Application of nano based drug delivery channel against leukemia chemotherapeutic resistance

Leukemia has been modern time’s most devastating diseases, killing millions every year. This has been the twentiethcentury health challenges without limits against a human with the unregulated proliferation of the cancerous cells with a very complex treatment process [1]. This demonstrates diagnostic variance with treatment resistance due to the complexity of the phenotypic and genetic frameworks [1]. Treatment of cancer in any form has attracted several therapies with certain specifi ed disadvantages and adverse impacts with the emergence of resistance to chemotherapy [2]. Limited FDA-approved drugs tackle leukemia cancer cells actively, triggering recurrences that are resistant to treatment as transplantation with the stem cell is the only recognized therapy that counters their activity [2]. Anti-cancer drugs are administered clinically to patients through chemotherapy, a routine procedure, to neutralize cell proliferation alongside surgical elimination, hormone, and radiation therapy. (Sutradhar & Amin, 2014) [2] Meanwhile, several complications occur with the unspecifi ed targeting by anticancer drugs, and negative drug distribution system [2]. As the formulation of cancer chemotherapy drugs requires a complex process that is attributed to highly developed polymer chemistry and electronic engineering [2]. However, the key task is to extricate cancer cells from the regular cells within the body systems and to develop the drug in a manner that cancerous cells can be detected and inhibit differentiation and replication. Unfortunately, modern chemotherapies have failed to selectively exterminate cancer cells without disrupting normal cells of the body with severe adverse effects with organ Abstract


Introduction
Leukemia has been modern time's most devastating diseases, killing millions every year. This has been the twentiethcentury health challenges without limits against a human with the unregulated proliferation of the cancerous cells with a very complex treatment process [1]. This demonstrates diagnostic variance with treatment resistance due to the complexity of the phenotypic and genetic frameworks [1]. Treatment of cancer in any form has attracted several therapies with certain specifi ed disadvantages and adverse impacts with the emergence of resistance to chemotherapy [2]. Limited FDA-approved drugs tackle leukemia cancer cells actively, triggering recurrences that are resistant to treatment as transplantation with the stem cell is the only recognized therapy that counters their activity [2]. Anti-cancer drugs are administered clinically to patients through chemotherapy, a routine procedure, to neutralize cell proliferation alongside surgical elimination, hormone, and radiation therapy. (Sutradhar & Amin, 2014) [2] Meanwhile, several complications occur with the unspecifi ed targeting by anticancer drugs, and negative drug distribution system [2]. As the formulation of cancer chemotherapy drugs requires a complex process that is attributed to highly developed polymer chemistry and electronic engineering [2]. However, the key task is to extricate cancer cells from the regular cells within the body systems and to develop the drug in a manner that cancerous cells can be detected and inhibit differentiation and replication. Unfortunately, modern chemotherapies have failed to selectively exterminate cancer cells without disrupting normal cells of the body with severe adverse effects with organ failure, leading to poor care at low therapeutic doses with eventual death [3]. Characterized by the presence of this type of cancer, leukemia poses particular treatment challenges as bone marrow, which creates blood cells, is impaired by the condition. Leukemia is a premature blood-generating stem cell growth characterized as cancer of the white blood cells [1]. Chemotherapy is the fi rst phase of therapies to disrupt cancerous white blood cells, but if the leukemia stem cells within the marrow of the bone survive, they can recur in a form resistant to therapy. Under 20 % of children and up to two-thirds of older patients with leukemia report a relapse as adults with relapse experience a survival rate of less than 30 percent, while the survival rate of fi ve years posts relapse for children, is around two thirds [4]. Chemotherapy would not boost the response to treatment for these patients if a relapse occurs as to why scientists have a pressing necessity to design a treatment that can attack chemotherapy-resistant cells more effectively [4].  There are several limitations of chemotherapy. The disruption of the rapidly dividing cells, which is the key property of neoplastic cells is usually frustrated by typical chemotherapeutic agents as the reason why chemotherapy destroys bone marrow cells, healthy hair follicles, macrophages, and the digestive tract [6]. In other words, as they are not selective only to cancerous cells, they lead to known side effects like mucositis which is the infl ammation of the gastrointestinal tract, myelosuppression that decreased the development of immunosuppression by white blood cells, alopecia, organ dysfunction, anemia, or thrombocytopenia, dose reduction and delay in treatment or discontinuation of treatment [7].
Cell division can be effectively prevented in the circumstance of solid tumors, causing chemotherapy drugs insensitive to treatment. Chemotherapeutic drugs are also unable to infi ltrate the center of solid tumors with failure in destroying the cancerous cells [8]. Standard chemotherapeutics are frequently fi ltered out of the macrophage-engulfed circulation thus persist in the circulation for a short period with the inability to obstruct the cancer cells [7]. Similarly, poor solubility of the treatments is a big concern, allowing them not to traverse the biological layers [8] and the inability of chemotherapeutics drugs to penetrate the nucleus inside the cells as explained in Figure 1 [7]. P-glycoprotein, a multidrug resistance component that is overexpressed on the cell surface which inhibits the absorption of drugs behaves as an effl ux pump that regulates the emergence of anticancer therapy resistance.

Nanotechnology in cancer cells targeting
The aspect of science that typically addresses the size range around several nanometers, designed for a specifi c application, is what nanotechnology is portraying [2]. Some years ago, the development of concise drug delivery applications has become an area of focus as it gives signifi cant advantages to surmount the drawbacks of conventional chemotherapies [2]. Nano cancer therapy is very convincing both in diagnosis and treatment phases since it can penetrate tissues cellularly [2]. In other words, nanomedicine is now technically being evaluated and applied in cancer therapy refl ecting a signifi cant milestone in the identifi cation, diagnosis, and control of the diseases. That is, drug delivery techniques with the approach of nanotechnology can drastically enhance detection sensitivity and stability of drug for combating multidrug resistance, particularly with solid tumors, as nanoparticles conveniently active due to their enhanced absorption coeffi cient and stabilization effect [9].
Different studies have been conducted to explore more precise treatment options with nanotechnology that mitigates the side effects of conventional chemotherapies (Sutradhar & Amin, 2014) [2]. It has now been designed to help the targeted therapies navigate across biological membranes, activate molecular interactions, and recognize alterations in molecules. Particularly in comparison to macroparticles, they possess a huge surface area with confi gurable biological, optical, mechanical, and magnetic properties [2]. Recent drug delivery with metallic nanoparticles for cancer therapy encompasses polymeric micelles, nanospheres, dendrimers liposomes, nano-capsules, and nanotubes that are already marketed under Abraxane and DOXIL (liposomal doxorubicin) (albumin-bound paclitaxel) [2].
In the scenario of targeted delivery, nanoparticles infused with chemotherapy entities are formulated to react directly with the defective cells. Thus, the substrate of the nanoparticles is altered to tackle the cancer cells as targeting entities are affi xed to the surface of nanoparticles for molecular defi nitions. They are attacked by engineered nanoparticles either by antibody-antigen recognition or ligand-receptor engagement [10]. Three main modules for a targeted delivery structure centered on nanotechnology are anticancer management with an inducing agent, targeted moiety-penetration mechanism, and a mobilizer. To develop a nanoparticle, materials such as polymers, ceramics, metals, and lipids are widely used materials [2]. And typically, synthetic and natural composites with lipids are utilized as vectors of drug delivery. Chemotherapy based particles are absorbed by phagocytic cells with easy clearance by the Reticuloendothelial Mechanism (RES) [2]. Arrays of procedures have been introduced to preserve nanoparticles within the bloodstream as the modifi cation of the carrier's polymeric composition which is to prevent washing out and circulation in the blood system for a longer time frame as they are encapsulated by hydrophilic polymers that effectively target cancerous cells. Around the nanoparticle surface, hydrophilic polymer coating resists plasma proteins as they evade opsonization and washing (cloud effects) [11]. Polyethylene Glycol (PEG), polyoxins, poloxamers, and polysaccharides especially are frequently employed hydrophilic polymers [11]. At the molecular level, cancer cells have certain peculiar properties that distinguish them from healthy cells as certain receptors are been over-activated on their surfaces which distinguish the function. The Connection to the surface of nanoparticles with the corresponding ligands induces them to attack only cancer cells. As the nanoparticles entangle to the receptors, they actively allow receptor-mediated cell endocytosis or phagocytosis, culminating in encapsulated drug cell internalization [12].
Meanwhile, a successful targeted delivery system of drugs is linked with a mechanism that transports a certain quantity or both of a therapeutic or diagnostic agent to the defected organ within the body systems (Anarjan, 2019) [13]. Drug-loaded nanoparticles are employed in the identifi cation of particular receptors/antigens on target cells by the addition of ligands or unique physical or chemical engineering structures due to limitations of non-specifi c drug delivery in whole body cells and decreasing cytotoxicity and adverse impacts of drugs on healthy cells and organs that are unlikely in conventional chemotherapy. Vehicles with intelligent nanoparticles have been licensed for the treatment of a wide range of human cancers [13].
The application of drug delivery can be divided into two criteria which are either active drug targeting which can be used for antibody, receptor, and carbohydrate, or passive drug targeting which can be used for direct use, oncolytic therapy and leaky vasculature as explained in the fi gure. Active drug delivery targeting also referred to as the ligand-mediated targeted strategy, requires identifi cation, acquisition, and encourage acceptance by the targeted cells based on their affi nities [14]. Various unique molecular interactions such as receptor-ligand-dependent attachments, charge-based interactions, and facilitated motif-based interactions with substrate molecules are based on chemical affi nity for active targeting [15] A ligand may be various biomolecules, including antibodies, proteins, nucleic acids, peptides, carbohydrates, and tiny organic molecules such as vitamins [16]. Surface molecules released in diseased cells, proteins, sugars, or lipids present in the tissues, secreted tumor cells in the microenvironment of a cancer cell or with the local environment can be the target substrates [17]. Smart, targeted systems based on nanomaterials leverage the multivalent nature of ligands' interactions with the target antibodies. There is an exponential rise in the exactness of nanoparticles for their cognate target [18] as several ligand molecules are accumulated in the nanosystems. In particular, the coupling of one ligand molecule usually promotes the interaction by coordinated actions of the resulting metabolites, signifi cantly increasing the binding effi ciency and subsequent behavior. With passive targeting, Intravenous administration is perhaps the most common delivery system for nanomaterial-based anticancer drugs. The absorption phase through the intestinal epithelium needed after oral administration is bypassed by this approach [19]. This deposition of the drug at the location of the tumor is a passive procedure that requires extended-release for adequate delivery of the drug. The accumulation of nanocarriers depends primarily on physicochemical characteristics such as scale, shape, surface characteristics, and chemistry [20].
The degrees of the aggregation of nanomaterials at the site of the tumor is dictated by their thickness. Nanocarriers have to be less to the dimension in the neovasculature, having the scale that acutely alters the extravasation of the tumor. Similarly, blood perfusion, passive interactions with biomolecules, and immunological clarifi cations affect the biodistribution of the nanomaterial-drug formulation [21].
Nanotechnology typically has the opportunity to overcome many limitations in traditional therapeutic preparations as important progress has been achieved in the development of engineered nanomaterials with high precision, responsiveness, and effectiveness for cancer therapy. Predictably, nanomaterials Citation: Bhattacharjee  pH sensitivity of Nano drug delivery with a stabilized carrier at the cellular level with the prepared suspension that was spray-dried by dispersing the microsphere at a lower pH with the cancerous tissue and the nanospheres as they distribute the drug over time [25]. In the case of their effi cient endo-lysosomal recovery, biodegradable nanoparticles have been derived through copolymers of poly (d, l-lactide-co-glycolide). The mechanism behaved by specifi cally altering the substrate charge of these nanoparticles in the acidic endo-lysosomal cavity, enabling the nanostructures to react with the endo-lysosomal layer directly to the cytosol) [26]. For sustainable therapeutic impacts, these nanoparticles can distribute a variety of therapeutic agents especially deoxyribonucleic acid at a gradual rate [26]. Hence, scientists have invented pH-responsive, thermo-responsive, and environmentally friendly nanoparticles for the application of nanotechnology in cancer therapy through the implantation of ecofriendly poly-(d, l-lactide) against methacrylic acid and N-isopropyl acrylamide. The concentration of the drug which is hydrophobic with the easy cross of the plasma membrane in the target tissue may be appropriate for a delivery mechanism [27].

Biochemistry of nanostructured targeting agents
Nanocarriers including anticancer drugs, targeting substituents, and composites are engaged as targeting agents for cancer therapy with a spectrum of nano-carriers including the dendrimers, carbon nanotubes, liposomes nano-capsules, micelles, and nanospheres which covalently enclosed the therapeutic agents within the entrapped nanoparticles [28]. Liposomes are lipid bilayers where the center may be hydrophobic or hydrophilic where single bilayer lipid possesses a soluble center that encapsulates water-soluble drugs, while the other contains lipid-soluble drugs [28]. However, as macrophages rapidly nullify their activity, they are coated for balanced physiological conditions with an inert polymer matrix of Polyethylene Glycol (PEG) with liposomes [29]. In vivo research indicates that Hyaluronan (HA) coated liposomes optimize circulation time and improves the selection of HA receptor-expressing tumors [30]. The classes of liposomal treatment delivery in terms of passive and active selection can be accomplished as liposomal nanoparticles can be paired with either antibodies or appropriate drug delivery ligands with the benefi ts of being biodegradable, non-antigenic, and a high transport rate [31]. Dendrimers are three dimensional and treelike formations with a polyfunctional center from elements that are either synthetic or natural, such as amino acids, sugars, and nucleotides [32]. They are synthesized to preserve the desired shape and size by coordinated polymerization of the monomeric units due to their particular branching nature, several entities, including both hydrophobic and hydrophilic molecules for conjugation [33]. Through hydrophobic, hydrogen bonds, or chemical interconnections, they may also be fi lled with drugs by using cavities in their cores to deliver genes, medications, and anticancer agents. Micelles are circular entities where the central core is developed by molecules with a hydrophobic end aggregate and hydrophilic ends of other molecules in association with the core's surrounding liquid atmosphere as they are an appropriate medium for the distribution of nonaqueous drugs in their hydrophobic part [34]. Nanospheres are Therefore, whenever the encapsulated drug mimics a nucleic acid, the intracellular dissemination of the carrier is transformed [2]. As the pH is more acidic around the cancerous cells, any carriers that switch solubility at lower pH may be adopted in the attack and activate drug release [22].
The extracellular environment of blood cancers conversely is acidic and through their cellular compartments, there will be an altered pH level. Consequently, nanoparticles that are responsive to pH gradients are encouraging for the distribution of drugs and treatments as a pH-sensitive nanoparticle comprises a shell with a center that reacts to pH as it alters the pattern of solubility [23]. Core-shelled nanoparticles with polymer frameworks are developed to be based on residual pH of 7.4 with their reduced critical temperature [23]. At low pH, the resultant shift in LCST induces the core-shell nanoparticles to degrade with precipitation in acidic conditions in and around the cancerous cells, catalyzing the therapeutic activity [24]. A sustained approach for designing a pH-responsive and release model for the cancer treatment was stated in several reports [25]. Their method employs solid non-hydrophilic nanospheres storing drug molecules that are coated with a pH-responsive spherical particles, consisting of a matrix material where the drug is distributed uniformly by encapsulation or attachment with a surface that can be manipulated for targeting motives by the insertion of ligands or antibodies. Conversely, nanocapsules are like membranes with a central structure where a drug is enclosed with a polymeric surface wrapping the core [35]. In the shape of a hollow tube, nanotubes with fullerenes are a family of molecules with carbon as their atoms are trapped as receptors or ligands to be attached to their targeting surface [36]. To be water-soluble and activated, carbon nanotubes are modifi ed for the connection to several active molecules like peptides, proteins, nucleic acids, and active therapeutic agents [37]. Poly (alkyl cyanoacrylates), poly (methylidene malonate), and polyesters such as poly (lactic acid), poly (glycolic acid), poly (e-caprolactone), and their copolymers are suitable polymers for nanoparticles synthesis [38]. In terms of biocompatibility and biodegradability, poly (-caprolactone), glycolic acid (PGA), lactic acid (PLA) with their copolymers are the most extensively investigated [39]. surfactants [40]. The applications of the polymerized medium on preformed particles subsequently induce drugs to be stuck to the polymeric wall as polymer precipitation is the basis of the preparation of particles from preformed polymers. An aqueous system with or without a surfactant layer, allows the organic fraction of the polymer to be emulsifi ed while at the second phase with the facilitation of particle deposition, the organic solvent is eliminated by methods such as salting out, evaporation, and diffusion with stirring at which the encapsulated substance needs to be at least partially soluble in an organic solvent [40].

Recent methodologies for nano-based anticancer (leukemia) therapy
Hence, the coating of hydrophilic bio compounds like peptides, proteins, or nucleic acids is thus a major drawback. Therefore, to enhance the formulation capacity of hydrophilic molecules, alternative processes such as the derivative of the hydrophilic substrate to form a complex structure that is hydrophobic have been established [40]. The typical way is to apply a double emulsion technique, where the hydrophilic compound in an aqueous system is initially emulsifi ed into the polymer's organic solution and the main emulsion, with or without a surfactant, is then drained into a signifi cant quantity of water.
As regards the hydrophilic compounds, the double emulsion method retains good entrapment effi ciency; nevertheless, the size of the particles is typically larger than the simplest emulsion mode. The spray-drying system, where the drug is absorbed or distributed inside an organic polymer solution to be atomized in a heated airfl ow as the solvent is rapidly volatilized and the dried nanoparticles are freely obtained. To increase the trapping performance of lipophilic compounds or to generate a sustained release mechanism, the nano-capsule technique offers several benefi ts just like the hydrophilic drugs, especially oily insulin suspensions. Nano-capsules can also be produced from alkyl cyanoacrylate monomer units through interfacial polymerization. In a solution of ethanol and oil, the drug product and the monomer are then dissolved or suspended with magnetic agitation [40].
Intracellular drug delivery applies to medicinal delivery agents inside the cell to particular compartments or organelles.
The delivery of targeted intracellular drugs results in higher bioavailability of the therapeutic agent at the place of action, improves the pharmacological impact, and decreases the drug's side effects [34]. Drug-loaded nanoparticles carry drugs to the appropriate cellular targets inside the cell as a drug storehouse [41,42]. inhibitory effects on the un-doped TiO2.On the growth of K562 cells and their viability. In conclusion, such nanoparticles can be of potential use in CML photocatalytic therapy [42,45].

PVP-coated AgNPs of different dimensions in an antileukemia effect against different lines of human AML cells.
In a dose-dependent way, AgNPs limited the viability of therapeutic isolates of AML patients. The authors investigated that the primary isolates of AML patients were higher; and that the cytotoxic effects of AML cells were stronger than normal hematopoietic cells. The biochemistry for AgNPs in preventing AML cell growth has been related to the release of oxygen radicals and silver ions to exert their cytotoxic effect. The dose was stated to play a critical role in cytotoxicity along with both the size and surface area of nanoparticles [42,46].
Mouse leukemia cell lines preserved in the DMEM culture are L1210 cells from the culture media for Cytotoxicity and cellular absorption of PLGA (ETO-PLGA NP) and PLGA-MPEG (ETO-PLGAMPEG NP) etoposide-loaded nanoparticles on L1210 cells [38]. For L121 cells, the IC50 values were 18.0, 6.2, and 4.8 μM respectively for ETO, ETO-PLGA NP, and ETO-PLGAMPEG NP. The higher cytotoxicity was due to increased cell absorption of the nanoparticles. By quantifying the percentage of fl uorescence using 6-coumarin as the fl uorescent marker in the nanoparticles, the cellular uptake of the nanoparticles was determined. To visualize the cellular absorption of the nanoparticles by L1210 cells, confocal microscopy was used [47].

Diagnosis of leukemia using gold-nanoparticle
Leukemia diagnosis and detection are diffi cult. Presently combinations of the available methods for leukemia diagnosis apply cytochemical studies of bone marrow and peripheral blood, including immunophenotyping by fl ow cytometry or microarray, and amplifi cation by chain reaction with polymerase (PCR) of malignant cell mutations. Multiple antibody criteria for immunophenotyping. Samples for correct cell detection, which enhances the diffi culty of both and the method's cost. Methods based on PCR do not explicitly detect Cells and before examination requires complex pretreatment. There is a here new technology for the rapid, easy, and economical diagnosis of whole-blood leukemia need to be developed. Also, precise and delicate Methods for the diagnosis of leukemia would make it easier for the selection of clinicians' successful treatment) [42].
These diagnostic problems may be solved by nanotechnology in the case of leukemia. Recently a new, rapid, homogeneous approach to testing fl uorescence-based detection of leukemic cells in the whole blood established anisotropy [48]. The combined methodology provides the benefi ts of targetoriented near-infrared fl uorescent nanoparticles Aptamersspecifi c to cells. The phase of fl uorescence anisotropy gives a technique of rapid homogeneous recognition for leukemic detection without the need for complex separation steps, cells are in the entire blood. Aptamers have recently been recognized for diagnostic purposes. As reliable as antibodies, since they can easily be synthesized for Analysis, which does not require animal destruction [42].
Recently, there are reports of an introduction of a vastly selective, rapid, and sensitive DNA nano-sensor that could differentiate between the mismatched one-base oligonucleotide sequences for chronic lymphocytic leukemia detection.
Centered on a Porphobilinogen Deaminase (PBGD) probe, this highly sensitive DNA sensor was constructed to detect a particular sequence of porphobilinogen deaminase genes highly associated with CLL cancer. A DNA probe of 25 nucleotides was modifi ed with-SH was initially reacted chemically by selfassembly around the nanoparticles of gold. The detector was focused on the detection of sequence-specifi c DNA linked to chronic lymphocytic leukemia by Electrochemical Impedance Spectroscopy (EIS) [42].

Application of gold nanoparticles for drug distribution
The fl exibility of gold-NPs been a critical drug delivery agent has been documented by numerous studies [49].
Without any safety and effi cacy diffi culties, drug delivery was very successful in moving the drug as nasal, mouth, eye, rectal, buccal, and inhalation are common distribution routes [49]. Due to the possible enzymatic destruction of most biomolecules, such as proteins, antibodies, peptides, genes, and vaccines, drugs were not able to be distributed through the aforementioned methods [50]. These macros and biomolecules, due to their molecular size, cannot be freely absorbed into the bloodstream as the key diffi culties for protein and peptidebased drugs to be distributed with the nanoneedle array will therefore be the principal challenge. Consequently, to improve the reproducibility, specifi city, reliability, and sensitivity in the targeted areas, several drug delivery techniques have been established. Therefore, in transmitting excited molecules through the cells, acoustic drug delivery is actively engaged with the ultrasound system [50]. The process of distributing thinfi lm medications required readily disintegrating polymeric materials that could be easily assimilated through contact with the oral region [51]. Microemulsion for unique ouzo effects has been applied in the auto-micro emulsifi cation drug distribution arrangement. The delivery process for neurological drugs could direct the therapies into the particular impaired nervous system) [52]. In nanomedicines, drug delivery systems have been a major encouragement as one of the critical and extensively employed resources in nanomedicine with the production of gold nano colloids. In several cases around the world, leukemia, which results in death, is a form of cancer that typically includes blood cells and bone marrow. However, the most common form of childhood cancer is acute lymphoblastic leukemia with the chemotherapy of Dau, which is an anthracycline antibiotic, which is a recognized chemotherapeutic drug. Dau's clinical administration has been reduced especially in adolescents, due to its accumulated cardiotoxicity. There are reports of an aptamer with protein and tyrosine kinase-7 (PTK7), for Dau-specifi c delivery to Molt-4 cells [57].

Conclusion
In certain ways, nanotechnology has already redefi ned cancer therapy and is transforming the pattern of treatment