Abstract

The review study examines the development along with the importance of tailored drug delivery systems (DDS) in improving treatment efficacy while reducing side effects. It focuses on a variety of new carrier structures, such as liposomes, niosomes, dendrimers, nanoparticles, & microspheres, which are critical to the delivery of drugs success. The paper examines the history of these structures, beginning with the introduction of disposable acrylate nanoparticles in 1977 and focusing on nanotechnology breakthroughs that have resulted in the creation of smart polymers or hydrogels. These advancements enable the stable functioning of drug delivery methods that adapt to physiological variations like blood sugar levels, pH, and temperatures. The review also addresses the challenges faced by conventional drug delivery methods and the pressing need for more efficient alternatives. By integrating biological components like integrin ligands and antibodies, targeted DDS can deliver pharmaceutical agents with higher precision to specific organs or cell types. Despite the promising results observed in preclinical studies, the paper notes that only a limited number of these technologies have received FDA approval. Overall, the review underscores the ongoing quest for innovation in drug delivery systems, aiming to improve patient outcomes through personalized medicine approaches.

Keywords

Liposomes, Niosomes, Nanoparticles, Nanospheres, Nanocapsules, Microspheres.

Introduction

Technologically improved systems, frequently referred to as systems for drug delivery, play a significant role within the field of medicine, producing and storing drug molecules. These drug molecules are changed into appropriate forms for administration, which might be available in options such as tablets or liquid solutions. The primary function of such sophisticated devices is to send medicines to precisely defined places in the body lacking postponement or difficulty, which is critical because not only will the curative effectiveness of the medicinal product be increased, but additionally the amount of any undesirable accumulation of drugs in inaccurate areas will be significantly reduced. [1,2,3] For instance, liposomes, proliposomes, microspheres, gels, prodrugs, and cyclodextrins. The procedure of developing an innovative medicinal chemical is expensive and taking time.[4] The significance of employing nose and pulmonary pharmaceutical delivery pathways to treat illnesses in humans is expanding. These techniques present fascinating alternative to parenteral medicine delivery, particularly for peptides and protein treatments. For this reason, several medication delivery strategies have been devised, including pulmonary & nasal delivery, which are currently being investigated.

HISTORY OF TARGETED DRUG DELIVERY SYSTEM:

Historically, people relied on healing plants. Notwithstanding their benefits, pharmaceutical administration lacked uniformity in behavior, uniformity and sensitivity. [1,4,5] When Jatzkewitz developed the initial polymer-drug combination in 1955, they described the first therapeutic application of nanoparticles. The initial type of nanotechnology, known as liposomes (lipid vesicles), came to light in the 1960s. [6,7] Couvreur et al. developed the very first rapidly disintegrating acrylic nanoparticles in 1977, and their research also investigated the nanoparticles' lysosomotropic effects.[8]

likewise, hydrogels and programmable polymers were created to stabilize systems for drug delivery that are impacted by physiological fluctuations in glucose, pH, the temperatures, other electrical fields. In addition, biodegradable polymers present in nanoparticle characteristics, such as micelles made from polymers including chitosan, lipids, or dendrimers, were employed to develop tailored nanotechnology DDS targeting cancer treatment gene delivery. The idea was to modify the nanoparticles so that the human body could take in particles directly and store the drug at the point of action. The FDA approved only a few drugs, notwithstanding knowing that the nanotechnology-based DDS had tremendous success in suppressing tumor development in animal studies.[8,9].

Targeted drug delivery systems have also greatly evolved and changed over the last few decades, mainly in the ways pharmaceutical agents can be precisely delivered to a particular organ or specific type of cells with a higher level of efficiency and a lower degree of associated side effects (Ye & Yang, 2009).[10] The pressing need to address and overcome numerous constraints that are commonly associated with conventional drug delivery techniques often propels the progress and evolution of these highly advanced systems. Simultaneously, there is a constant pursuit focused on bettering the therapeutic output that eventually benefits the patient.

So many inventions have been developed, in addition to the continual development of tailored medication delivery systems, which is societally anchored in a continuous and powerful desire for innovation. There exists a rich history of targeted drug delivery systems, comprising a myriad of approaches in addition to innovative carrier systems. In the development process, initially, physical and chemical methods of enhancing the delivery of therapeutic agents were primarily used. Nevertheless, over the years, there has been significant and rapid evolution in biological approaches. Molecules which direct these delivery systems, such as integrin ligands, antibodies, plus various types of peptides, have all played important roles in this research. Furthermore, forms of transportation vehicles like as polymers and plasmids or vectors of viruses are quite important. In addition to these, numerous carrier systems have been devised and used, which include but are not restricted to liposomes, niosomes, dendrimers, nanoparticles that and microspheres, which contribute to the general efficacy and efficacy of targeted drug administration.

This is particularly true regarding the intricate complex design of various forms of carriers applied in these systems. In addition, much has been centered on the specific mechanisms undertaken to effectively target particular parts of the body, coupled with careful formulation of the drugs themselves. Over the years, this field has taken great transition with huge strides that begin from relatively simple physical and chemical approaches to highly sophisticated and complex biological methods. Even in this domain, advanced methods include the use of nanosponges, innovative biotechnology solutions, and highly specialized site-specific drug delivery systems, as discussed by Dhumal et al. (2022) and Shree et al. (2021). [11,12]

Such development continues to move forward and evolve as a dynamic and adaptive response to the growing importance of targeted drug delivery within the overall context of personalized medicine. This advance is particularly critical for the successful treatment of diseases in general, with a strong focus on areas that include cancer therapy, disorders with relevance to the central nervous system, and diseases with relevance to the colon. [13,14,15]

CHALLENGES ASSOCIATED WITH CURRENT DRUG DELIVERY SYSTEM:

The hunt for ways to transfer medications from different kinds of plants to their target areas to be used in the human organism has advanced significantly in the past few decades, with numerous delivery systems being employed effectively. Nonetheless, there are numerous limitations and challenges to what these structures may achieve when it comes of treatment, a few of which are discussed below. The scarcity and variability of available literature provide a substantial barrier to the advancement of medicine delivery systems. The availability of crucial information in the literature is critical to the advancement of any investigation, particularly nanomedicine treatment techniques. One key hurdle to the growth of nanotechnology utilization in healthcare is the variation in published research in terms of documented characterization of given empirical results.  [16].

Future advances in nanomedicines may be hampered by the incomplete and inconsistent data that ought to serve as a guide for industry, delaying the transition from laboratory and research to clinical application [17]. The beneficial effects of nanoparticles are becoming more widely recognized, and many academics believe that their properties can be both good and negative. However, nothing is commonly referred to about the security of these fragments, their ability to communicate with non-target protein molecules, and how they migrate across and communicate with tissues other than their designated target organs. [18].

The use of considerably less large particles for distribution to the mammalian biological system solves the challenges associated with employing much bigger particles. Some of these methods of delivery use big particles as an carriers, and these are not especially beneficial to therapy because they can pose challenges such as inadequate absorption along with solubility, in vivo unpredictability, low bioavailability, target-specific difficulties with delivery, and several negative consequences upon administration. [19]. All systems of delivery face the challenge of delivering meeting particular targets.

Target-specific administration has been shown to be more successful and less harmful, but its performance cannot be assured unless it makes it to the intended site in sufficient quantities. This can be seen while siRNA is delivered systematically; they are rarely delivered to the intended cell or organs due to how they quickly break down by body enzymes. While administered in huge amounts, their negative charge grows an obstacle to the cells' capacity to absorb them, resulting in very little the absorption by the body.  [20]. Small particles of lipids known as liposomes as well as miceelles are being investigated for target pharmaceutical delivery; however, the disadvantage of this strategy is that how the body responds to these nanoparticles, which include phagocytic ingestion and hepatic filtration, might diminish their efficiency and induce toxicity. [21]. Targeted delivery faces various obstacles, include the impossibility of administering an adequate amount to a partially unconscious patient, restricted solubility and permeability in the area of interest, the possibility of food interactions, plus the potential destruction by gut flora. [22].

Another significant difficulty confronting drug delivery systems is the cytotoxicity of the particles used in dissemination; certain nanoparticles can be dangerous to both individuals as well as the environment.  [23]. Studies performed both in vivo in addition to in vitro have indicated the negative impacts of utilizing silver, gold, silica, and titanium as drug-delivering and interacting nanoparticles. [19]. The nanotubes of carbon (CNTs) are now widely used in medicine delivery, therapeutic gene transfer, including bioimaging. [24]. Since it was recently revealed that carbon nanostructures can pass through membranes of cells even when employed as transporters for biomolecules. [25]. However, investigations have shown that the presence of carbon nanotubes can affect embryos for research purposes genes, the heart, liver, neurons, and the immune system. [19] Scientists have reservations about the characteristics of nanotubes made of carbon, particularly their application in medicine administration. Even though nanotubes made from carbon have proven promising findings in their application, essential testing for toxicity must be undertaken to ensure that they are secure prior to a widespread use in therapy [24]. Their negative effects make them challenging to utilize as treatment for cancer. [26].

Scientists have successfully developed medications that can serve as carriers as well as therapeutics. Nevertheless, one of the key difficulties facing systems for drug delivery is their acceptance (the capacity for penetration into the body without stimulating the immune system to react) and biological compatibility (the the body's response to substances that are biological differs substantially than that of manufactured materials).

 [23]. The barrier between the blood and the brain (BBB) is permeable selectively, making it challenging to attain therapeutic medication concentrations in brain regions. The BBB also prohibits particles that carry drugs from reaching the cerebellum and throughout the central nervous system, resulting in the inefficiency of medicinal products un in the management of cerebral disorders because of the inability to adequately distribute and sustain targeted medications within the brain. [27]. In addition, the intricate structure within the human system may present inherent hurdles to the operation carried out by these delivery systems. Furthermore, monoclonal antibody molecules (mAb) constitute the most common carriers in the body as they attach to liposome surfaces, forming immunoliposomes. However, because liposomes can induce an immunological response and have poor levels of digestion, distribution, metabolism, and elimination throughout the human system, their usefulness are limited, making liposomes challenging to use successfully as site-specific drug carriers. [28]. The urinary tract and liver are natural detoxifying organs in the body that may deal with nanoparticles as waste products. Their effects may impair medication delivery and lead to nanoparticle accumulation in these tissues. Nanomaterials are predominantly found inside the liver's cells known as Kupffer cells, stellate cells of the liver, sinusoidal cells called endothelial cells, among macrophages. Hepatocytes also have a minor quantity of nanoparticles. Nanomaterials penetrate the renal system and their fate is dictated according to the kidney's size, charge, its shape. [29].

TARGETED DRUG DELIVERY SYSTEM:

This procedure is a complex technology that is currently gaining popularity due to its reduced adverse consequences and greater effectiveness. Drugs are supplied to their target site using a device that increases drug concentration as it moves through a predetermined sequence [30]. The drug's strength and efficacy are unaffected even when the dosage is decreased to reduce negative effects. Among other drug carriers used in this method are artificial cells, liposomes, soluble polymers, biodegradable microsphere polymers, neutrophils, and micelles [30].

This therapy is getting increasingly popular because it works, especially in the fight versus malignancy. Murugun's investigation found that this drug delivery mechanism is effective when applied. Topotecan (TPT) and quercetin (QT) were provided for the targeting of aggressive breast cancer cells (TNBC) (MDA-MB-231) with resistant to multiple drugs breast cancer cells (MCF-7) using polyacrylic acid and chitosan surface-modified mesoporous silicon nanoparticles (MSN).[31]. Arg-Gly-Asp sequences contain RGD-peptides, that have been grafted onto the nanoparticles' surfaces. To effectively target v?3 integrin, this must have been done. The RGD peptide improved cancerous cells' intracellular absorption and the effective release of encapsulated medicines. In both cell lines, the cell's nucleus, endoplasmic reticulum, physiological mitochondria exhibited structural, molecular, physiological cell death changes. In addition, an additive antiproliferative effect was seen. [31]. Wu et al. conducted a study and found found Fe 3 O 4 MgAl-LDH (layered double hydroxide) nanoparticles that having a size of roughly 230 nm, demonstrated an enhanced release of methrotrexate (MTX). [32]. After 48 hours, they observed an 84.94% emission in the malignancy at a pH of 3.5. Anticancer activity was shown to be higher in every one of the cell lines studied. Lin et al. used this method to specifically target HeLa cells. To assess their therapeutic efficacy on HeLa cells, 10-hydroxycamptothecin (HCPT) with mitomycin C (MMC) was co-delivered utilizing a folate-functionalized soybeans phosphatidyl choline micellar nano formulation.  [33]. In compared to free drugs, the study demonstrated increased intracellular permeability in vitro in addition to in vivo, as well as a bigger decrease in tumor burden. These as well as additional results indicate that academics should focus greater attention on the topic of personalized drug delivery systems.

LIPOSOMES:

Liposomes, which were first introduced in 1965, are artificial phospholipid vesicles that are made composed of bilayer membranes of lipids producing closed structures that partition an outer environment into a single aqueous inner compartment.  [34,35]. Since the notion of liposomes originally emerged in 1965, a substantial amount of research regarding the physicochemical properties of liposomes has been gained. The prospective use of artificial lipid vesicles as drug and enzyme carriers in preventative and therapeutic medicine has been made possible by the vast experience that has been developed in this field. Enzyme replacement treatment was originally studied on a patient with Type II glycogenosis, a lysosomal storage disorder sometimes referred to as Pompe's disease in 1976. Even if the liposomes' endurance in blood circulation was evaluated, there were still a few major obstacles to overcome before the extended application to other instances of enzyme-deficient illnesses could occur [36].

Apart from having different functions, liposomes possess the characteristic feature of showing topological conversions characterized by a process that resembles opening and, as a result, the direct leakage of their inner vesicles in the outer environment (Hotani et al., 2003; Nomura, 2000 [36,37]

To summarize, liposomes have enormous potential for a wide range for applications including drug administration and immunology, as well as for studying intricate biological processes. These vesicles can encapsulate within their aqueous compartment the water-soluble substances and simultaneously associate and interact with lipid-soluble molecules embedded in their lipid bilayers (Latif & Bachhawat, 1984; Lizo?ová et al., 2021). [38,39] An advanced concept in liposomes is the multi-lobed magnetic liposomes (MMLs), which have a combination of magnetic properties with a great payload capacity (Lizo?ová et al., 2021). While research continues, liposomes remain to be investigated along with biological nanoparticles such as extracellular vesicles, opening to the possibility of hybrid systems that possess the best qualities of artificial and natural vesicles (Koog et al., 2021) [40].

       
           
       
THERANOSTIC LIPOSOMES:

Theranostic liposomes are a class of multifunctional nanocarriers that outline the possible integration of diagnostic and therapeutic functionalities into one device; hence they display great promise for further development and improvement of personalized medicine approaches. The nanostructures have a remarkable ability to encapsulate many species of agents, such as small molecular compounds, genetic materials like DNA or RNA, or imaging probes, utilized in visualization of various biological processes, thus making them highly versatile tools for identification and therapeutic intervention for a wide variety of diseases and medical conditions (Imam et al., 2022; Xing et al., 2016) [41,42]. Liposomes have gained much attention and interest within the dynamic field of nanomedicine due to their specific and controlled particle size, which can be precisely modulated for numerous requirements. Their ease in preparation also explains much about their popularity, making them available for research and application. Furthermore, these structures can be expertly engineered to allow for various surface modifications which can potentially significantly enhance targeted delivery mechanisms (Xin et al., 2018) [43].

Unexpectedly, despite the fact that theranostic liposomes have lately been shown to be exceptionally successful for the management of both cancer and viral disorders, the BBB has suddenly surfaced as a barrier to their usage in brain cancer therapy. Several research investigations have been conducted, some of them have concentrated on transferrin-conjugated TPGS-coated liposomes that with the goal of enhancing permeability across the blood-brain barrier. The goal is to achieve more accurate localization of the brain for medicinal and imaging agents.an improvement that is widely welcomed in scientific literature by researchers, as observed by Sonali et al. in their 2016 study [44].

Besides this, hybrid liposomal cerasomes have been developed, which are more stable than traditional liposome technology. This is because several limitations associated with conventional liposome technology were identified and overcome, as mentioned by Yue and Dai in their 2015 research [45].

In summary, theranostic liposomes form an exceptionally powerful tool for the effective implementation of combined modality approaches that merge both imaging and therapeutic techniques. This brings up a plethora of possibilities for enhancing personalized therapy customized specifically to individual patient demands. These nanoscale carriers are extremely versatile and can be designed for practically any conceivable application. [46,47].

The future development of this field of research could also make theranostic liposomes an important contributor to nondinvasive diagnostic methods and to real-time imaging guidance and even remotely controlled therapeutic interventions-all of which would lead to very effective and highly individualized treatment (Verma et al., 2020; Yue & Dai, 2015) [48].

PEGYLATED LIPOSOMES:

Among the most promising and innovative drug delivery systems developed up to now, PEGylated liposomes stand out compared to conventional liposomes. The advantage of these more stable PEGylated liposomes is the longer circulation time in the bloodstream. They are not only more stable but also entrap drugs with greater efficiency, which lead to much better therapeutic results (Atyabi et al., 2009; Cho et al., 2015; Yousefi, 2009). [49,50,51]

PEGylation is a process wherein the surface of the liposome gets covered with an appropriately attached layer that is formed by the polymer of polyethylene glycol, often abbreviated as PEG, which is known to be hydrophilic in nature and nontoxic. The PEG coating may create a protective safety envelope formed around the vesicle that enhances stability and functionality (Kaurav et al., 2022) [52].

Interestingly, it must be noted that though PEGylation in general will enhance delivery of drugs, said increase can vary with the type of drug that is to be encapsulated or entrapped within these carriers. According to Dadashzadeh et al., in their 2007 issue, amphoteric drugs have been indicated to induce an increase in leakage rates once placed inside PEGylated liposomes. Nevertheless, it should be stated that in most cases, PEGylated liposomes show significant advantages concerning pharmacokinetics in comparison with the carrier-free, non-PEGylated ones. For example, AUC, MRT, and half-life values for preparations prepared with PEGylated liposomes are significantly higher according to, but not limited to, the research conducted by Dadashzadeh et al. in 2007 as well as by Yang et al. in 2007 [53,54].

The PEGylated liposomes do not have limitations up to the advantageous drug delivery systems. Besides being favorable, these also show remarkable improvement in solubility and stability as well as the whole efficacy of the targeting tissues or cells as a whole (Kaurav et al., 2022; Yadav & Dewangan, 2020) [55]. These liposomes can be used effectively in cancer therapy as the studies have already proven their effectiveness. [50,56].This has, however underscored that their efficacy is also determined by length, density, and PEG conjugating method among many other factors, hence more research is needed to maximize the efficacy of PEGylated liposomes in particular biomedical applications.

LIGAND TARGETED LIPOSOMES:

Ligand-targeted liposomes are designed to improve optimal delivery of therapeutic compounds to specific tumor locations, thus minimizing side effects and optimizing therapeutic effectiveness (Fathi & Oyelere, 2016) [57]. Targeted therapy employs modified liposomal solutions containing numerous targeted ligands, including small molecules, immunoglobulins peptides, and aptamers, capable of interacting with overexpressed receptors on malignant cells. (Liu et al., 2021) [58].

According to Allen and Moase (1996), the targeted moiety is typically conjugated to the terminus of a hydrophilic polymeric material, such as PEG, to maximize its action. [59].It is intriguing that, so far, despite the extensive research in this field, no small molecule ligand-conjugated liposome has been approved for anticancer therapy (Fathi & Oyelere, 2016). However, the results indicate that the receptors that internalize are targeted more efficiently than the non-internalizing receptors (Allen & Moase, 1996). Additionally, the flexible liposome surface allows for flexible positioning of targeting ligands, and this may enhance their binding potential with the cell surface receptors (Liu et al., 2021). Ligand-targeted liposomes thus open up the possibility of drug delivery improvement in cancer therapy. They may be demonstrated to bind specifically and increase cytotoxicity to cells in vitro compared with nontargeted liposomes (Allen & Moase, 1996).

More issues still include the 'binding site barrier' in advanced solid tumors and rapid clearance of immunoliposomes (Allen et al., 1998). These efforts involve advancements in long-circulating immunoliposomes and novel methods of ligand coupling to liposome surfaces, further enhancing their potential for therapeutic application.[60]

NIOSOMES:

The increased awareness with respect to niosomes, which represent advanced vesicular systems based on non-ionic surfactants, and are designed especially for targeted drug delivery, has garnered much attention from the research community. Above all, this increased awareness is mainly owing to the multiple advantages associated with niosomes, thereby firmly placing them as a preferred alternative instead of conventional liposomes widely utilized in that field. These nanocarriers, which have been developed from biocompatible materials and are known to be secure, have exhibited extraordinary stability in various conditions and a significant decrease in levels of toxicity, thus being remarkable for medical use. Furthermore, their cost-effectiveness enhances their attraction to all these factors that have been brought out and made clearer by comprehensive studies conducted by Hazira & Reddy (2023) and Jawale & Kashikar (2022), pointing towards their significance in modern pharmaceutical formulations [61,62].

One of the most significant benefits of niosomes is their ability to encapsulate hydrophilic and lipophilic medicines, hence increasing drug availability at specific target areas while also providing regulated release, according to arguments by Dineshkumar et al. (2021) and Varshney et al. (2024). [63,64] This flexibility has made niosomes invaluable in various targeted drug delivery applications such as brain-focused therapy, cancer treatment, and management of infectious diseases (Hazira & Reddy, 2023; Varshney et al., 2024). The inherent vesicular architecture of niosomes, provided through the help of non-ionic surfactants, ensures ongoing retention of drugs in targeted areas as illustrated in the work of Jawale & Kashikar (2022).

Generally speaking, in a nutshell, niosomes have been proved to represent a highly dynamic and effective mechanism for the targeted drug delivery of such a nature that it will particularly suit a myriad of avenues of administration. Avenues include oral routes, parenteral methods, ocular applications, transdermal techniques, vaginal delivery, and even inhalation methods. Such versatility and effectiveness of niosomes in drug delivery systems are hugely emphasized by the research work undertaken by Jawale & Kashikar in 2022. The exceptional capability of niosomes to enhance therapy efficacy is derived from several main mechanisms: extension of circulation time of drugs in the body, efficient protection against fluctuations in a biological environment, and capability for focus therapeutic effects on targeted cells. Such an innovative combination places niosomes on the list of one of the most promising resources in the ever-changing field of personalized medicine. (-et al., 2023; Patel et al., 2022) [65,66]. More research would be required to formulate techniques that would improve stability to be reinforced and problems associated with the upscaling and commercialization of niosome technology, based on the findings of Chen et al. (2019) and Varshney et al. (2024) [67].

NANOPARTICLES:
Currently, at the front of innovation in medicine, these nanoparticles, functioning at a quite tiny scale of size from 1 to 100 nanometers, become one of the most important instruments in the field of targeted medication systems for administration.

such tiny micropharmaceutical agents have caused a drastic change in the entire traditional practices related to drug delivery, mostly by offering a number of advantages leading to the advancement of therapeutic intervention outcomes. These agents have been highly engineered to act as nanoscale drug carriers and the minute particles of which are involved in the modulation of cellular and molecular interactions. Additionally, they advance the accurate delivery and dispersion of cancer-specific chemotherapeutic agents across the whole body. This crucial aspect has been highlighted the most in the work published by Dhanasekaran in 2015 as well as in the research studies published by Singh et al. in 2018 [68,69]. A particularly important domain in this interesting field is the very recent development of what might be called "smart" nanoparticles. This is indeed a step radically new for the rapidly evolving drug delivery technology domain.

These advanced particles demonstrate an unmatched capability to give a highly controlled and precise response, intelligently and efficiently to a wide variety of both internal and external stimuli. It is this singular responsiveness that makes them enable drugs to be released with much accuracy at targeted sites, but are also linked with the crucial minimization of undesirable side effects due to treatment. This aspect of their functionality is given much prominence in the findings as presented by Singh et al. (2018). Some forms of nanoparticles utilized in targeted drug delivery include nanoemulsions, the nanogels, solid-lipid nanoparticles, liposomes, micelles, dendrimers, nanotubes made of carbon, and nanoshells. which are distinguished by their different features and significantly contributed to the transport of therapeutic agents, as indicated by studies like that of Bhattacharjee et al. (2010) and Singh et al. (2018) [70].

In brief, the research domain focused on targeted drug delivery schemes derived from nanoparticles opens very large scope that could significantly expand the overall efficacy of many treatments, particularly in the special area of cancer therapy. These new and highly sophisticated systems are even better suited to enhance drug concentrations specifically to tumor cells while fine-tuning pharmacokinetic profiles associated with the respective treatments and at the same time also try their best to minimize side reactions as compared with a traditional chemotherapy formulation. The phenomenal difference in relevance is obvious with the extensive research conducted by Zhao et al. (2020) [71].

Furthermore, nanocarriers' exceptional and spectacular ability to effectively permeate the extremely selective blood-brain barrier provides unprecedented and unrivaled prospects for the efficient and precise delivery of medications to the brain. Such enormous potential has been well observed and documented in the detailed investigations conducted by Shah et al. (2021)[72].On the background of further significant scientific exploration findings within the field, mechanisms for targeted drug delivery based on nanoparticles are poised to assume an increasingly critical and vital role within the area of personalized medicine. The new strategies will also improve therapy strategies through a wide range of conditions within the medical field, to be more effective and personalized therapeutic interventions.

Nanospheres and Nanocapsules:

Nanospheres and nanocapsules represent two of the most important and commonly employed varieties of nanoparticles as they are heavily in use designing advanced drug delivery systems, and they have distinctive characteristics that significantly influence drugs' ability to be encapsulated as well as delivered to targeted body regions.The nanospheres are distinguished by their solid polymeric content, which features a stable structure thus ideally suited for encapsulating drugs of different types. The nanocapsules, on the other hand, have an inner liquid core covered by a polymeric wall, creating an environment that can host the drugs within. Such structural differences are important since they determine the loading and release efficiencies of drugs from these nanoparticles [73]. There is the complex loading and release behavior that is crucially dependent on a large number of factors coming into play. The factors include the specificity of preparation techniques used in their formation but also the varied physicochemical properties of different drugs being encapsulated within these nanoscale carriers.

the case of nanospheres, in particular, specific properties of drugs to be loaded exercise an important influence on the encapsulation process, which affects the encapsulating efficiency and effectiveness in drug delivery. On the contrary, the method of preparation in nanocapsules defines the overall efficiency in drug encapsulation inside nanoparticles. This delicate and intricate balance among drug properties and the precise preparation methods used underscore a fine, detailed care that is needed when making thorough, Making sound decisions on the usage of these novel nanoparticles for various delivering medications applications. When the release of drugs becomes the focus point, it has been discovered that nanospheres have significantly faster rates of release than nanocapsules. More significantly and notably, there is the indication that nanospheres can effect complete drug release in an extremely short and brief time span of merely 2 hours [73,74].

The rapid release characteristic of nanospheres makes them perform consistently across the board regardless of the properties characteristic of the drugs that are being encapsulated within. This particularly tremendous characteristic points toward their great potential for use in scenarios that require immediate drug delivery, and time is somewhat critical. In contrast, the release kinetics of drugs contained in nanocapsules are much more variable and become very closely associated with the unique attributes or qualities of the individual specific drug. This variability underlines the importance of the need for a tailored approach when considering the use of nanocapsules for controlled drug applications in therapeutic scenarios for effectiveness.

Within a nutshell, the features of nanospheres therefore nanocapsules differ, and they play an important part in the enormous expanse of constantly changing drug delivery systems.Because of their distinct releasing kinetics various structural compositions, the two kinds of nanoparticles are particularly helpful for a wide range of applications involving drug delivery and conditions. For instance, nanospheres can be very useful in situations where drugs need to be released into the system quickly or rapidly. On the other hand, nanocapsules can really shine in formulations that require sustained and long-term release over time. For this reason at any percentage, which underlying the two would be employed would rely on numerous aspects including the particular features regarding the issue of drug loading needs and desired profiles, as well as the individual requirements and attributes of the medications to be used in each case. [73].

Furthermore, the positive results and announcing capabilities demonstrated by these innovative tiny particles systems in a wide range of diverse fields, including cancer treatment, applications in dentistry, and targeted drug delivery, highlight their outstanding adaptability as well as the enormous potential impact they hold for future progress in different fields of medicine.[75,75,76]

MICROSPHERES AND MICROPARTICLES:

Microspheres have transformed the subject of specific drug delivery systems with their novel technology, which provides numerous benefits that much outweigh the advantages of traditional procedures. These adaptable and dynamic powders, frequently made comprised of disposable enzymes or polymers made from synthetic materials, exhibit a stunning particle size range of 1–1000 µm. Moreover, they can be formulated with precise control over the delivery of pharmaceutical agents precisely to targeted sites with defined pre-set release kinetics as cited by recent studies (Walia et al., 2021; Yadav et al., 2024) [77,78].

       
           
       
By major strides, a large area involves the development of magnetic microspheres, which offer a compelling alternative to conventional radiation methods notorious for intrinsic toxicity and side effects resulting from deep penetration, as reported by many significant studies (Chandna et al., 2013; Sharma & Sharma, 2017) [79,80].

These magnetic carriers can then be navigated precisely to various destinations using external magnetic fields, reducing the percentage of freely circulating medication and highly amplifying accuracy in targeting, as widely addressed in literature currently (Chandna et al., 2013). The field of mucoadhesive microspheres also has great promise in enhancing drug absorption by prolonging the time of drug residence at absorption sites; this development has been well documented in the current research publications (Raj et al., 2021) [81].

Fundamentally, microspheres are a versatile and customizable drug delivery platform that addresses almost every scope of therapeutics in medicine. Its capability to be customized for various modes of administration and targeting sites such as the lung, liver, bones, brain, colon, and eyes manifests a great promise for applications in precision medicine, according to Yawalkar et al. (2022) [82].

Microspheres, which with the capacity to modify their surface properties, encapsulate an assortment of drug formulations, and help with the controlled release system, unquestionably play an important part in the advancement of customized healthcare as well as the enhancement of therapeutic outcomes in a broad spectrum of diseases, thus being an integral component of the constantly changing domain of drug discovery and development.  (-et al., 2023; Bobade et al., 2023) [65,83].

Remarkably, pH-sensitive drug delivery using hydrogel microspheres has demonstrated potential, especially when it comes to small intestine targeting. Studies have indicated that hydrogel microcapsules based on alginate have good stability and sensitivity to pH, releasing little in simulated gastric fluid but a lot in simulated intestinal fluid [84]. This underlines the possibility for precise control over drug release in specific physiological settings.

FUTURE DIRECTIONS AND CONCLUSIONS

The delivery of drugs and nanotechnology in medicine are regarded as among the most intriguing fields of contemporary scientific research; in the past few years, there has been a lot of attention in regards to study, testing, including clinical trials.  [85]. Notwithstanding the challenges that have stopped it from being deployed in clinical settings, the new drug method of administration has a lot of promise. To attain this efficiency, we must work across theory from academia, experimental trial and error, medical knowledge, pharmacological knowledge, and good research. [86]. the research of Vargason et al., the use of cell therapies can greatly improve the bio-acceptability issues that pharmaceutical delivery systems face. They also say that it will end up in a successful single injection that prevents a large accumulation of drugs in the system. In reality, cell therapies promise to break down innate biological boundaries, generate responses that appear natural within the system, and deliver a seemingly constant stream of complex biologics.[87] Adepu suggested using molecular imprinted polymers, microfluids, and artificial mesoporous nanomaterials as solutions to overcome some of the issues involved with medicine administration. [88]

According to Khalid et al., one method for increasing drug delivery efficacy is to use preparing agents that may change the biological setting within which the drugs are administered—particularly those which can change tissue form and function in a way which renders the administered drug beneficial without compromising the patient. Furthermore, because cells are an inherent component of the human organism, cell-based drug systems—which combine cells with nanotechnology to maximize drug delivery—should be considered in the field of nanomaterials. There is a fresh and theoretical technique that appears to be highly innovative, encouraging the usage of drug delivery technologies in the expectation of achieving the best medication delivery pattern.Much more research and clinical trials are needed to establish the efficiency of these modern drug delivery techniques as well as the problems connected with their administration.

REFERENCES

1. Ezike TC, Okpala US, Onoja UL, Nwike CP, Ezeako EC, Okpara OJ, Okoroafor CC, Eze SC, Kalu OL, Odoh EC, Nwadike UG, Ogbodo JO, Umeh BU, Ossai EC, Nwanguma BC. Advances in drug delivery systems, challenges and future directions. Heliyon. 2023 Jun 24;9(6):e17488. doi: 10.1016/j.heliyon.2023.e17488. PMID: 37416680; PMCID: PMC10320272.
2. Rayaprolu B.M., Strawser J.J., Anyarambhatla G. Excipients in parenteral formulations: selection considerations and effective utilization with small molecules and biologics. Drug Dev. Ind. Pharm. 2018;44:1565–1571. doi: 10.1080/03639045.2018.1483392. [PubMed] [CrossRef] [Google Scholar]
3. Vargason A.M., Anselmo A.C., Mitragotri S. The evolution of commercial drug delivery technologies. Nat. Biomed. Eng. 2021;5:951–967. doi: 10.1038/s41551-021-00698-w. [PubMed] [CrossRef] [Google Scholar]
4. Akala E.O. Theory Pract. Contemp. Pharm. CRC Press; Florida: 2004. Oral controlled release solid dosage forms; pp. 333–366. [Google Scholar] [Ref list]
5. Bangham A.D., Horne R.W. Negative staining of phospholipids and their structural modification by surface-active agents as observed in the electron microscope. J. Mol. Biol. 1964;8 doi: 10.1016/S0022-2836(64)80115-7. 660-IN10. [PubMed] [CrossRef] [Google Scholar] [Ref list]
6. Bangham A.D., Standish M.M., Watkins J.C. Diffusion of univalent ions across the lamellae of swollen phospholipids. J. Mol. Biol. 1965;13 doi: 10.1016/S0022-2836(65)80093-6. 238-IN27. [PubMed] [CrossRef] [Google Scholar] [Ref list]
7. Couvreur P., Tulkens P., Roland M., Trouet A., Speiser P. Nanocapsules: a new type of lysosomotropic carrier. FEBS Lett. 1977;84:323–326. doi: 10.1016/0014-5793(77)80717-5. [PubMed] [CrossRef] [Google Scholar]
8. Zhang W., Zhao Q., Deng J., Hu Y., Wang Y., Ouyang D. Big data analysis of global advances in pharmaceutics and drug delivery 1980-2014. Drug Discov. Today. 2017;22:1201–1208. doi: 10.1016/j.drudis.2017.05.012. [PubMed] [CrossRef] [Google Scholar] [Ref list
9. Park K. Controlled drug delivery systems: past forward and future back. J. Contr. Release. 2014;190:3–8. doi: 10.1016/j.jconrel.2014.03.054. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
10. Ye X, Yang D. Recent Advances in Biological Strategies for Targeted Drug Delivery. Cardiovascular & Hematological Disorders-Drug Targets. 2009 Sep 1;9(3):206–21.
11. Dhumal G, Patil T, Dambe R, Kulkarni A, Thorat V, Dhayagonde K, et al. NANOSPONGES?: A New Approach for Drug Delivery System. International Journal of Scientific Research in Science and Technology. 2022 Nov 5;170–8.
12. Suma Shree CH, Muni Raja Lakshmi K, Lakshmi Priya N. Nano Sponges: A Novel Approach for Targeted Drug Delivery Systems. Journal of Drug Delivery and Therapeutics. 2021 Mar 15;11(2):247–52.
13. Ghosh S, Majumder S, Chowdhury A, Ganguly D. Advancement of Targeted Drug Delivery Over Conventional Drug Delivery System Targeting to Colonic Region. International Journal of Pharmaceutical Sciences Review and Research. 2022 Apr 15;92–6.
14. Tiwari C, Jaiswal PK, Malik P, Chahar RK. Brain-Targeted Drug Delivery System: A Novel Approach. Journal of Drug Delivery and Therapeutics. 2022 Nov 15;12(6):171–8.
15. Xu W, Xing FJ, Dong K, You C, Yan Y, Zhang L, et al. Application of traditional Chinese medicine preparation in targeting drug delivery system. Drug Delivery. 2014 Mar 10;22(3):258–65.
16. Y.S. Youn, Y.H. Bae, Perspectives on the past, present, and future of cancer nanomedicine, Adv. Drug Deliv. Rev. 130 (2018) 3–11, https://doi.org/10.1016/j. addr.2018.05.008
17. G. Pasut, Grand challenges in nano-based drug delivery, Front. Med. Technol. 1 (2019) 10–13, https://doi.org/10.3389/fmedt.2019.00001.
18. S. Sharma, R. Parveen, B.P. Chatterji, Toxicology of nanoparticles in drug delivery, Curr. Pathobiol. Rep. 9 (2021) 133–144, https://doi.org/10.1007/s40139- 021-00227-z.
19. J.K. Patra, G. Das, L.F. Fraceto, E. Vangelie, R. Campos, P. Rodriguez, L. Susana, A. Torres, L. Armando, D. Torres, R. Grillo, Nano based drug delivery systems : recent developments and future prospects, J. Nanobiotechnol. (2018) 1–33, https://doi.org/10.1186/s12951-018-0392-8.
20. A. Khalid, S. Persano, H. Shen, Y. Zhao, E. Blanco, J. Wolfram, W.C. Medicine-qatar, W.C. Medicine, W.C. Medicine, W.C. Medicine, HHS Public Access 14 (2018) 865–877, https://doi.org/10.1080/17425247.2017.1243527.Strategies.
21. S.M. Zargar, D.K. Hafshejani, A. Eskandarinia, M. Rafienia, A.Z. Kharazi, A review of controlled drug delivery systems based on cells and cell membranes, J. Med. Signals Sens. 9 (2019) 181–189, https://doi.org/10.4103/jmss.JMSS_53_18.
22. J. Gautami, Research and Reviews: Journal of Pharmaceutics and Nanotechnology IMPLANTABLE DRUG DELIVERY SYSTEM 3 (2015) 24–31.
23. N. Singh, A. Joshi, A.P. Toor, G. Verma, (Chapter 27) - Drug delivery: Advancements And Challenges, Elsevier Inc., 2017, https://doi.org/10.1016/B978-0- 323-46143-6/00027-0.
24. H. Zare, S. Ahmadi, A. Ghasemi, M. Ghanbari, N. Rabiee, M. Bagherzadeh, M. Karimi, T.J. Webster, M.R. Hamblin, E. Mostafavi, Carbon nanotubes: smart drug/gene delivery carriers, Int. J. Nanomed. 16 (2021) 1681–1706, https://doi.org/10.2147/IJN.S299448. T.C. Ezike et al. Heliyon 9 (2023) e17488 17
25. O.M. Perepelytsina, A.P. Ugnivenko, A. V Dobrydnev, O.N. Bakalinska, A.I. Marynin, M. V Sydorenko, Influence of carbon nanotubes and its derivatives on tumor cells in vitro and biochemical parameters, cellular blood composition in vivo, Nanoscale Res. Lett. 13 (2018) 286, https://doi.org/10.1186/s11671-018- 2689-9.
26. V. Hafeez, Muhammad Nadeem Celia, Christian, Petrikaite, Challenges towards targeted drug delivery in cancer nanomedicines, Processes 9 (2021) 1527, https://doi.org/10.3390/pr9091527.
27. M. Danaei, M. Dehghankhold, S. Ataei, F. Hasanzadeh Davarani, R. Javanmard, A. Dokhani, S. Khorasani, M.R. Mozafari, Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems, Pharmaceutics 10 (2018) 1–17, https://doi.org/10.3390/ pharmaceutics10020057.
28. J.T. Spitler Ryan, H.J.Q. Zanganeh Saeid, Khakpash Nasser, Erfanzadeh Mohsen, S. Nastaran, Drug delivery systems: possibilities and challenges, in: Biomater. Towar. Med. Serv., 2017, pp. 1–51, https://doi.org/10.1142/9789813201057_0001.
29. R. Bartucci, A. Paramanandana, Y.L. Boersma, P. Olinga, A. Salvati, Comparative study of nanoparticle uptake and impact in murine lung, liver and kidney tissue slices, Nanotoxicology 14 (2020) 847–865, https://doi.org/10.1080/17435390.2020.1771785.
30. K. Rani, S. Paliwal, A review on targeted drug delivery: its entire focus on advanced therapeutics and diagnostics, Scholars J. Appl. Med. Sci. 2 (2014) 328–331.
31. C. Murugan, K. Rayappan, R. Thangam, R. Bhanumathi, K. Shanthi, R. Vivek, R. Thirumurugan, A. Bhattacharyya, S. Sivasubramanian, P. Gunasekaran, S. Kannan, Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy, Sci. Rep. 6 (2016), 34053, https://doi.org/10.1038/srep34053.
32. J. Wu, A. Deng, W. Jiang, R. Tian, Y. Shen, Synthesis and in vitro evaluation of pH-sensitive magnetic nanocomposites as methotrexate delivery system for targeted cancer therapy, Mater. Sci. Eng. C. Mater. Biol. Appl. 71 (2017) 132–140, https://doi.org/10.1016/j.msec.2016.09.084.
33. J. Lin, Y. Li, H. Wu, X. Yang, Y. Li, S. Ye, Z. Hou, C. Lin, Tumor-targeted co-delivery of mitomycin C and 10-hydroxycamptothecin via micellar nanocarriers for enhanced anticancer efficacy, RSC Adv. 5 (2015) 23022–23033, https://doi.org/10.1039/C4RA14602F.
34. Luisi PL, Walde P, Oberholzer T. Lipid vesicles as possible intermediates in the origin of life. Current Opinion in Colloid & Interface Science. 1999 Feb 1;4(1):33–9.
35. Nozawa Y. Advance and Perspective in Medical Application of Liposomes. In springer us; 1986. p. 31–8
36. Hotani H, Inaba T, Nomura F, Takeda S, Takiguchi K, Itoh TJ, et al. Mechanical analyses of morphological and topological transformation of liposomes. Biosystems. 2003 Aug 26;71(1–2):93–100.
37. Nomura F. Morphological and topological transformations of lipid bilayer vesicles. In american institute of physics; 2000. p. 426–34.
38. Latif N, Bachhawat BK. Liposomes in immunology. Journal of Biosciences. 1984 Oct 1;6(4):491–502.
39. Lizo?ová D, Frei S, Zadražil A, Balouch M, Št?pánek F. Multilobed Magnetic Liposomes Enable Remotely Controlled Collection, Transport, and Delivery of Membrane-Soluble Cargos to Vesicles and Cells. ACS applied bio materials. 2021 Mar 11;4(6):4833–40.
40. Van Der Koog L, Nagelkerke A, Gandek TB. Liposomes and Extracellular Vesicles as Drug Delivery Systems: A Comparison of Composition, Pharmacokinetics, and Functionalization. Advanced Healthcare Materials. 2021 Jun 24;11(5):2100639.
41. Imam SS, Zafar A, Alshehri S, Alruwaili NK. Chapter 10 - Liposomes and their theranostic applications in infectious diseases. In: Nanotheranostics for Treatment and Diagnosis of Infectious Diseases. elsevier; 2022. p. 275–87.
42. Xing H, Lu Y, Hwang K. Recent Developments of Liposomes as Nanocarriers for Theranostic Applications. Theranostics. 2016 Jan 1;6(9):1336–52.
43. Xin H, Jiang Y, Lv W, Xu J. Chapter 9 - Liposome-Based Drug Delivery for Brain Tumor Theranostics. In: Nanotechnology-Based Targeted Drug Delivery Systems for Brain Tumors. elsevier; 2018. p. 245–66.
44. Sonali S, Singh RP, Singh N, Sharma G, Vijayakumar MR, Koch B, et al. Transferrin liposomes of docetaxel for brain-targeted cancer applications: formulation and brain theranostics. Drug Delivery. 2016 Mar 31;23(4):1261–71.
45. Yue X, Dai Z. Multifunctional Liposomes for Imaging-Guided Therapy. In springer nature; 2015. p. 301–36.
46. Petersen AL, Hansen AE, Gabizon A, Andresen TL. Liposome imaging agents in personalized medicine. Advanced Drug Delivery Reviews. 2012 Sep 12;64(13):1417–35.
47. Tang WL, Tang WH, Li SD. Cancer theranostic applications of lipid-based nanoparticles. Drug Discovery Today. 2018 Apr 13;23(5):1159–66.
48. Verma A, Saraf S, Jain SK, Jain A, Bidla P, Panda PK, et al. Liposomes for Advanced Drug Delivery. In springer; 2020. p. 317–38.
49. Atyabi F, Farkhondehfai A, Dinarvand R, Esmaeili F. Preparation of pegylated nano-liposomal formulation containing SN-38: In vitro characterization and in vivo biodistribution in mice. Acta Pharmaceutica. 2009 Jun 1;59(2):133–44.
50. Cho HY, Lee CK, Lee YB. Preparation and Evaluation of PEGylated and Folate?PEGylated Liposomes Containing Paclitaxel for Lymphatic Delivery. Journal of Nanomaterials. 2015 Jan 1;2015(1):1–10.
51. Yousefi A. Preparation and In Vitro Evaluation of A Pegylated Nano-Liposomal Formulation Containing Docetaxel. Scientia Pharmaceutica. 2009 Jan 1;77(2):453–64.
52. Kaurav M, Minz S, Gautam L. PEGylated Liposomes. In bentham science; 2022. p. 133–68.
53. Dadashzadeh S, Vali AM, Rezaie M. The effect of PEG coating on in vitro cytotoxicity and in vivo disposition of topotecan loaded liposomes in rats. International Journal of Pharmaceutics. 2007 Nov 23;353(1–2):251–9.
54. Yang T, Cui FD, Choi MK, Cho JW, Chung SJ, Shim CK, et al. Enhanced solubility and stability of PEGylated liposomal paclitaxel: In vitro and in vivo evaluation. International Journal of Pharmaceutics. 2007 Feb 13;338(1–2):317–26.
55. Yadav D, Dewangan HK. PEGYLATION: an important approach for novel drug delivery system. Journal of Biomaterials Science, Polymer Edition. 2020 Sep 27;32(2):266–80.
56. Kim CE, Lim SK, Kim JS. In vivo antitumor effect of cromolyn in PEGylated liposomes for pancreatic cancer. Journal of Controlled Release. 2011 Sep 16;157(2):190–5.
57. Fathi S, Oyelere AK. Liposomal drug delivery systems for targeted cancer therapy: is active targeting the best choice? Future Medicinal Chemistry. 2016 Oct 24;8(17):2091–112.
58. Liu Y, Liu J, Castro Bravo KM. Targeted liposomal drug delivery: a nanoscience and biophysical perspective. Nanoscale Horizons. 2021 Jan 1;6(2):78–94.
59. Allen TM, Moase EH. Therapeutic opportunities for targeted liposomal drug delivery. Advanced Drug Delivery Reviews. 1996 Sep 1;21(2):117–33.
60. Allen TM, Hansen CB, Stuart DD. Chapter 4.6 - Targeted sterically stabilized liposomal drug delivery. In: Medical Applications of Liposomes. elsevier; 1998. p. 297–323.
61. Hazira R, Reddy M. Niosomes: A nanocarrier drug delivery system. GSC Biological and Pharmaceutical Sciences. 2023 Feb 28;22(2):120–7.
62. Jawale JK, Kashikar VS. An Overview on Nano Niosomes: As an Optimistic Drug Delivery System in Targeted Drug Delivery. Journal of Pharmaceutical Research International. 2022 Apr 23;14–25.
63. Dineshkumar B, Joy C, Krishna Kumar K, Nair SK. Niosomes as Nano-carrier Based Targeted Drug Delivery System. Journal of Drug Delivery and Therapeutics. 2021 Aug 15;11(4-S):166–70.
64. Varshney S, Alam MA, Dhoundiyal S, Kaur A. Niosomes: A Smart Drug Delivery System for Brain Targeting. Pharmaceutical nanotechnology. 2024 Apr 1;12(2):108–25.
65. - M, - P, - P, - K. Review On Targeted Drug Delivery System And Its Carriers As Drug Targeted To A Specific Organ. International Journal For Multidisciplinary Research. 2023 Mar 23;5(2).
66. Patel A, Deepak K, Payghan S, Sharad K, Mayur S, Kamble T. Niosomes: A Camouflaged Carrier for Drug Delivery System. International Journal of Advanced Research in Science, Communication and Technology. 2022 Dec 10;316–22.
67. Chen S, Hanning S, Falconer J, Locke M, Wen J. Recent advances in non-ionic surfactant vesicles (niosomes): Fabrication, characterization, pharmaceutical and cosmetic applications. European Journal of Pharmaceutics and Biopharmaceutics. 2019 Aug 22;144:18–39.
68. Dhanasekaran S. SMART Drug Based Targeted Delivery: A New Paradigm for Nanomedicine Strategies. International Journal of Immunotherapy and Cancer Research. 2015 Aug 20;1(1):008–12.
69. Singh AK, Yadav TP, Pandey B, Gupta V, Singh SP. Chapter 15 - Engineering Nanomaterials for Smart Drug Release: Recent Advances and Challenges. In: Applications of Targeted Nano Drugs and Delivery Systems. elsevier; 2018. p. 411–49.
70. Bhattacharjee H, Wood GC, Balabathula P. Targeted Nanoparticulate drug-delivery Systems for Treatment of Solid Tumors: a Review. Therapeutic Delivery. 2010 Nov 1;1(5):713–34.
71. Zhao P, Li F, Huang Y. Chapter 10 - Nanotechnology-based targeted drug delivery systems and drug resistance in colorectal cancer. In: Drug Resistance in Colorectal Cancer: Molecular Mechanisms and Therapeutic Strategies. elsevier; 2020. p. 173–98.
72. Shah A, Aftab S, Nisar J, Ashiq MN, Iftikhar FJ. Nanocarriers for targeted drug delivery. Journal of Drug Delivery Science and Technology. 2021 Feb 13;62:102426.
73. Memisoglu-Bilensoy E, ?en M, Hincal AA. Effect of drug physicochemical properties on in vitro characteristics of amphiphilic cyclodextrin nanospheres and nanocapsules. Journal of Microencapsulation. 2006 Jan 1;23(1):59–68.
74. Valente I. Polymeric nanocapsules for pharmaceutical applications. politecnico di torino; 2012.
75. Du B, Wang H, Tang H, Guan M, Wang J, Zhang Z, et al. Facile fabrication of gold particles decorated silk-on-silk nanocapsules. Materials Letters. 2016 Oct 20;187:106–10.   
76. Elizabeth PS, Néstor MM, David QG. Chapter 23 - Nanoparticles as dental drug-delivery systems. In: Nanobiomaterials in Clinical Dentistry. elsevier; 2019. p. 567–93. 
77. Walia S, Dua JS, Prasad DN. A Novel Drug Delivery of Microspheres. Journal of Drug Delivery and Therapeutics. 2021 Nov 15;11(6):257–64.
78. Yadav M, Mandhare TA, Jadhav V, Otari K. A Review on Microspheres as a Promising Drug Carrier. Journal of Drug Delivery and Therapeutics. 2024 Jul 15;14(7):120–8.
79. Chandna A, Batra D, Kakar S, Singh R. A review on target drug delivery: magnetic microspheres. Journal of Acute Disease. 2013 Jan 1;2(3):189–95.
80. Sharma D, Sharma A. MAGNETIC MICROSPHERE AN EMERGING DRUG DELIVERY SYSTEM. Asian Journal of Pharmaceutical and Clinical Research. 2017 Jun 1;10(6):54.
81. Raj H, Sharma A, Sharma S, Verma KK, Chaudhary A. Mucoadhesive Microspheres: A Targeted Drug Delivery System. Journal of Drug Delivery and Therapeutics. 2021 Apr 15;11(2-S):150–5
82. Yawalkar AN, Pawar MA, Vavia PR. Microspheres for targeted drug delivery- A review on recent applications. Journal of Drug Delivery Science and Technology. 2022 Aug 4;75:103659.
83. Bobade N, Atram S, Pande SD, G Ingle TK, Wankhede V. Formulation and Evaluation of Microspheres for Colon Targeted Drug Delivery Using Anthelminthics Drugs. Asian Journal of Pharmaceutical Research and Development. 2023 Aug 13;11(4):36–45.
84. Qiao S, Chen W, Zheng X, Ma L. Preparation of pH-sensitive alginate-based hydrogel by microfluidic technology for intestinal targeting drug delivery. International Journal of Biological Macromolecules. 2023 Nov 7;254(Pt 2):127649.
85. A. Pandit, D.I. Zeugolis, Twenty-five years of nano-bio-materials: have we revolutionized healthcare? Nanomedicine (Lond). 11 (2016) 985–987, https://doi. org/10.2217/nnm.16.42.
86. S. Haider, Nanoparticles : the Future of Drug Delivery 38 (2020) 1–2.
87. A.M. Vargason, A.C. Anselmo, S. Mitragotri, The evolution of commercial drug delivery technologies, Nat. Biomed. Eng. 5 (2021) 951–967, https://doi.org/ 10.1038/s41551-021-00698-w.
88. S. Adepu, S. Ramakrishna, Controlled drug delivery systems: current status and future directions, Molecules 26 (2021), https://doi.org/10.3390/.