24 nm), zeta potential (−15.6 ± 0.09 mV), and for storage stability. In-vitro release study indicated initial burst release of 20 ± 0.63 % followed by sustained release up to 30 h (66 ± 1.40 %) for ApoE3@LDC-NP. The cell-line study on HEK293 indicated no significant cytotoxic effect and greater cell uptake through U87MG cell line. The pharmacokinetic and bio-distribution study indicated 2.5-fold greater brain-targeting of ApoE3@LDC-NP as compared to LVM solution. It proved safe in the haemolysis study and exhibited the absence of tissue necrosis. Thus, ApoE3@LDC-NP might be a promising approach for effective brain-targeting of LVM for improved clinical response in BTE.

Computational Amendment of Parenteral In Situ Forming Particulates' Characteristics: Design of Experiment and PBPK Physiological Modeling.

Lipid and/or polymer-based drug conjugates can potentially minimize side effects by increasing drug accumulation at target sites and thus augment patient compliance. Formulation factors can present a potent influence on the characteristics of the obtained systems. The selection of an appropriate solvent with satisfactory rheological properties, miscibility, and biocompatibility is essential to optimize drug release. This work presents a computational study of the effect of the basic formulation factors on the characteristics of the obtained in situ-forming particulates (IFPs) encapsulating a model drug using a 21.31 full factorial experimental design. The emulsion method was employed for the preparation of lipid and/or polymer-based IFPs. The IFP release profiles and parameters were computed. Additionally, a desirability study was carried out to choose the optimum formulation for further morphological examination, rheological study, and PBPK physiological modeling. Results revealed that the type of particulate forming agent (lipid/polymer) and the incorporation of structure additives like Brij 52 and Eudragit RL can effectively augment the release profile as well as the burst of the drug. The optimized formulation exhibited a pseudoplastic rheological behavior and yielded uniformly spherical-shaped dense particulates with a PS of 573.92 ± 23.5 nm upon injection. Physiological modeling simulation revealed the pioneer pharmacokinetic properties of the optimized formulation compared to the observed data. These results assure the importance of controlling the formulation factors during drug development, the potentiality of the optimized IFPs for the intramuscular delivery of piroxicam, and the reliability of PBPK physiological modeling in predicting the biological performance of new formulations with effective cost management.

Anti‐Epileptic Drug‐Lipid Conjugates for Delivery to the Brain: In Silico ADMET Prediction, Molecular Docking and Molecular Dynamics Simulations

AbstractNeurological disease epilepsy has unfortunately become widespread, affecting around 50 million individuals worldwide. Levetiracetam (LVM) is a newer‐generation drug but its hydrophilic nature restricts its BBB (blood‐brain barrier) permeability. This results in increased dose, dosing frequency, and side effects. Therefore, different lipid‐drug conjugates (LDCs) were studied to identify the compound capable of BBB permeation. The binding potential of LDCs with human brain fatty‐acid binding protein (HBFABP) (PDB id: 1FDQ) was determined by molecular docking through extra‐precision (XP) algorithm of Maestro. In simulations, OPLS3e force field was applied. The ADMET prediction was performed by QikProp and pkCSM web tool. The selected compounds were investigated for LDC‐BFABP complex stability through molecular dynamics (MD) study. All compounds indicated good pharmacokinetic profiles. The LVM‐palmitic acid and LVM‐stearic acid conjugates indicated higher docking scores and greater stability than LVM alone. Thus, they can be selected as potential molecules for further drug development to obtain clinically useful LDC for treatment of CNS disorder.

Modulation of release and pharmacokinetics from nanoscale lipid prodrugs of dexamethasone with variable linkage chemistry.

In an attempt to tune drug release and subsequent pharmacokinetics once administered intravenously, we have synthesized three lipid-drug conjugates (LDCs) of dexamethasone (DXM) each possessing a different lipid-drug chemical linkage: namely ester, carbamate and carbonate. These LDCs were thoroughly characterized before being turned into nanoscale particles by an emulsion-evaporation process using DSPE-PEG2000 (Distearoyl-sn-Glycero-3-Phosphoethanolamine-N-(methoxy(polyethylene glycol)-2000) as the only excipient. Spherical nanoparticles (NPs) of about 140-170 nm, with a negative zeta potential, were obtained for each LDC and exhibited good stability upon storage at 4 °C for 45 days with no recrystallization of LDCs observed. LDC encapsulation efficacy was above 95% for the three LDCs, leading to a LDC loading of about 90% and an equivalent DXM loading above 50%. Although the ester and carbonate NPs did not exhibit any toxicity up to an equivalent DXM concentration of 100 μg/mL, the carbamate LDC NPs appeared very toxic towards Raw264.7 macrophages and were discarded. Both ester and carbonate LDC NPs were shown to exert anti-inflammatory activity on LPS-activated macrophages. DXM release from LDC NPs in murine plasma was faster from ester than from carbonate NPs. Finally, pharmacokinetics and biodistribution were conducted, showing a lower exposure to DXM from carbonate LDC NPs than from ester LDC NPs, correlated with the slower DXM release from carbonate LDC NPs. These results outline the need for extended studies to find the best prodrug system for extended drug release.

Quantum Dot loaded BQCA‐Octadecylamine conjugate nanosystems for theranostic applications in Alzheimer’s Disease.

AbstractBackgroundAlzheimer’s Disease (AD) is one of the most common types of dementias in the world and is characterized by progressive, irreversible neurodegeneration. Benzyl quinolone carboxylic acid was shown to have beneficial in management of AD. The current challenge with BQCA is its low brain half‐life, permeability and rapid elimination. The above challenge can be answered by formulating lipid drug conjugates of BQCA, with octadecyl amine (BQCA‐ODA). Quantum dots (QDs) with their unique optical properties, with high sensitivity and stability emerging as theranostic agents in several neurodegenerative diseases. Hypothesizing the co‐delivery of QDs and BQCA for the effective treatment of AD, in the present study we have formulated lipid nano carriers loaded with quantum dots (QDs) surface modified with Polysorbate 80, called PS80‐QD‐BQCA‐ODA‐NPs, for integrating imaging and therapy for effective management of AD.MethodBQCA was conjugated to Octadecyl amine (ODA), to form BQCA‐ODA LDC conjugate. The amphiphilic nature of the BQCA‐ODA conjugate allows the formation of self‐assembled nanoparticles. Here, we have employed solvent injection method followed by sonication, while addition of QDs in the organic phase and P80 in the aqueous phase to form PS80‐QD‐BQCA‐ODA‐NPs . The optimized formulation was evaluated for physicochemical properties (particle size, zeta potential and polydispersity index) surface morphology and in vitro drug release. The in vitro biocompatibility of the PS80‐QD‐BQCA‐ODA‐NPs was assessed on RBC and SHSY‐5Y cell lines. Further the application of PS80‐QD‐BQCA‐ODA‐NPs was assessed by in vivo imaging and behavioural studies on STZ induced mice models of AD.ResultThe formation of BQCA‐ODA conjugate formation was confirmed 13C‐NMR, 1H‐NMR, LC‐MS. The optimized PS80‐QD‐BQCA‐ODA‐NPs were found to have a near spherical shape with a particle size (PS) of 152.62 ± 1.82 nm, zeta potential (ZP) of 18.59 ± 0.56 mV and polydispersity index (PDI) of 0.214±0.08. PS80‐QD‐BQCA‐ODA‐NPs. The NPs shown improved brain permeability, with greater fluorescence intensity in mouse brains when compared to free QDs. In the in vivo efficiency studies PS80‐QD‐BQCA‐ODA‐NPs shown a significant improvement in memory in mice models.ConclusionThe PS80‐QD‐BQCA‐ODA‐NPs nanomedicine was successfully prepared, thoroughly characterized and has shown theronostic benefits in AD mice models.

Solid Lipid Nanoparticles: Formulation, Preparation, and Characterization: A Review

The nano drug delivery system has emerged as a novel therapeutic approach for improved efficacy of the existing drug molecules. Polymeric nanoparticles, lipid based nanoparticles such as solid lipid nanoparticles (SLNs), nanostructured lipid carriers, lipid drug conjugates, ethosomes, liposomes, and self-emulsifying drug delivery systems are a few of the nano carriers used for drug delivery. Among the lipid based nanoparticles, SLNs are promising in terms of a biocompatible carrier for enhancing the bioavailability, controlled release, and targeted drug action. This review explains the formulation components of SLN, various methods of preparation of SLNs, and the characterization parameters of SLNs. The current successful research on SLN formulation also enlightens. The capability of various drugs for increasing therapeutic efficacy can be achieved through SLN and in the future, new directions in further improvement are expected.

Lipid-Drug Conjugates and Nanoparticles for the Cutaneous Delivery of Cannabidiol.

Lipid nanoparticles are currently used to deliver drugs to specific sites in the body, known as targeted therapy. Conjugates of lipids and drugs to produce drug-enriched phospholipid micelles have been proposed to increase the lipophilic character of drugs to overcome biological barriers. However, their applicability at the topical level is still minimal. Phospholipid micelles are amphiphilic colloidal systems of nanometric dimensions, composed of a lipophilic nucleus and a hydrophilic outer surface. They are currently used successfully as pharmaceutical vehicles for poorly water-soluble drugs. These micelles have high in vitro and in vivo stability and high biocompatibility. This review discusses the use of lipid-drug conjugates as biocompatible carriers for cutaneous application. This work provides a metadata analysis of publications concerning the conjugation of cannabidiol with lipids as a suitable approach and as a new delivery system for this drug.

Lipid Nanoparticles for the Posterior Eye Segment.

This review highlights the application of lipid nanoparticles (Solid Lipid Nanoparticles, Nanostructured Lipid Carriers, or Lipid Drug Conjugates) as effective drug carriers for pathologies affecting the posterior ocular segment. Eye anatomy and the most relevant diseases affecting the posterior segment will be summarized. Moreover, preparation methods and different types and subtypes of lipid nanoparticles will also be reviewed. Lipid nanoparticles used as carriers to deliver drugs to the posterior eye segment as well as their administration routes, pharmaceutical forms and ocular distribution will be discussed emphasizing the different targeting strategies most recently employed for ocular drug delivery.

Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer.

Targeted delivery of drugs to tumor cells, which circumvent resistance mechanisms and induce cell killing, is a lingering challenge that requires innovative solutions. Here, we provide two bioengineered strategies in which nanotechnology is blended with cancer medicine to preferentially target distinct mechanisms of drug resistance. In the first ‘case study’, we demonstrate the use of lipid–drug conjugates that target molecular signaling pathways, which result from taxane-induced drug tolerance via cell surface lipid raft accumulations. Through a small molecule drug screen, we identify a kinase inhibitor that optimally destroys drug tolerant cancer cells and conjugate it to a rationally-chosen lipid scaffold, which enhances anticancer efficacy in vitro and in vivo. In the second ‘case study’, we address resistance mechanisms that can occur through exocytosis of nanomedicines. Using adenocarcinoma HeLa and MCF-7 cells, we describe the use of gold nanorod and nanoporous vehicles integrated with an optical antenna for on-demand, photoactivation at ~650 nm enabling release of payloads into cells including cytotoxic anthracyclines. Together, these provide two approaches, which exploit engineering strategies capable of circumventing distinct resistance barriers and induce killing by multimodal, including nanophotonic mechanisms.

Interface-sensitized prodrug nanoaggregate as an effective in situ antitumor vaccine

In situ antitumor vaccines have been widely explored as an effective strategy to inhibit tumor growth by stimulating antitumor immune responses. Herein, we reported a simple and effective in situ antitumor vaccine, which was prepared by co-assembling cationic lipids (DOTAP) with the disulfide bond-linked lipid-drug conjugates of camptothecin and resiquimod. The resulting vaccine had a rod-sharped morphology with nanoscale sizes (average hydrodynamic diameter of ∼163.7 nm) and positively-charged interfaces (zeta potential ∼ +36.2 mV). The interfacial cationization of nanoaggregate resulted in 1000 folds faster redox-responsive drug release than that of unmodified ones, which induced a much more potent in vivo antitumor immune by accelerating the glutathione-responsive drug release at the tumor site. Such cationic lipid-drug nanoaggregates displayed many benefits, such as high co-loading capacity, simple preparation process, and wide applicability, which would serve as a promising new approach to design effective in situ antitumor vaccines.

Development of Lipid-Drug Conjugate Nanoparticles for Hydrophilic and Lipophilic Drug: A Comparative Ex vivo Gut and Caco-2 Cell Permeability Study

Background: The lipid-drug conjugate nanoparticles (LDC NPs), amongst other lipidbased nanoparticles, are the most accepted ones for the oral delivery of both hydrophilic and hydrophobic drugs with poor bioavailability. Besides, the LDC NPs show altered physicochemical properties of the drug and have the potential applications in targeting the drug to a specific organ. Objective: To synthesize hydrophilic Valacyclovir (VACV)-stearic acid (SA) and lipophilic Acyclovir (ACV)-stearic acid conjugates (VACV-SAC and ACV-SAC), and develop their nanoparticles (VACV-LDC-NPs and ACV-LDC-NPs) for improved intestinal permeability. Methods: Both VACV-SAC and ACV-SAC were synthesized and confirmed using FTIR, NMR, and DSC techniques and characterized for assay. The lipid drug conjugate nanoparticles (LDC NPs) were prepared using cold high-pressure homogenization technique and characterized for drug content, mean particle size, zeta potential, ex vivo gut permeability using rat gut sac model, and Caco-2 cell permeability. Results: The FTIR, NMR, and DSC results confirmed the successful synthesis of LDCs. The assay of VACV-SAC and ACV-SAC was found to be 51.48±5.6% and 41.2±6.2%, respectively. The VACV-LDC-NPs and ACV-LDC-NPs showed %EE of 99.10±6.71% and 86.84±5.32%, the mean particle size of 338.7±8nm and 251.3±7nm and zeta potential of -10.8±2.31mV and -11.2±3.52mV respectively. About 91±5.2% of VACV and 84±6.5% of ACV were found permeated across the rat intestine after 480 minutes from their respective NPs. Furthermore, VACV-LDC-NPs and ACVLDC- NPs displayed a significantly higher permeability coefficient (61.5×10-6 and 59.8×10-6 cm/s, respectively) than their plain solutions. Conclusion: The obtained remarkable permeability characteristics indicate developed LDC NPs are the potential, promising and translational approaches for effective oral delivery of poorly bioavailable hydrophilic and lipophilic drugs. Furthermore, this approach may result in moderately to significantly enhanced oral bioavailability of hydrophilic drugs as the conjugation results in amphiphilic molecules, which are further absorbed through different mechanisms across the intestinal mucosa (mainly through passive diffusion mechanism).

Highlight on lipids and its use for covalent and non-covalent conjugations

Lipids are organic fatty or waxy compounds which are used to make nanocarriers that are promising for drug delivery. When lipids associated covalently (lipid-drug conjugate LDC) or non- covalently (drug-lipid complex) to drugs to form Lipid Drug Conjugates (LDC). Most common types of lipids
 
 used for drug conjugation are fatty acids, glycerides, steroids, and phospholipids. Conjugation with lipids may change the properties of the drug and significantly increase the drug lipophilicity. Lipid-drug conjugation could improve the delivery of drugs by the lymphatic system, enhance bioavailability of oral administered drugs, improve drug targeting in tumor diseases, enhance the loading of drugs into some delivery carriers, increase drug stability, and many others. Lipid-drug conjugates can be prepared through different strategies for conjugation and by chemical linkers depending on the chemical structure of both drugs and lipids, careful selection of lipids and drug are necessary in designing the lipid-drug conjugate to achieve maximum benefits.

Lipid Drug Conjugates for Improved Therapeutic Benefits.

Lipid drug conjugates (LDCs) are the chemical entities, which are commonly referred to as lipoidal prodrug. They contain the bioactive molecules, covalently or non-covalently linked with lipids like fatty acids, glycerides or phospholipids. Lipid drug conjugates are fabricated with the aim of increasing drug payload. It also prevents leakage of a highly polar bioactive(s) from the lipophilic matrix. Conjugating lipidic moieties to bioactive molecules improves hydrophobicity. It also modifies other characteristics of bioactive(s). These conjugates possess numerous merits encompassing enhanced tumor targeting, lymphatic system targeting, systemic bioavailability and decreased toxicity. Different conjugation approaches, chemical linkers and spacers can be used to synthesize LDCs based on the chemical behaviour of lipidic moieties and bioactive(s). The factors such as coupling/ conjugation methods, the linkers etc. regulate and control the release of bioactive(s) from the LDCs. It is considered as a crucial parameter for the better execution of the LDCs. The purpose of this review is to explore widely the potential of LDCs as an approach for improving the therapeutic indices of bioactive(s). In this review, the conjugation methods, various lipids used for preparing LDCs, and advantages of using LDCs are summarized. Though LDCs might be administered without using a carrier; however, majority of them are incorporated in an appropriate nanocarrier system. In the conjugates, the lipidic component may considerably improve the loading of lipoidal bioactive(s) in the lipid compartments. This results in high % drug entrapment in nanocarriers with greater stability. Several nanometric carriers such as polymeric nanoparticles, micelles, liposomes, emulsions and lipid nanoparticles, which have been explored, are reviewed here.