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
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
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.
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.
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.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.
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) .
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 . 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].
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 . According to the World Health Organization (WHO), over 90% of cervical cancer deaths occur in developing nations . Other factors, in addition to HPV infection, can raise your risk of cervical cancer.
➢ Cigarette smoking and carcinogen (benzo[a]pyrene, BaP ).
➢ 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
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.
Figure-2A Classification of HPV and association development of CC
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
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.
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.  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.
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 :
➢ Curative surgery
➢ Preventive surgery
➢ Diagnostic surgery
➢ Staging surgery
➢ Debulking surgery
➢ Palliative surgery
➢ Supportive surgery
➢ Restorative surgery
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 :
➢ 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: 
First-line novel agent Second-line novel agent
Carboplatin + paclitaxel Pazopanib
Carboplatin + bevacizumab + paclitaxel Cisplatin – cetuximab
Carboplatin based Erlotinib
Docetaxel based Gefitnib;Imatinib;Cetuximab;Temsirolimus;
Topotecan; Gemcitabine ; Ifosfamide Immunotherapy
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 .
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 .
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 .
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 .
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 . 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 .
Nanoparticles are generated from a dispersion of preformed polymer .
Preparing biodegradable nanoparticles from poly (lactic acid), poly (D, L-glycolide), poly (D, L-
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
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 .
The nanoprecipitation method, also called solvent displacement, was developed by Fessi et al.
. The formation of particles is based on the precipitation and subsequent solidification of the
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 .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.
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) . 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    .
Bindschaedler et al.  first modified the emulsion process that results in salting- out process that avoids surfactants and chlorinated solvents .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
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 . 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.
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 .
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) 
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 .
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
(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 . 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 .
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. 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:
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  .
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 .
Table2.Component of Emulsion Polymerization 
Water-soluble initiator 2-2-Azobis( 2-amidinopropane)dihydrochloride K2S2O8
APS( Ammonium persulfate) H2O2( Hydrogenperoxide)
Partially water soluble t-butyl hydroperoxide succinic acid peroxide
4,4- azobis( 4- cyanopentonic acid ) Redox system Persulfate with ferrous ion
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
Sadium lauryl sulfonate
Sodium dodecyl benzene sulfonate Cationic surfactant Dodecylammoniumchloride
Non-ionic Polyethylene oxide
Polyvinyl alcohol Hydroxyethyl cellulose
Acrylic acid Butadiene Styrene Acrylonitrile Acrylate ester Methacrylate ester Vinylacetate Vinylchloride Dispersion medium Water
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.
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 .
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).
Interfacial polymerization is affected by many variables, resulting in various polymer topology types, such as ultra-thin films , nanocapsules, and nanofibers .
The polymerization of monomers obtains Oil-containing nanocapsules at the oil/water interface of an excellent oil-in-water micro- emulsion . 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  .
Controlled / Living radical polymer
Controlled / Living radical polymerization (C/LRP) processes have opened a new area using an old polymerization technique . 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
polymeric nanoparticles with precise particle size and size distribution control, is crucial for the future commercial success of C/LRP .
Among the available controlled/living radical polymerization methods, successful and extensively studied methods are following:
➢ Nitrogen mediated polymerization (NMP) 
➢ Atom transfer radical polymerization ( ATRP) 
➢ Reversible addition and fragmentation transfer chain polymerization ( RAFT) 
➢ 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
Polymer Used Why This Polymer
Method Of Preparati on
SIZE SPECIFIC ITY
Paclitaxel mucous poly(lactic- PLGA 340n polymer 
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
tic and ence&
cervicova release of
ginal drug from
Nanopar methoxy PCL- solid 43.34 improve 
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
EPR(enh with PTX.
ance permeati on &
SLNs polyethylene TAT- use emulsific 83n TAT- 
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
OS] ible particles easily cross leaky microvasc ulatue of tumer cell, incerease EPR effects .
cisplatin genistein , Genistein involving 
phosphatidyli - inhibit both NF-
nositol 3- tyrosine KB and
kinase kinase, mTOR
cell induced by
ion , and
nuclear genistein .
kappaβ ( &
NF-k β), genistein
ulating n is less
phosphor toxic in
& 4E- cancer
Nanofibr polycaprolact chitosan- passive 400- ability to 
es one [PCL], polycatio drug 500 control the
chitosan nic loading nm. drug
nature method. release at
mucoadh nt, goo
helps to properties.
increase the residence time.
PCL- high drug payload , uniform distributi on of drug molecule s.
5- mucoad cyclodextrin cyclodext cold More 
flourouracil hesive rin- a method concentrat
gel carrier ed gels
o a reported to
facilitate dissolve at
thedissol a slower
ution of rate than
d. ed ones
because of the
decreased water diffusion coefficient for the rate of water diffusing into the gel
mucoad polycarbophil polycarb direct The 
hesive , chitosan. ophil- compress desired
tablets ability to ion bioadhesio
swell and nachieved
retard the with the
drug addition of
suitable combinatio n played key role in the
bioadhesio n and subsequent
maintains the pH independe nt drug release without initial burst release pattern.
bioadhes ive cervical patch
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.
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
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
PEVA chosen as the
material to manufactur e the DSF- loaded vaginal rings. The vaginal rings has an excellent content uniformity . the rings provided
diffusion controlled release of DSF cisplatin
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 &
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
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
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.
Curcumin polymeri c
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 )
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 .
gold nanopart icles
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.
flavonoid rutin- fucoidan
natural product complex
fucoidan - sulfated polysacc haride of brown seaweed, g the reactive functiona l
chemoprev entive potential of RuFu complex shows that is able to disrupt cell cycle
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.
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 . 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].
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.
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. 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].
Table: 4 Folate based formulation in Nanotechnology Folate
Drug /Natural Poduct / Therapeutic
Site of Acton Result Refere
modified self- microemulsifying drug delivery system
curcumin Colon folate-polyethylene glycol- cholesteryl hemisuccinate
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
nanostructured lipid carriers
cisplatin cervical cancer Implying that NLCs formulations
shown higher cytotoxicity against cervical cancer cells.
decreased the IC50 value by one-third over CIS- NLCs (p50.05).
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.
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 
Liposome Daunorubicin leukemia and
certain olid tumor
FR-targeted F-L-DNR was compared with non- targeted L-DNR for antitumor activity in vivo
shown to be more effective in prolonging the survival of
ascites tumor-bearing mice.
Polymeric liposome paclitexal Nasopharyngea l carcinoma
paclitaxel-loaded FA- TATp-PLs shows higher antitumor activity and reduces toxicity and
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.
The authors have no rival interests.
All the authors have contributed to the literature review preparation and editing of the manuscript.
Funding None References
1. Prabhu Rashmi H Vandana B Patravale Medha D Joshi. Polymeric nanoparticles for targeted treatment in oncology: current insights. International Journal of Nanomedicine 2015:10 1001–1018
2. Schiffman M, Castle PE, Jeronimo J, et al. Human papillomavirus and cervical cancer.
Lancet. 2007; 370: 890–907.
3. ICO/IARC HPV Information Center Institute Catala d'Oncology Avada. Gran Via de I’Hospitallet, 199-20308908 L’Hospitalet de Llobregat(Barcelone, Spain)pg;6- 7.www.hpvcentre.net
4. Cancer Facts And Figures 2019, American cancer society, Inc. No.500819. pg no.26-27.
5. https://www.iarc.fr/wp-content/uploads/2018/09/pr263_E.pdf 6. https://onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21492
7. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. doi:10.3322/caac.21492.
8. Human Papilloma virus and Related Cancers, Fact Sheet 2018 (2019-06-17)
9. Ho, G.Y.F., Burk, R.D., Klein, S., Kadish, A.S., Chang, C.J., Palan, P., Basu, J., Tachezy, R., Lewis, R., Romney, S., 1995. Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia. J. Natl. Cancer Inst. 87, 51–59
10. Kjaer, S.K., van den Brule, A.J., Paull, G., Svare, E.I., Sherman, M.E., Thomsen, B.L., Suntum, M., Bock, J.E., Poll, P.A., Meijer, C.J., 2002. Type specific persistence of high risk
human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women: population based prospective follow up study. BMJ 325, 572.
11. Moore E. E., Wark J. D., Hopper J. L., Erbas B. & Garland S. M. The roles of genetic and environmental factors on risk of cervical cancer: a review of classical twin studies. Twin Res Hum Genet 15, 79–86 (2012). [PubMed]
12. Maher D. M. et al.. Curcumin suppresses human papillomavirus oncoproteins, restores p53, Rb, and PTPN13 proteins and inhibits benzo[a]pyrene-induced upregulation of HPV E7. Mol Carcinog 50, 47–57 (2011). [PubMed]
14. Murray, Robert K; Victor W Rodwell; David A Bender; Kathleen M Botham; Peter J Kennelly. Harper's Illustrated Biochemistry, 28th Edition. McGraw Hill Publication; 2009.
15. Howkins & Bourne, Shaw's Textbook of Gynaecology,16thedition , e-Book ISBN:
9788131238712. Elsevier India ; 2015: Pg: 485-506.
17. https://www.cancerresearchuk.org/about-cancer/cervical-cancer/treatment/radiotherapy 18. Marth, C., Landoni, F., Mahner, S., McCormack, M., Gonzalez-Martin, A., & Colombo, N.
(2017). Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Annals of Oncology, 28(suppl_4), iv72–iv83.doi:10.1093/annonc/mdx220
19. Marth, C., Landoni, F., Mahner, S., McCormack, M., Gonzalez-Martin, A., & Colombo, N.
(2017). Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Annals of Oncology, 28(suppl_4), iv72–iv83.doi:10.1093/annonc/mdx220
20. Kipp JE (2004). The role of solid nanoparticle technology in the parenteral delivery of poorly water-soluble drugs. International Journal of Pharmaceutics; 284(1–2):109-122.
21. Ould Ouali L, Noppe M, Langlois X, Willems B, TeRiele P, Timmerman P, Brewster ME, Arien A, Preat V (2005). Self-assembling PEG-p (CL-co-TMC) copolyme- rs for oral delivery of poorly water-soluble drugs: a case study with risperidone. Journal of controlled Release; 102(3):657-668.
22. Zhang Q, Chuang KT (2001) Adsorption of organic pollutants from effluents
of a kraft pulp mill on activated carbon and polymer resin. Adv Environ Res 5: 251-258.
23. Fonseca C, Simoes S, Gaspar R (2002) Paclitaxel-loaded PLGA nanoparticles: preparation, physicochemical characterization and in vitro anti-tumoral activity. Journal of Controlled Release 83: 273-286.
24. Nagavarma B V N, Hemant K.S.Yadav*, Ayaz A, Vasudha L.S, Shivakumar HG Different Techniques For Preparation Of Polymeric Nanoparticles- A Review. Asian J Pharm Clin Res, Vol 5, Suppl 3, 2012, 16-23
25. Kiruba Krishnaswamy, Valérie Orsat, in Nano- and Microscale Drug Delivery Systems, 2017 26. Jaiwal J, Gupta SK, Kreuter J. Preparation of biodegradable cyclosporine nanoparticles by high pressure emulsification solvent evaporation process. J Control Release 2004; 96(1):169- 78.
27. Hoa LTM, Chi NT, Nguyen LH, Chien DM. Preparation and characterization of nanoparticles containing ketoprofen and acrylic polymers prepared by emulsion solvent evaporation method. J Exp Nanosci 2012; 7 (2): 189- 97.
28. H. Fessi, F. Puisieux, J.-P. Devissaguet, N. Ammoury, and S. Benita. Nanocapsule formation by interfacial deposition following solvent displacement. Int. J. Pharm. 55:R1–R4 (1989).doi:10.1016/0378-5173 (89)90281-0.
29. Christine Vauthier, Kawthar Bouchemal. Methods for the Preparation and Manufacture of Polymeric Nanoparticles. Pharmaceutical Research, Vol. 26, No. 5, May 2009 (# 2008) .DOI: 10.1007/s11095-008-9800-3.
30. Rao JP, Geckeler KE. Polymer nanoparticles: Preparation techniques and size-control parameters. Prog Polym Sci 2011; 36(7):887-913.
31. Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm 1989; 55(1):R1-4.
32. Kumar Ganesh, Dhyani Archana, KothiyalPreeti.Review Article on Targeted Polymeric nanoparticles: An Overviw.American Journal of Advanced Drug Delivery.2015; 196-215.
33. D. Quintanar-Guerrero, É. Allémann, H. Fessi, and E. Doelker. Influence of stabilizing agents and preparative variables on the formation of poly(-lactic acid) nanoparticles by an emulsification–diffusion technique. Int. J. Pharm. 143:133–141 (1996).doi:10.1016/S0378- 5173 (96)04697-2.
34. S. Guinebretière. Nanocapsules par émulsion–diffusion desolvant: obtention, caractérisation et mécanisme de formation. Ph.D. Université Claude Bernard Lyon 1 (2001).
35. Battaglia, M. Trotta, M. Gallarate, M. E. Carlotti, G. P. Zara,and A. Bargoni. Solid lipid nanoparticles formed by solvent-in water emulsion–diffusion technique: Development and influence on insulin stability. J. Microencapsul. 24:672–684 (2007).doi:10.1080/02652040701532981.
36. D. Quintanar-Guerrero, A. Ganem-Quintanar, E. Allemann, H. Fessi, and E. Doelker.
Influence of the stabilizer coating layer on the purification and freeze-drying of poly(D,L- lactic acid) nanoparticles prepared by an emulsion–diffusion technique. J. Microencapsul.
15:107–119 (1998). doi:10.3109/02652049809006840.
37. Pal , S.L., U. Jana, P. Manna, G. Mohanta, and R. Manavalan , Nanoparticle: An overview of preparation and characterization. Journal of Applied Pharmaceutical Science, 2011; 1: 228- 234.
38. Pinto Reis . C, R J Neufeld, A .n.J, Ribeiro, and F. Veiga. Nanoencapsulation I Methods for preparation of drug –loaded polymeric nanoparticles: Nanomedicine : Nanotechnology, Biology and Medicine, 2006;2: 8-21.
39. Quintanar-Guerrero, D., E. Allemann, H. Fessi, and E. Doelker, Preparation techniques and mechanisms of formation of biodegradable nanoparticles from preformed polymers. Drug Dev Ind Pharm, 1998; 24: 1113-28.
40. Fessi, H., F. Puisieux, J.P. Devissaguet, N. Ammoury, and S. Benita, Nanocapsule formation by interfacial polymer deposition following solvent displacement. International Journal of Pharmaceutics, 1989; 55: R1-R4.
41. Bindschaedler C, Gurny R, Doelker E (1990) Process for preparing a powder of water- insoluble polymer which can be redispersed in a liquid phase, the resulting powder and utilization thereof. US Patent 4,968,350.
42. Patel A, Khanna S, Xavier GK, Khanna K, Goel B. Polymeric Nano-Particles for Tumor Targeting – A Review. Int J Drug Dev & Res.2017; 9: 50-59.
43. Azin Jahangiri , Leila Barghi . Polymeric nanoparticles: review of synthesis methods and applications in drug delivery.Journal of advanced chemical and pharmaceutical materials.
44. Galindo-Rodriguez, S., E. Allemann, H. Fessi, and E. Doelker, Physicochemical parameters associated with nanoparticle formation in the salting-out, emulsification-diffusion, and
nanoprecipitation methods. Pharm Res, 2004; 21: 1428-39.
45. Mendoza-Munoz, N., D. Quintanar-Guerrero, and E. Allemann, The impact of the salting-out technique on the preparation of colloidal particulate systems for pharmaceutical applications.
Recent Pat Drug Delivery Formula, 2012; 6: 236-49.
46. Ya-Ping Sun, Mohammed J. Meziani, Pankaj Pathak, and LiangweiQu . Polymeric Nanoparticles from Rapid Expansion of Supercritical FluidSolution. Chem. Eur. J. 2005, 11, 1366 – 1373 DOI: 10.1002/chem.200400422
47. Kalani, R. Yunus, Int. J. Nanomedicine 2011, 6, 1429
48. Ranjith Kumar Kankala, Yu Shrike Zhang, Shi-Bin Wang, Chia-Hung Lee,and Ai-Zheng Chen. Supercritical Fluid Technology: An Emphasis on Drug Delivery and Related Biomedical Applications. Adv. Healthcare Mater. 2017, 6, Pg 1-31.DOI:
49. K. Mishima, Adv. Drug Del. Rev. 2008, 60, 411
50. Odian G. Emulsion polymerization,Principles of polymerization. Fourth edition John Wiley
&Sons ,Inc; 2004:350-371
51. Harkins WD. A general theory of the mechanism of emulsion polymerization. Journal of the American Chemical Society. 1947; 69(6):1428-1444
52. Ron Lewarchik . The Fundamentals of Emulsion Polymerization. Prospector.
53. El-hoshoudy, A. N. M. B. Emulsion Polymerization Mechanism. Recent Research in Polymerization. (2018) doi:10.5772/intechopen.72143
54. Jose M. Asua. Miniemulsion Polymerization. Progress science. 27 (2002) 1283- 1346 55. Micro-Emulsion. c2016. Derby (UK): Enviroquest; [accessed 2016 Jun
56. "Current trends in interfacial polymerization chemistry". Progress in Polymer Science. 63:
57. Ji, J (2001-10-15). "Mathematical model for the formation of thin-film composite hollow
fiber and tubular membranes by interfacial polymerization". Journal of Membrane Science. 192 (1–2): 41–54. doi:10.1016/S0376-7388(01)00496-3.
58. Li, Shichun; Wang, Zhi; Yu, Xingwei; Wang, Jixiao; Wang, Shichang. "High-Performance
Membranes with Multi-permselectivity for CO2
Separation".AdvancedMaterials.(2012) 24 (24):31963200. doi:10.1002/adma.201200638.
59. De Cock, Liesbeth J.; De Koker, Stefaan; De Geest, Bruno G.; Grooten, Johan; Vervaet, Chris; Remon, Jean Paul; Sukhorukov, Gleb B.; Antipina, Maria N.. "Polymeric Multilayer Capsules in Drug Delivery". AngewandteChemie International Edition. (2010)49 (39): 6954–
60. Khoury-Fallouh AN, Roblot-Treupel L, Fessi H, DevissaguetJP, Puisieux F. Development of a new process for the manufacture of poly isobutylcyanoacrylatenanocapsules. Int J Pharm 1986; 28:125–36.
61. Gallardo M, Couarraze G, Denizot B, Treupel L, Couvreur P, Puisieux F. Study of the mechanisms of formation of nanoparticles and nanocapsules of poly(isobutyl-2- cyanoacrylate). Int J Pharm 1993; 100:55–64.
62. Aboubakar M, Puisieux F, Couvreur P, Deyme M, Vauthier C. Study of the mechanism of insulin encapsulation in poly(isobutylcyanoacrylate) nanocapsules obtained by interfacial polymerization. J Biomed Mater Res A 1999; 47:568–76.
63. Matyjaszewski K, Xia J (2001) Atom transfer radical polymerization. Chem Rev 101: 2921- 2990.
64. Zetterlund PB, Kagawa Y, Okubo M (2008) Controlled/Living radical polymerization in dispersed systems. Chem Rev 108: 3747-3794.
65. Abdollahi, E., Abdouss, M., Salami-Kalajahi, M., & Mohammadi, A. (2016). Molecular Recognition Ability of Molecularly Imprinted Polymer Nano- and Micro-Particles by Reversible Addition-Fragmentation Chain Transfer Polymerization. Polymer Reviews,56(4), 557–583.doi:10.1080/15583724.2015.1119162
66. Braunecker WA, Matyjaszewski K (2007) Controlled/Living radical polymerization:
features, developments, and perspectives. Prog Polym Sci 32: 93-146.
67. Cunningham MF (2008) Controlled/Living radical polymerization in aqueous dispersed systems. Prog Polym Sci 33: 365-398.
68. Nicolas J, Ruzette AV, Farcet C, Gerard P, Magnet S, et al. (2007) Nanostructured latex particles synthesized by nitroxide-mediated controlled/Living free-radical polymerization in emulsion. Polymer 48: 7029-7040
69. Farcet C, Lansalot M, Charleux B, Pirri R, Vairon JP (2000) Mechanistic aspects of nitrox- ide-mediated controlled radical polymerization of styrene in miniemulsion, using a water- soluble radical initiator. Macromolecules 33: 8559-8570.
70. Khezri, Kh.; Haddadi-Asl, V.; Roghani-Mamaqani, H.; Salami-Kalajahi, M. "Polystyrene- organoclay nanocomposites produced by in situ activators regenerated by electron transfer for atom transfer radical polymerization", J. Polym. Eng. 2012, 32, 235–243.
71. Asfadeh, A.; Haddadi-Asl, V.; Salami-Kalajahi, M.; Sarsabili, M. R.; Roghani-Mamaqani, H.
"Investigating the effect of MCM-41 nanoparticles on the kinetics of atom transfer radical polymerization of styrene", Nano. 2013, 8, 1350018 (1–9), Doi:
72. Roghani-Mamaqani, H.; Haddadi-Asl, V.; Khezri, Kh.; Salami-Kalajahi, M.; Najafi, M.;
Sobani, M.; Mirshafiei-Langari, S. A. "Confinement effect of graphene nanoplatelets on atom transfer radical polymerization of styrene: Grafting through hydroxyl groups", Iran.
Polym. J. 2015, 24, 51–62.
73. G .Gody, T.Maschmeyer, P.B.Zetterlund, S.Perrier. Macromolecules. 2014. 47, 639-649.
74. Roghani-Mamaqani, H.; Haddadi-Asl, V.; Salami-Kalajahi, M. "In situ controlled radical polymerization: A review on synthesis of well-defined nanocomposites", Polym. Rev. 2012, 52, 142–188.
75. Yang, M., Yu, T., Wang, Y.-Y., Lai, S. K., Zeng, Q., Miao, B.,Tang.C.,Simons.W.,Ensign.
M.,Liu. G.,Chan .Y., Juang. Y.,Mert .O.,Wood. J.,McMohan .T.,Wu .C.,Hung.F., Hanes, J.
(2013). Vaginal Delivery of Paclitaxel via Nanoparticles with Non-MucoadhesiveSurfaces Suppresses Cervical Tumor Growth. Advanced Healthcare Materials, 3(7), 1044–
76. YanXin Yu, Shan Xu, Hong You, YinJie Zhang, Bo Yang, XiaoYang Sun, LingLin Yang, Yue Chen, ShaoZhi Fu &JingBo Wu (2017) In vivo synergistic anti-tumor effect of
paclitaxel nanoparticles combined with radiotherapy on human cervical carcinoma, Drug Delivery, 24:1, 75-82, DOI: 10.1080/10717544.2016.1230902
77. Liu, B., Han, L., Liu, J., Han, S., Chen, Z., & Jiang, L. (2017). Co-delivery of paclitaxel and TOS-cisplatin via TAT-targeted solid lipid nanoparticles with synergistic antitumor activity against cervical cancer. International Journal of Nanomedicine, Volume 12, 955–
78. K. Sahin, M. Tuzcu, N. Basak, B. Caglayan,4 U. Kilic, F. Sahin, O. Kucuk. Sensitization of Cervical Cancer Cells to Cisplatin by Genistein: The Role of NFκB and Akt/mTOR Signaling Pathways. Journal of Oncology,Volume 2012, Article ID 461562, Pg: 1- 7.doi:10.1155/2012/461562.
79. Aggarwal, U., Goyal, A. K., & Rath, G. (2017). Development and characterization of the cisplatin loaded nanofibers for the treatment of cervical cancer. Materials Science and Engineering: C, 75, 125–132. doi:10.1016/j.msec.2017.02.013 .
80. Bilensoy, E., Çırpanlı, Y., Şen, M., Doğan, A. L., &Çalış, S. (2007). Thermosensitive mucoadhesive gel formulation loaded with 5-Fu: cyclodextrin complex for HPV-induced cervical cancer. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 57(1-4), 363–
81. Pendekal, M. S., &Tegginamat, P. K. (2012). Development and characterization of chitosan-polycarbophil interpolyelectrolyte complex-based 5-fluorouracil formulations for buccal, vaginal and rectal application. DARU Journal of Pharmaceutical Sciences, 20(1), 67. doi:10.1186/2008-2231-20-67
82. Woolfson ,D., McCafferty, D.F., McCarron , P.A., Price , JH Liquid Scintillation Spectrometry of 5- Fluorouracil in cervical tissue following in-vitro surface application of a bioadhesive cervical patch. Pharmaceutical Research, Vol. 11, No.9, 1994.Pg:1-5.
83. Choi, J.-S., & Park, J.-S. (2016). Development of docetaxel nanocrystals surface modified with transferrin for tumor targeting. Drug Design, Development and Therapy, Volume11, 17–26. doi:10.2147/dddt.s122984
84. Boyd, P., Major, I., Wang, W., & McConville, C. (2014). Development of disulfiram- loaded vaginal rings for the localised treatment of cervical cancer. European Journal of
Pharmaceutics and Biopharmaceutics, 88(3), 945–953. doi:10.1016/j.ejpb.2014.08.002 85. Xu S, Du X, Feng G, Zhang Y, Li J, Lin B, Yang L, Fu S, Wu JEfficient inhibition of
cervical cancer by dual drugs loaded in biodegradable thermosensitive hydrogel composites. Oncotarget, 2018, Vol. 9, (No. 1), pp: 282-292
86. Zaman, M. S., Chauhan, N., Yallapu, M. M., Gara, R. K., Maher, D. M., Kumari, S.,Sikander M, Khan S, Zafar N, Jaggi M,. Chauhan, S. C. (2016). Curcumin Nanoformulation for Cervical Cancer Treatment. Scientific Reports, 6(1), 1- 14.doi:10.1038/srep2005
87. Sajomsang, W., Gonil, P., Saesoo, S., Ruktanonchai, U. R., Srinuanchai, W.,
&Puttipipatkhachorn, S. (2014). Synthesis and anticervical cancer activity of novel pH responsive micelles for oral curcumin delivery. International Journal of Pharmaceutics, 477(1-2), 261–272. doi:10.1016/j.ijpharm.2014.10.042
88. Madhusudhan, A., Reddy, G., Venkatesham, M., Veerabhadram, G., Kumar, D., Natarajan, S., … Singh, S. (2014). Efficient pH Dependent Drug Delivery to Target Cancer Cells by Gold Nanoparticles Capped with Carboxymethyl Chitosan.
International Journal of Molecular Sciences, 15(5), 8216–
89. Deepika, M. S., Thangam, R., Sheena, T. S., Sasirekha, R., Sivasubramanian, S., Babu, M. D., … Thirumurugan, R. (2019). A novel rutin-fucoidan complex based phytotherapy for cervical cancer through achieving enhanced bioavailability and cancer cell apoptosis. Biomedicine & Pharmacotherapy, 109, 1181–
90. Yu, X., Trase, I., Ren, M., Duval, K., Guo, X., & Chen, Z. (2016). Design of Nanoparticle-Based Carriers for Targeted Drug Delivery. Journal of Nanomaterials, 2016, 1–15. doi:10.1155/2016/1087250
91. Danhier, F., Feron, O., &Préat, V. (2010). To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anticancer drug delivery. Journal of Controlled Release, 148(2), 135–146.doi:10.1016/j.jconrel.2010.08.027
92. Kumar Khanna, V. (2012). Targeted Delivery of Nanomedicines. ISRN Pharmacology, 2012, 1–9. doi:10.5402/2012/571394
93. Byrne, J. D., Betancourt, T., & Brannon-Peppas, L. (2008). Active targeting schemes for nanoparticle systems in cancer therapeutics. Advanced Drug Delivery Reviews, 60(15), 1615–1626.doi:10.1016/j.addr.2008.08.005
94. Zhang L, Zhu W, Yang C, Guo H, Yu A, Ji J, Gao Y, Sun M, Zhai G. A novel folate- modified self-microemulsifying drug delivery system of curcumin for colon targeting. Int J Nanomedicine. 2012; 7:151-62. doi: 10.2147/IJN.S27639.
95. Ye, P., Zhang, W., Yang, T., Lu, Y., Lu, M., Gai, Y., … Xiang, G. (2014).Folate receptor- targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting. International Journal of Nanomedicine, 2167.doi:10.2147/ijn.s60178
96. Zhang, G., Liu, F., Jia, E., Jia, L., & Zhang, Y. (2015). Folate-modified, cisplatin-loaded lipid carriers for cervical cancer chemotherapy. Drug Delivery, 1–
97. Chen, H., Ahn, R., Van den Bossche, J., Thompson, D. H., & O'Halloran, T. V.
(2009). Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide. Molecular Cancer Therapeutics, 8(7), 1955–
98. Choi, Y., Kang, Park, Kang, & Park. (2013). Folic acid-tethered Pep-1 peptide-conjugated liposomal nanocarrier for enhanced intracellular drug delivery to cancer cells: conformational characterization and in vitro cellular uptake evaluation. International Journal of Nanomedicine, 1155.doi:10.2147/ijn.s39491
99. XING Q. PAN and ROBERT J. LEE. In Vivo Antitumor Activity of Folate Receptor-targeted Liposomal Daunorubicin in a Murine Leukemia Model.Anticancer Research25: 343-346 (2005).
100. Niu, R., Zhao, P., Wang, H., Yu, M., Cao, S., Zhang, F., & Chang, J. Preparation, characterization, and antitumor activity of paclitaxel-loaded folic acid modified and TAT peptide conjugated PEGylated polymeric liposomes. Journal of Drug Targeting, (2010).