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Polymeric Nanoparticles for Targeted Treatment and Management in Cancer Cervix: Current Insights

Authors: Popsy Raj1, Manoj M.Gadewar2, Anita Singh 3, Neelam Pawar4, Rubal Dhaka5, Alpi Pruthi6, Suchitra Nishal7, Parmita Phaugat8,Jyot Bajaad9,Rinki Kumari10

Authors Affiliations-1. K.R.ManglamUniversity,Sohna Road, Haryana-122103,India. [ Orid ID 0000-0002-3851-3413]

2. K.R.ManglamUniversity,Sohna Road, Haryana-122103,India.

3. Sunder Deep Pharmacy Collage,Ghaziabad.

4. Chaudhary Bansilal University, Bhiwani, Haryana. [Orid ID 0000-0003-2553-8950]

5.PDM Collage Of Pharmacy, Bahadurgarh, Haryana.[Orid ID 0000-0001-8427-8525]

6.Safety Associate, IQVIA. [Orid ID 0000-0003-0666-5161]

7.G D Goenka University, Gurugram. India.[Orid ID 0000-0003-1315-7480]

8. G D Goenka University, Gurugram. India.[Orid ID 0000-0002-8867-8793]

9.G D Goenka University, Gurugram. India. [Orid ID 0000-0003- 4118-489X]

10.Department of Microbiology, Hind Institute of Medical Sciences, Mau Ataria, Sitapur Rd, Uttar Pradesh, India-261303

* Corresponding author's name: Popsy Raj and Manoj M.Gadewar Email ID: [email protected] and [email protected]

Abstract

Cervical cancer (CC) is the third most prevalent life-threatening cancer globally, and in India, 2nd most common female cancer. The high-risk strain – "human papillomavirus"16 and 18 associated with pathogenesis and high incidence of CC incidence globally. Furthermore, two HPV oncoproteins, E6 and E7, caused carcinogenesis by targeting various cellular pathways, including HPV DNA integration with host DNA, progression, disturbance of cell-cycle checkpoints, and apoptosis.Despite the success of CC prevention vaccines, therapy for the disease is significantly less satisfactory because of multidrug resistance and side effects.

Nanotechnological interventions have greatly improved cancer therapy by overcoming the present limitations in conventional chemotherapy, such as suboptimal biodistribution, cancer cell

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drug resistance, and significant systemic adverse effects. Because of their passive and ligand- based targeting mechanisms, nanoparticles (NPs) accumulate preferentially at tumor sites.The recent utilization of nanotechnology in CC diagnosis and therapy and the development of HPV vaccinations. Drugs containing polymeric nanoparticles (PN) have better pharmacological and therapeutic properties. PN has been touted as a promising carrier for anticancer drugs among targeted drug delivery systems.We reviewed numerous ways for directing nanoparticles to a specific site and preparation processes, patent inventions, and prospects in this study.

Keywords: cervix cancer, HPV, E6, and E7 oncoprotein, CDKs, p53, p21, p27, and RB.

Background

Cancer is the second most prevalent cause of female mortality globally, marked by the uncontrolled growth and spread of cancerous cells. Surgery, radiation, hormone therapy, and chemotherapy are some of the current cancer treatments. Chemotherapy is a standard treatment method for cancer. Traditional chemotherapy is nonspecific in its targeting of malignant cells, leaving normal healthy cells vulnerable to the drug's side effects. This dramatically reduces the drug's maximum permitted dose[1].

Furthermore, rapid clearance and selective distribution into targeted organs and tissues necessitate administering a large dose of medicine, which is costly and frequently results in unfavorable effects. Nanoparticles (NPs) are tailored drug delivery vectors that can selectively target huge dosages of chemotherapeutic drugs or therapeutic genes into cancer cells while leaving healthy cells alone. By addressing the limitations of conventional chemotherapy, such as poor biodistribution, cancer cell drug resistance, and significant systemic adverse effects, NPs hold great promise of drastically transforming the face of oncology[1-2].

NP systems are currently being used to treat cancer in a variety of ways. The features of these systems have been tweaked to improve tumor delivery; for example, hydrophilic surfaces give NPs stealthy properties for extended circulation durations, while positively charged surfaces can help cancer cells internalize more rapidly[1].Dendrimers, for example, are a kind of NP now being studied for cancer therapeutic purposes.This article reviews the targeting features of cancer therapy as well as numerous polymer-based nanocarriers.

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Epidemiology &EtiologyandMolecular Mechanism of CC

Over the last decade, epidemiologic and molecular evidence has connected genital human papillomavirus (HPV) infection to the development of cervical cancer, the second most frequent malignancy in women globally. The genital HPV varieties linked to cervical cancer are classified as high-risk, while the rest are classified as low-risk. Even infection with a high-risk HPV strain, however, is frequently undetectable and self-limited. Although HPV infection precedes the onset of cervical cancers, other factors such as prolonged high-level viral expression, immunological condition, and genetic background appear to influence the progression to malignancy[5-8].

With an expected 569,847 new cases and 311,365 deaths in 2018, cervical cancer is the third most frequent malignancy among women worldwide (GLOBOCAN) (Figure-1). Squamous cell carcinoma is the most common kind, followed by adenocarcinomas. CC is the second most prevalent cause of female cancer in India, affecting women aged 15 to 44 years. In India, roughly 96,922 new cervical cancer cases are diagnosed each year, with 60,078 fatalities (expected for 2018) [2].

Invasive cervical cancer will be detected in 13,170 instances in the United States in 2019.

Between 1975 (14.8 per 100,000) and 2015 (6.8 per 100,000), the incidence rate dropped by more than half, and the death rate in 2016 (2.2 per 100,000) was less than half of what it was in 1975 (5.6 per 100,000), owing to widespread Pap test screening [3-9]

Lung cancer, breast cancer, and colorectal cancer are the three most commonly diagnosed malignancies in affluent countries, while breast cancer, cervix cancer, and lung cancer are the top three diseases diagnosed in developing countries [4]. According to GLOBOCAN 2018, there were 569,847 new cases (4th in the world, accounting for 3.2 percent of all cancers in women) and 311,365 deaths from cervical cancer (3.3 percent of all cancer deaths in women) [5-6].

According to current estimates in India, 96922 women are diagnosed with cervical cancer each year, with 60078 dying due to the disease. It is the second most common cancer among females [7-13].

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Figure 1: The Pie charts represent the distribution of (a) new cases and (b) deaths in women worldwide. Source: GLOBOCAN 2018

Human papillomavirus (HPV) (figure-2A,C,D) infection is linked to nearly all occurrences of cervical cancer. Cervical intraepithelial neoplasia (CIN) and cervical cancer can result from infection with specific forms of high-risk human papillomaviruses (HPV), particularly types 16 and 18, potentially due to the actions of viral oncoproteins E6 and E7 [4][5]. According to the World Health Organization (WHO), over 90% of cervical cancer deaths occur in developing nations [4]. Other factors, in addition to HPV infection, can raise your risk of cervical cancer.

These include:

➢ Cigarette smoking and carcinogen (benzo[a]pyrene, BaP [6][7][8]).

➢ long-term use of birth control tablets (five or more )

➢ A personal history of cervical, vaginal, or valva dysplasia.

➢ A history of cervical cancer in the family

➢ Chlamydia and other infections

➢ Immune system issues, such as HIV/AIDS, make it more challenging to combat infections like HPV.

➢ Being born to a mother who used the medication diethylstilbestrol (DES) during pregnancy.

➢ Age is also a consideration.

➢ Having a large number of sexual partners

The ability of high-risk HPV types to immortalize cultured human keratinocytes is linked to their relationship with cervical cancer; low-risk varieties lack this ability under similar growth conditions. Immortalization is connected to the viral genes E6 and E7, which are also the two

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viral genes preferentially maintained and expressed in cervical malignancies and cell lines produced from tumors. E6 from high-risk HPV types binds and degrades wild type p53 significantly more efficiently than E6 from low-risk virus types, whereas E7 from high-risk virus types binds and inactivates pRb better than E7 from low-risk virus types[11-13].

CC, preventable malignancies, because of the availability of screening tests and vaccines to prevent HPV infections. Cancer begins in the cervix, the narrow passage from the vaginal canal into the uterus(fig-2B-D). Squamous cell tumors account for the majority of cervical malignancies (about 90%). The second most frequent kind of cervical cancer is adenocarcinoma (about 10 percent ). CC is generally treated when detected early and is associated with a prolonged survival time and an excellent quality of life [1-4,14-18].

Those who smoke cigarettes and have somewhat aberrant cytology are more likely to develop more significant and more severe histology abnormalities. Tobacco smoke ingredients (such as nitrosamines) have been found in cervical mucus, and higher smoking-related DNA adducts have been found in normal epithelium close to cervical intraepithelial and invasive neoplasia, indicating a direct DNA-level abnormality. Individual sensitivity to tobacco-related carcinogens may be determined by differences in cervical expression of cytochrome P450 enzymes, which activate carcinogenic nitrosamines, and glutathione S transferase, which denatures them[9].

Figure-2A Classification of HPV and association development of CC

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Figure 2B: Schematic representation of pathogenesis of oncogenic HPV and events leading to cervical cancer progression. (a) HPV infects basal epithelial cells through micro-abrasions in the cervical epithelium, and the viral genomes migrate to the nucleus, viral genomes are amplified.

Most of the time, our immune system (cell-mediated immunity) naturally clears HPV infection from our body. (b) When high-risk-HPV is integrated into the host genome, E6 and E7 are over- expressed, leading to enhanced proliferation and cellular mutation accumulation. This leads to loss of cellular differentiation capacity, and cancerous cells invade the dermal layer and

surrounding tissues.

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Figure 2C: Integration of HPV DNA with host DNA. HPV DNA integration with a host proto- oncogene interrupts the viral DNA within the E1/E2 open reading frame, leading to preferential retention of the long control region (LCR) and overexpression of the oncoproteinsE6 and E7.

Figure 2D: Cell cycle with checkpoints. The cell cycle is controlled by the complex interplay of cyclin-dependent kinase and cyclins. Cyclin –D-CDK4, cyclin D-CDK6, and cyclin E-CDK2 regulate the G1 to S transition. Cyclin B –CDK1 is essential for the G2 to M transition[9].

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Cervical Cancer Treatment Approaches Vaccination

Gardasil-quadrivalent, Gardasil 9, and Cervarix-bivalent are all effective against HPV strains 16 and 18, which cause 70 percent of cervical cancers, and the quadrivalent vaccine is also effective against HPV 6 and 11, which cause genital warts. According to research, immunization is beneficial in women who have already cleared the virus naturally. On existing lesions or healthy virus carriers, it has no therapeutic benefits. [14] In underdeveloped countries, vaccination policies will not be as effective. Vaccination measures will be ineffective in both poor and rich countries, where the disease is one of the leading causes of mortality among women, and screening programs have significantly lowered the incidence of this malignancy. Vaccination is also ineffective in several situations, such as in women who have had previous cervical intraepithelial neoplasia (CIN), pregnant and lactating women, and immunocompromised patients.

Surgery

Cancer surgery removes the tumor and nearby tissue during an operation. Surgery is the oldest type of cancer treatment, and it is still effective for many types of cancer today.

Different types of surgery are helpful to people with cancer. Some surgeries are used in combination with other types of treatment. Types of surgeries include [15]:

➢ Curative surgery

➢ Preventive surgery

➢ Diagnostic surgery

➢ Staging surgery

➢ Debulking surgery

➢ Palliative surgery

➢ Supportive surgery

➢ Restorative surgery

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Radiation Therapy

Radiation therapy is a non-invasive cancer treatment that uses high-energy X-rays or other types of radiation to destroy cancer cells and stop further cancer growth. Radiation therapy is done under the supervision of an experienced team of radiation oncologists. The experts administer radiation in a dedicated radiation site. Radiation treatment for cervical cancer could include these therapies [16]:

➢ Externally by directing a radiation beam at the affected area of the body ( external beam radiation)

➢ Internal by placing a device filled with radioactive material inside the vagina, usually for only a few minutes ( Brachytherapy)

➢ Both externally and internally Chemotherapy

Chemotherapy involves a single drug or combination of drugs (Table-1)to kill /destroy cancerous cells or slow down their growth while causing the least possible damage to healthy cells.

Chemotherapy may be given if the cervical is advanced or returns after treatment and may be combined with radiation therapy. Chemotherapy is directly delivered to the vein using a drip. It can be combined with radiotherapy to cure cervical cancer, or it can be used as a sole treatment for advanced cancer to slow its progression and relieve symptoms.

Table-1WHO guideline for treatment regimen of cervical cancer: [17]

First-line novel agent Second-line novel agent

Platinum-based Bevacizumab

Cisplatin-based Lapatinib

Carboplatin + paclitaxel Pazopanib

Carboplatin + bevacizumab + paclitaxel Cisplatin – cetuximab

Carboplatin based Erlotinib

Docetaxel based Gefitnib;Imatinib;Cetuximab;Temsirolimus;

Topotecan; Gemcitabine ; Ifosfamide Immunotherapy

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Immunotherapy is promising for the treatment of advanced or recurrent cervical cancer.

Immunotherapy, also called biologic therapy, is designed to boost the body's natural defense system to fight cancer. It uses materials made either by the body or in a laboratory to improve, target, or restore immune system function.

Pembrolizumab works by blocking this attachment. This therapy is used to treat cancer that has stopped responding to chemotherapy, cannot be removed by surgery, or has returned [18].

Common side effects include skin reactions, flu-like symptoms, diarrhea, and weight changes.

Nanoparticles (NPs) mediated targeting plays a significant role in inhibiting inflammation, angiogenesis, and tumor progression. Nanoparticles (NPs) generally <100 nm can be used in targeted drug delivery at the site of disease to improve the uptake of poorly soluble drugs, targeting of drugs to a specific location, and drug bioavailability [19][20].

Polymeric nanoparticles broadly expand and play a crucial role in a broad spectrum of areas ranging from medicine to biotechnology, pollution control, and environmental technology [21].

Polymeric nanoparticles (PNPs) have a matrix architecture composed of biodegradable and biocompatible polymers of synthetic or natural origin. Among the new drug delivery systems, polymeric nanoparticles have been considered favorable and rising carriers for anticancer agents [22].

Polymer-based nanoparticles effectively carry drugs, proteins, and DNA to target cells and organs. Their nanometer-size promotes effective permeation through cell membranes and stability in the bloodstream. Polymers are very suitable materials for manufacturing countless and varied molecular designs that can be integrated into unique nanoparticle constructs with many potential medical applications [23]. PNPs can be either nanosphere or nanocapsules. Two main strategies used to prepare PNPs are the "top-down" approach and the "bottom-up"

approach. In the "top-down" approach, a dispersion of preformed polymers produces polymeric nanoparticles, whereas, in the bottom-up approach, polymerization of monomers leads to polymeric nanoparticles [24].

Nanoparticles are generated from a dispersion of preformed polymer [23].

Preparing biodegradable nanoparticles from poly (lactic acid), poly (D, L-glycolide), poly (D, L-

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lactide-co-glycolide) (PLGA), and poly (cyanoacrylate) involves dispersing the drug in premade polymers (PCA). These can be performed in a variety of ways, as detailed below

a) Solvent evaporation b) Nanoprecipitation

c) Emulsification/solvent diffusion d) Salting out

e) Dialysis

f) Supercritical fluid technology (SCF)

Methods for preparation of nanoparticles from polymerization of monomers a) Emulsion

b) Mini emulsion c) Micro emulsion

d) Interfacial polymerization

e) Controlled/Living radical polymerization(C/LRP) Ionic gelation or coacervation of hydrophilic polymers

Solvent evaporation method:

The production of an emulsion combining aqueous and organic phases is the goal of this procedure. The polymer is dissolved in the organic solvent in which the medication is dissolved or disseminated (e.g., dichloromethane, ethyle acetate, chloroform). The resultant solution is then homogenized and added to an aqueous phase containing a surfactant/emulsifying agent (polysorbate 80, poloxamer 188, polyvinyl alcohol, etc.) to form an emulsion. The organic solvent is evaporated/eliminated after developing a stable emulsion, either by increasing the temperature under reduced pressure or by continuous stirring.The nanosuspension produced is freeze-dried using 5% mannitol as a cryoprotectant obtain a fine powder of nanoparticles [25][26].

Nano-precipitation method

The nanoprecipitation method, also called solvent displacement, was developed by Fessi et al.

[27]. The formation of particles is based on the precipitation and subsequent solidification of the

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polymers due to the interfacial deposition of the polymer after displacement of semi-polar solvents miscible with water from a lipophilic solution. The Nano-precipitation method procedure contains three essential ingredients: the polymer, the polymer solvent, and the polymer's non-solvent [28].Drug and polymer are dissolved in a water-miscible organic solvent and added to the aqueous phase containing the stabilizer. The decrease in interfacial tension between the aqueous and organic phases allows organic solvent to diffuse quickly into the aqueous phase. During the solvent flow, diffusion, and surface tension at the organic solvent interface and the aqueous phase, tiny droplets of nanoparticles with well-defined size and narrow distribution form immediately, generating turbulence. The nanosuspension is freeze-dried with 5% mannitol as a cryoprotectant[29][30].

Emulsification / solvent diffusion method

In this method, the polymer is dissolved in a partial water-miscible solvent such as ethyl acetate or propylene carbonate and saturated with water to ensure the initial thermodynamic equilibrium of both liquids. Afterward, the polymer- water-saturated solvent phase is emulsified in an aqueous solution containing stabilizer (e.g. PVA, Pluronic F 68, Sodium taurodeoxy cholate) [31][32][33][34][35]. As a result of the solvent diffusion to the exterior phase, nanospheres or nanocapsules are formed. Finally, depending on the boiling point of the solvent, it is removed by evaporation or filtration. High encapsulation efficiencies of lipophilic medicines are among the benefits of this approach. This process requires removing large amounts of water from the suspension, which can be considered a drawback. During emulsification, leakage of water- soluble drugs into the saturation–aqueous exterior phase reduces encapsulation efficiency. As a result, this technology is suitable for encapsulating lipophilic medicines [36] [37] [38] [39].

Salting out

Bindschaedler et al. [40] first modified the emulsion process that results in salting- out process that avoids surfactants and chlorinated solvents [41].This method is a modification of the emulsion diffusion technique. In this method, drug and polymer are dissolved in a water-miscible organic solvent like acetone, followed by emulsification into an aqueous gel containing a salting- out agent (magnesium chloride, calcium chloride, magnesium acetate, polyvinyl alcohol, and

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non-electrolyte: sucrose) and a colloidal stabilizer (polyvinyl pyrrolidon (PVP), hydroxyethyl cellulose (HEC), polyvinyl alcohol (PVA), is added to achieve stability for the dispersion phase of the emulsion [42][43][44][45]. Dilute it with sufficient water to facilitate the acetone diffusion into the aqueous phase resulting in salting-out as nanosphere/particles. Both the solvent and salting agent are removed via cross-flow filtration.

Dialysis

The polymer and drug are dissolved in an organic solvent in the dialysis procedure, and then the mixed solution is dialyzed. The PNPs remain frapped by the dialysis membrane because of their vast size. The medicine concentration in the external medium is monitored throughout time until it reaches a stable level. The attention of free drugs on both sides of the dialysis membrane has equalized. The moment when the free-drug dialysis balance is achieved is known as the free- drug dialysis balance time. The free drug concentration is then determined from the drug concentration in the medium, which is subsequently used to calculate the drug encapsulation efficiency. This procedure is straightforward and does not require the use of surfactants.However, the broad particle size distribution is a disadvantage, and toxicological problems may result from the solvent residues obtained by this method [44].

Supercritical fluid technology

Supercritical fluid technology Supercritical CO2 is the most widely used supercritical fluid because of its mild critical conditions (Tc = 31.1 °C, Pc = 73.8 bars); it is non-toxicity, non- flammability, and low price. The mainly supercritical fluid used in two main techniques:

1) Supercritical anti-solvent (SAS)

2) Rapid expansion of critical solution (RESS) [45]

Supercritical anti-solvent (SAS) is also called PCA (precipitation with compressed antisolvent) or GAS (gas antisolvent).Aswith any precipitation process, the antisolvent can be addedto the solution (normal-addition precipitation), or the solution can be added to the antisolvent (reverse- addition precipitation). The method requires that the supercritical antisolvent be miscible with the solution solvent and that the solute be insoluble in the supercritical antisolvent [45].

The SAS process is proposed to process the molecules with poor solubility in supercritical fluid (SCF). This process predominantly utilizes an organic solvent such as acetone, dichloromethane

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(DCM), and dimethyl sulfoxide (DMSO) to dissolve the materials, where SCF behaves as a non- solvent to solute/API. The mixture expands to super saturation during the process and results in fast nucleation, demonstrating the high mass transfer ratio due to the low viscosity and high diffusivity of SCF [46]. The outcome of this process utterly depends on the order of addition of solvent, SCF, and other substrates. Additionally, factors such as temperature, pressure, the chemical composition of solute (drug, polymer), and organic solvent must be optimized [47].

SCF operates as a solvent carrier for the RESS procedure, extending this system adiabatically and rapidly decreasing temperature and pressure, adding small amounts of organic solvent after spraying to boost the affinity of polar drug molecules[48]. RESS is the most straightforward and most effective approach in SCF technology;however,its relatively low cost and solution of the polymer dust can be used in its application.

Monomer polymerization method of preparation:

Emulsion

Goodyear Tire & Rubber Company developed the emulsion polymerization method in the 1920s. The emulsion-polymerization process results in a latex particle (stable emulsion), a polymer dispersion in waterusinga soap or detergent as the emulsifying agent commonly. The main components of emulsion polymerization media involve monomer, dispersing medium, emulsifier, and water-soluble initiator [49] [50].

In emulsion polymerization,(table-2) monomers are first dispersed in the aqueous phase.

Initiator radicals are generated in the aqueous phase and migrate into the soap micelles that are swollen with monomer molecules. As the polymerization proceeds, more monomers migrate into the micelle to enable the polymerization to continue [51].

Table2.Component of Emulsion Polymerization [52]

Initiator

Water-soluble initiator 2-2-Azobis( 2-amidinopropane)dihydrochloride K2S2O8

APS( Ammonium persulfate) H2O2( Hydrogenperoxide)

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Partially water soluble t-butyl hydroperoxide succinic acid peroxide

4,4- azobis( 4- cyanopentonic acid ) Redox system Persulfate with ferrous ion

Cumyl hydroperoxide

Hydrogen peroxide with ferrous sulfite or bis sulfite iron Surface active initiator Bis [(2,4’-sulfophenyl) alkyl]

2,2’-azobis ( N-2’-methyl propanoyl-2-amino- alkyl-1-sulfonate) Surfactant

Anionic surfactant Sodium or potassium stearate Laurate

Palmitate Sulfates

Sadium lauryl sulfonate

Sodium dodecyl benzene sulfonate Cationic surfactant Dodecylammoniumchloride

Cetytrimethylammonium bromide

Non-ionic Polyethylene oxide

Polyvinyl alcohol Hydroxyethyl cellulose

Monomers Acrylamde

Acrylic acid Butadiene Styrene Acrylonitrile Acrylate ester Methacrylate ester Vinylacetate Vinylchloride Dispersion medium Water

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Mini emulsion

This procedure is used to dissolve the surfactant system in water, dissolve the co-stabilizer in the monomer, and stir. The mixture then is homogenized highly efficiently. When long-chain alcohol (e.g.,cetyl alcohol) is employed as a co-stabilizer, the longer chain alcohol is first combined with water and surfactants at temperatures higher than the spring of the alcohol, and the mixture is cooled to a room temperature more remarkable than the spring melting point. Then the monomer is added to the mini-emulsion by swirling and homogenization mixture[53].

Micro-emulsion

Microemulsions comprise two immiscible fluids, like oil and water stabilized through tensile and cosurfactant, thermodynamically stable emulsions. Microemulsions possess a heterogeneous nanostructure; however, these constructions are smaller than the wavelength of visible light.

Latex particles are produced with less than 50 nm by the microemulsion polymerization technique. Only one polymer with a mean molecular weight of above 1 million is found in the micro-emulsion particles average [54].

Interfacial polymerization

Interfaced polymerization is a sort of stage-growth polymerization that results in a polymer with a restricted interface at the interface of two immiscible phases (usually two liquids)[46].

Interfacial polymerization is affected by many variables, resulting in various polymer topology types, such as ultra-thin films [56][57], nanocapsules, and nanofibers [58].

The polymerization of monomers obtains Oil-containing nanocapsules at the oil/water interface of an excellent oil-in-water micro- emulsion [59]. The organic solvent, which was completely miscible with water, served as a monomer vehicle, and the interfacial polymerization was believed to occur at the surface of the oil droplets that formed during emulsification [60] [61].

Controlled / Living radical polymer

Controlled / Living radical polymerization (C/LRP) processes have opened a new area using an old polymerization technique [62][63]. The most critical factors contributing to this trend of the C/LRP process are increased environmental concern and the sharp growth of pharmaceutical and medical applications for hydrophilic polymers. The main aim is to control the characteristics of the polymer in terms of molar mass, molar mass distribution, architecture, and function.

Implementation of C/LRP in the industrially important aqueous dispersed systems, Forming

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polymeric nanoparticles with precise particle size and size distribution control, is crucial for the future commercial success of C/LRP [64].

Among the available controlled/living radical polymerization methods, successful and extensively studied methods are following:

➢ Nitrogen mediated polymerization (NMP) [65][67][68][69]

➢ Atom transfer radical polymerization ( ATRP) [70][71][72]

➢ Reversible addition and fragmentation transfer chain polymerization ( RAFT) [73]

➢ Stable free radical polymerization ( SFRP)

The nature and concentration of the control agent, monomer, initiator, and emulsion type (apart from temperature) are vital in determining the size of NPs. Novel formulation/research available for the treatment of cervical cancer-table-3

Table 3 List of novel formulations used to treat cervical cancer

Drug Formula

tin

Polymer Used Why This Polymer

Method Of Preparati on

SIZE SPECIFIC ITY

REFER ENCES

Paclitaxel mucous poly(lactic- PLGA 340n polymer [74]

penetrati co-glycolic &polycpr m based MPP

ng acid, olactone attributed

particles polycaprolact easily to the slow

(NPs) one immobili eliminatio

zed by n of MPP

the by

viscoelas mucosclear

tic and ence&

adhesive sustained

cervicova release of

ginal drug from

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mucus (CVM)

the particles.

Nanopar methoxy PCL- solid 43.34 improve [75]

ticles (polyethelyen hydropho dispersio to the

e glycol)- bic ,form n method 49.39 efficacy of

poly(E- a core for nm chemoradi

caprolactone) a ation

[MPEG-PCL] hydopho therapy by

bic drug developing

PTX, MPEG–

PEG- PCL

enhance loaded

EPR(enh with PTX.

ance permeati on &

retention) in

circulatio n

SLNs polyethylene TAT- use emulsific 83n TAT- [76]

glycol- in ation & m PTX/TOS-

disearoyl- payload solvent CDDP

phosphatidyle into cells, evaporati increases

thanolamine [ TOS- on rug

TAT-PEG- form of accomulati

DSPE], vit. E, on in

alpha- non-toxic tumor cell,

tocopherol[T ,biocopet nanosize

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OS] ible particles easily cross leaky microvasc ulatue of tumer cell, incerease EPR effects .

cisplatin genistein , Genistein involving [77]

phosphatidyli - inhibit both NF-

nositol 3- tyrosine KB and

kinase kinase, mTOR

cancer pathway

cell induced by

proliferat cisplatin

ion , and

inhibition inhibited

of by

nuclear genistein .

factor Cisplatin

kappaβ ( &

NF-k β), genistein

downreg combinatio

ulating n is less

phosphor toxic in

ylated Ttof

p70S6KI cervical

& 4E- cancer

BPI proteins.

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Nanofibr polycaprolact chitosan- passive 400- ability to [78]

es one [PCL], polycatio drug 500 control the

chitosan nic loading nm. drug

nature method. release at

possess vaginal

high environme

mucoadh nt, goo

esive thermal

property mechanical

helps to properties.

increase the residence time.

PCL- high drug payload , uniform distributi on of drug molecule s.

5- mucoad cyclodextrin cyclodext cold More [79]

flourouracil hesive rin- a method concentrat

gel carrier ed gels

molecule were

o a reported to

facilitate dissolve at

thedissol a slower

ution of rate than

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these less

compoun concentrat

d. ed ones

because of the

decreased water diffusion coefficient for the rate of water diffusing into the gel

mucoad polycarbophil polycarb direct The [80]

hesive , chitosan. ophil- compress desired

tablets ability to ion bioadhesio

swell and nachieved

retard the with the

drug addition of

release chitosan

and

polycarbop hil,

suitable combinatio n played key role in the

bioadhesio n and subsequent

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ly

maintains the pH independe nt drug release without initial burst release pattern.

bioadhes ive cervical patch

carbopol, glycerin

glycerin - used as plasticise r

casting knife technique

diam eter of 26 mm

patch secured to cervical surface, easy to apply and remove anf offering a high degree of patient acceptabili ty.

[81]

docetaxel nanocrys tal

transferrin transferri n- used as surface modifier , enhance cellular

nanopreci pitation method

300- 450 nm depe ndin g on pH

The higher expression of

transferrin receptor on cancer cells, its

[82]

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uptake ability to internalize, and the requiremen t of iron for cancer cell growth make this receptor a widely accessible portal for drug delivery.

disulfiram thermopl astic vaginal ring

polyethylene vinylacetate(

PEVA)

PEVA chosen as the

material to manufactur e the DSF- loaded vaginal rings. The vaginal rings has an excellent content uniformity . the rings provided

[83]

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diffusion controlled release of DSF cisplatin

(DDP)+pacli taxel(PTX)

hydrogel s

containi ng PTXmic ells

methoxy (polyethelyen e glycol)- poly(E- caprolactone) [MPEG-PCL]

PCL- hydropho bic ,form a core for a

hydopho bic drug PTX, PEG- enhance EPR(enh ance permeati on &

retention) in

circulatio n

one step solid dispersio n

PDMP most effective in prolonging survival time , inhibiting tumor growth, inducing G1 phase arrest, increase apoptosis rate.

PDMP teatmentre ulted in slower drug release, minor toxicity , effective inhibition of tumor growth

[84]

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Curcumin nanofor mulation

poly(lactic- co-glycolic acid) PLGA

PLGA- selected due to their biocomp atibility, biodegra dibility,

&high stability in

biologica l fluids and during storage.

nanopreci pitation method

~80n m

Nano- CUR effectively reduced the tumor burden in a pre-clinical orthotopic mouse model of cervical cancer by decreasing oncogenic miRNA - 21,

suppressin g nuclear β-catenin , and abrogating expression of E6/E7 HPV oncoprotei ns.

[85]

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Curcumin polymeri c

micelles

citosan chitosan - biocomp atible, biodegra dable, has low toxicity and low immunog enicity.

micelles were synthesiz ed in two steps: N- arylation of chitosan by Schiff basesfoll owed by reduction of the Schiff base intermedi ate with sodium cyanobor ohydride (Borch reduction )

100n m

Cellular uptake is observed 6-fold significant increase in the amount of CM loaded micelles compared to free CM in all cervical cancer cells. CM loaded micelles promoted an increase (30–55%) in the percentage of early apoptosis .

[86]

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doxorubicin(

DOX)

gold nanopart icles

carboxymethy l

chitosan(CM- chitosan), Nigericin

CM- chitosan- as the reducing and capping agent.

Nigeicin- an ionophor e that causes intracellu lar acidificat ion.

air-dried peel powder was used to reduce chloroaur ic acid.

Chloroau ric acid (HAuCl4 ) is used for AuNPs synthesis

10- 50 nm

The DOX loaded gold nanoparticl es are effectively absorbed by cervical cancer cells compared to free DOX and their uptake is further increased at acidic conditions induced by nigericin.

[87]*

flavonoid rutin- fucoidan

natural product complex

fucoidan, rutin

fucoidan - sulfated polysacc haride of brown seaweed, g the reactive functiona l

follow procedur

221 nm

the

chemoprev entive potential of RuFu complex shows that is able to disrupt cell cycle

[88]*

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groups such as carboxyli c,

sulphate and hydroxyl groups is reported to enhance the performa nce of several drugs especiall y the absorptio n and solvation propertie s. Rutin- hydropho bic polyphen olic flavonoid phytoche mical.

regulation and has the ability to induce cellular apoptosis via nuclear fragmentat ion, ROS generation and mitochond rial

potential loss. The hemolysis assay also reveals that the complex does not release hemoglobi n from human RBCs.

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General principles of drug targeting to cancer

• Passive targeting

• Active targeting Passive targeting

Tumor cells have blood-flowing arteries, a permeable, stimulating vascular endothelial growth factor (VEGF), and defective screening of particulates. This process, which makes tumor cells preferably absorb the large nanoparticles of bodies, enhances permeability and retention (EPR).

The rapidly growing tumor cells are affected by the system of lymphatic drainage and further increase the build-up. Nanoparticles and pharmaceuticals then accumulate selectively through the EPR effect [90]. Spontaneous drug build-up is a sort of passive targeting in locations with leaky vasculature.This is based on the development of drug carriers which avoid their removal via body mechanisms such as metabolization, excretion, opsonization, and phagocytoses so that the complex stays circulating in the bloodstream, allowing it to transmit to the target recipient through properties such as pH, temperature, molecular size or form[91-93].

Active targeting

Targeting ligands are applied on the nanocarrier's surface in active targeting to bind to suitable receptors on the target spot. Ligand is chosen to bind to a tumor cell- or tumor-vasculature- expressed receptor that is not normal. In addition, targeted receptors should be homogeneously expressed in all targeted cells, not lost into the blood circulation.

Active targeting benefits from overexpressingspecific receptors, like folate, on the tumor cell's surface.Targeted nanocarriers conventionally lead over their untargeted counterparts because they are more efficient at delivery and reduce unwanted potential toxicity[46].

Table-4 showing, the subsequent targeting is classic as it has been widely tried and tested in the last years in terms of the targeted supply of medicines[94]. Folate is overexpressed in several kinds of cancer, including ovarian carcinomas, osteosarcomas, and non-lymphomas. Hodgkin's Particles conjugated to the folate receptor are therefore more likely to be substantially absorbed in the process of overexpressing the folate receptors[94-100].

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Table: 4 Folate based formulation in Nanotechnology Folate

Formulation

Drug /Natural Poduct / Therapeutic

Agent

Site of Acton Result Refere

nce

modified self- microemulsifying drug delivery system

curcumin Colon folate-polyethylene glycol- cholesteryl hemisuccinate

[93]

Liposome imatinib cervical cancer FR-targeted imatinib liposomes promoted a six- fold

IC50 reduction on the non- targeted imatinib liposomes from 910 to 150 µM

[94]

nanostructured lipid carriers

cisplatin cervical cancer Implying that NLCs formulations

shown higher cytotoxicity against cervical cancer cells.

FA-CIS-NLCs also

decreased the IC50 value by one-third over CIS- NLCs (p50.05).

[95]

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Liposome Arsenic trioxide tumor cell results indicate that the nickel component within the folate-targeted arsenic

liposome serves as an adjuvant that stimulates the anticancer

the activity of the arsenic drug.

[96]

ligand–modified liposome

Pep-1 peptide cancer cell An in vitro cellular uptake the study revealed that the FP-Lipo nanocarrier system exhibited more than twofold enhanced

translocation into the folic acid receptor-positive HeLa cells compared with the single Pep-1

peptide–modified liposome [97]

Liposome Daunorubicin leukemia and

certain olid tumor

FR-targeted F-L-DNR was compared with non- targeted L-DNR for antitumor activity in vivo

and was

shown to be more effective in prolonging the survival of

ascites tumor-bearing mice.

[98]

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Polymeric liposome paclitexal Nasopharyngea l carcinoma

paclitaxel-loaded FA- TATp-PLs shows higher antitumor activity and reduces toxicity and

improves the

bioavailability

[99]

Conclusion and Future aspects

The presence of screening tests and HPV prevention vaccines is one of the most avoidable malignancies. HPV infection alone is not enough for cervical cancer, additional variables such as smoking cigarettes, weak immune, hereditary factors and positive history, hormonal contraception duration, and pregnancy influence the risk of cervical cancer are somewhat necessary. Women at double risk of developing cervical dysplasia with chlamydial infection compared to women not infected with the disease. E6 and E7 oncogenic proteins from HPV16 and18 can block p53 and Rb effects, interfering with normal proliferation.

Nanotechnology has been intensively researched to enhance cervical cancer management and to boost sensitivity using HPV for diagnosis. Several approaches for detecting viral DNA or viral proteins have been developed. Nanotechnology was utilized to tackle shortages of existing vaccines in vaccine development to enhance effectiveness and minimize adverse effects.

Anticancer medication nanodelivery is demonstrated to be more effective in cervical cancer therapy.

While comprehensive research with nanotechnology to handle cervical cancer has been conducted, further efforts have to be made to promote clinical translation. The simultaneous delivery of therapeutic drugs for the treatment of cervical cancer could be auspicious.

Therapeutic vaccinations with the lowest side effects may play a significant role in cervical cancer cells. The antigens expressed in HPV are unique in cancer cells or pre-cancer cells and can thus be targeted selectively with the appropriate vaccine.In addition, therapeutic vaccines can be combined to improve efficacy with targeted chemotherapy or photodynamic therapy.

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Disclosure

The authors have no rival interests.

Authors Contribution-

All the authors have contributed to the literature review preparation and editing of the manuscript.

Funding None References

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