Possible role of nanocarriers in drug delivery against cervical cancer

Figures & data

Figure 1. The mechanism of HPV infecting the host cells, its replication in epithelial cells, and integration into host cell’s DNA.

Figure 2. HPV virus productive phase, latent infection phase, regression phase, and integration of virus into host DNA.

Figure 3. Schematic representation of the molecular mechanisms of oncogenic HPV infection, binding of E6 and E7 oncoprotien to the p53 and pRb genes, and blocking of apoptosis; G1 arrest which leads to genomic instability and neoplasia.

Table 1. Schematic representation of chemotherapeutic drugs used in cervical cancer with their class, mechanism of action, dose, and side effects.

Name of drugs	Structure	Class of drug	Mechanism of action	Dose	Side effects
Cisplatin (Cis-diaamine-di-chloroplatinum(II))		Antimetabolites	Platinum complexes react in vivo, bind to DNA and cause crosslinking of DNA, which ultimately triggers apoptosis. Of the bases on DNA, guanine is preferred. Subsequent to formation of [PtCl(guanine-DNA)(NH3)2]^+, crosslinking can occur via displacement of the other chloride ligand, typically by another guanine	50–100 mg/m^2	Nephrotoxicity, neurotoxicity, ototoxicity, electrolyte disturbance, hemolytic anemia
Carboplatin		Antimetabolites	Alkylating agents work: attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylating bases, preventing DNA synthesis and RNA transcription from the affected DNA	300 mg/m^2	Hair loss, nausea, mild rash, mouth sores, constipation
Docetaxel		Taxol derivative	Docetaxel binds to the β-subunit of tubulin. Tubulin is the ‘building block’ of microtubules and the binding of docetaxel locks these building blocks in place	75 mg/m^2	Severe diarrhea, yellowing of the skin or eye or stomach pain, swollen stomach, ankles or feet, numbness and tingling in the hands or feet (peripheral neuropathy)
Paclitaxel		Taxol	Paclitaxel enhances the polymerization of tubulin to stable microtubules and also interacts directly with microtubules, stabilizing them against depolymerization by cold and calcium, which readily depolymerize normal microtubules	135 mg/m^2 (in injection)	Neutropenia, hypersensitivity, hypotension, transient brady cardia, peripheral neuropathy, GI disturbances, alopecia
Epirubicin			Epirubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex	Adult 60–90 mg/m^2	Heart failure, swelling, ankles/feet, hair loss, nausea, allergic reaction
Fluorouracil		Antimetabolites	As a pyrimidine analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA and RNA, finally inducing cell cycle arrest and apoptosis by inhibiting the cell’s ability to synthesize DNA. It is an S-phase-specific drug and only active during certain cell cycles	3 mg/kg	Mouth sores, a sore throat, and trouble swallowing, diarrhea and stomach pain, decreased white blood cell counts, red blood cell counts and platelet counts can also be reduced, sun sensitivity and easy sunburning

Figure 4. Various systemic drug delivery systems used in cervical cancer therapy.

Figure 5. Various localized drug delivery systems used in cervical cancer therapy.

Table 2. Liposome-based delivery systems, including cell lines/animal models used for cervical cancer therapy.

S. No.	Drug/antibody	Type/composition of liposomes	Cell lines/animal/clinical models	Reference
1.	Paclitaxel	Stearyl amine-based positively charged multilayered liposomes	HeLa cell lines	[42]
2.	Cisplatin	–	ME-180 cervical cancer cell line, cisplatin-resistant clone R-ME-180 and HeLa cells	[43]
3.	Cisplatin	Heat-activated thermosensitive liposome	–	[44]
4.	Doxorubicin	–	Cervical cancer patients	[45]
5.	IL-2	Anionic, cationic, and neutral liposomes	INBL cells
6.	Doxorubicin	Transferrin (Tf)-conjugated stealth liposomes (Tf-SL-DOX)	–	[47]
7.	Doxorubicin	Liposomes conjugated with folic acid and transferrin	HeLa cells	[48]
8.	IL-2	Cationic liposome containing	INBL cells induced tumor-containing immune-depressed CBA mice	[49]

Table 3. Nanoparticle-based delivery systems, including cell lines/animal models used for cervical cancer therapy.

S. No.	Drug	Type/composition of nanoparticles	Cell lines/animal models/neoplasm	References
1.	Docetaxel	Poly(ɛ-caprolactoneco-lactide)-D-α-tocopheryl polyethylene glycol succinate nanoparticles	Cervical cancer cells	[50]
2.	Docetaxel	Colic acid-PLGA-b-Vitamin E TPGS copolymer	–	[51]
3.	Cisplatin	Folic acid-conjugated gelatin nanoparticles	–	[52]
4.	–	Phenanthridinium (oligonucleotide intercalator)-functionalized mesoporous silica nanoparticles	HeLa cells	[53]
5.	Bleomycin sulfate	Nanostructured lipid particles	Cervical cancer cells	[54]
6.	Doxorubicin	Polynorbonene-cholesterol/poly(ethylene glycol)	–	[55]
7.	Doxorubicin	Mesoporous silica nanoparticles	HeLa cells	[56]
8.	Docetaxel	D-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(ε-caprolactone-ran-lactide) nanoparticles	Xenograft BALB/c nude mice tumor model	[57]
9.	Doxorubicin	Cyclodextrin-containing pH-sensitive poly(2-(dimethylamino) ethyl methacrylate) star polymer nanoparticles	–	[58]
10.	Paclitaxel	Poly(γ-glutamic acid-maleimide-co-l-lactide)-1,2-dipalmitoylsn-glycero-3-phosphoethanolamine (γ-PGA-MAL-PLADPPE) copolymer-based nanoparticles	–	[59]
11.	Docetaxel	Poly(lactide-co-glycolide) and pluronic F68	Cervical cancer cells	[60]
12.	Methotrexate and 5-flurouracil	Double hydroxide nanoparticles	–	[61]
13.	Hexylaminolevulinate (HAL)	Bioadhesive pellets of Carbopol 934	Cervical cancer cells	[62]
14.	Paclitaxel and curcumin	Polyethylene gycol phosphatidyl ethanolamine (PEG-PE)-based polymeric micelles	Multidrug-resistant ovarian cancer cells	[63]
15.	Doxorubicin	Folate (FA)-modified carboxymethyl chitosan (FCC)	HeLa cells	[64,65]
16.	Paclitaxel	Cremophor EL-free nanoparticles	HeLa cells	[66]
17.	Docetaxel	PLGA-TPGS, glycolide and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles	HeLa cells	[67]
18.	Paclitaxel	PEG/PCL biotin-conjugated nanoparticles	Normal human fibroblasts and HeLa cells	[68]
19.	Paclitaxel	Paclitaxel-loaded nanoparticles	MCF-7 and HeLa cells	[69]
20.	Doxorubicin	Oleoyl-chitosan (OCH) nanoparticles	HeLa cells	[70]
21.	Docetaxel	D-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(ε-caprolactone-ran-glycolide) nanoparticles	HeLa cells	[71]
22.	Docetaxel	D-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(ε-caprolactone-ran-lactide) nanoparticles	Xenograft BALB/c nude mice tumor model	[72]
23.	Silver nanoparticles	Polyethylene glycol	HeLa and CaSki cells	[73]

Table 4. Hydrogel-based delivery systems, including cell lines/animal models used for cervical cancer therapy.

S. No.	Drug/therapy/functional group	Type/Composition of gel	Cell lines /animal models/neoplasm	References
1.	Paclitaxel	Poly-N-isopropylacrylamide, tert-butyl 2-acrylamidoethyl carbamate and N-hydroxyethyl acrylamide	MCF7, T47D, and HeLa cells	[115]
2.	Doxorubicin	Fe3O4 magnetic nanoparticle-incorporated poly-(N-isopropylacrylamide)-chitosan-based nanohydrogels	HeLa cells	[116]
3.	Photothermal therapy	Hydrogel system containing polyacrylamide-based nanoparticles	HeLa cells	[117]
4.	Doxorubicin	Cryogel formulations based on chitosan-gelatin, chitosan-agarose and chitosan-agarose gelatin	HeLa cells	[118]
5.	Arginine-glycine-aspartic acid-serine	Magnetic iron oxide nanoparticles coated with polyethylene glycol hydrogel	HeLa cells	[119]
6.	5-fluorouracil	Pluronic F127 together with alternative mucoadhesive polymers, e.g. hyaluronic acid, Carbopol 934, and hydroxypropyl methylcellulose	HeLa cells	[120]
7.	Paclitaxel	Temperature-sensitive poly(organophosphazene)–PTX conjugate	HeLa cells and nude mice	[121]
8.	Doxorubicin, cyclophosphamide and cisplatin	Chitosan hydrogel	Mice containing TC-1 cervical cells	[122]
9.	5-aminolevulinic acid (5-ALA) ester hexylamionolevulinate	Poloxamer 407	Cervical intraepithelial neoplasia	[123,124]

Table 5. Brief overview of radiotherapy, photothermal therapy, and gene/recombinant protein therapy.

Types of therapy	Carrier system/formulation	Targeting ligand	Result	Reference
Radiotherapy	Bovine serum albumin nanoparticles as carriers of organic selenocompound,	Folate as a targeting ligand	Apoptosis as well as cell cycle arrest of cervical cancer cells	[161]
	multifunctional carbon nanohorn complexes	Ferromagnetic nanoparticles	Significant increase in the photothermal effect of complex due to laser irradiation leading to increased cell death in cervical cancer	[162]
	PEGylated glucose gold nanoparticles	Polyethylene glycol ligands	Better half-life, excellent in vivo stability, enhanced tumor targeting and radiotherapeutic effects	[163]
Photothermal therapy	Doxorubicin superparamagnetic iron oxide nanoparticles	Folic acid	Increased cellular uptake and therapeutic efficiency	[164]
	Doxorubicin-loaded graphene oxide	Polyethylene glycol	Excellent biocompatibility, high drug loading and photothermal conversion efficiency	[165]
	Doxorubicin-loaded silica graphene-serum nanoparticles		Higher photothermal conversion efficiency, and stability, increased storage and release capacity for doxorubicin, led to the enhanced cytotoxicity	[166]
	Hollow gold nanospheres of p65 siRNA and irinotecan	siRNA recognizing NF-κB p65	Significant increase in tumor apoptosis and growth delay	[167]
	Gold colloidal nanoparticles		Increased cytotoxic effect on epithelial cancer cells	[168]
Gene and recombinant protein therapy	DNA vaccine containing HPV oncoproteins and herpes virus gD protein	–	Enhanced stimulation of antigen-specific cytotoxic CD8(+) T-cell responses, full therapeutic antitumor effects	[169]
	Novel vaccine carrier composed of HPV-16 E7 and ricin toxin (RTB) lectin subunit fusion	–	Enhanced activity with respect to E7 immunization alone	[170]
	VLP-E7 vaccine	–	A potent and long-lasting immune response	[171]
	Recombinant IkBα-loaded curcumin nanoparticles	–	Enhanced therapeutic efficacy of recombinant IkBα protein led to apoptotic cell death	[172]
	Folate poly(ethylene glycol)-b-poly(D,L-lactide) gene-loaded nanoparticles for gene loading	–	Increase in nuclear uptake of genetic material	[173]
	CRISPR/Cas9 as targeting promoter of HPV 16 E6/E7 transcripts	–	Significant reduction in proliferation of cervical cancer cells in vitro and in vivo	[174]
	Phosphorothioate oligodeoxynucleotides (PT-oligos)	–	Significant antiproliferative activity against oncoproteins of HPV cancerous cells	[175]
	Recombinant vaccinia vaccine (TA-HPV) expressing E6 and E7 for HPV-16 and 18	–	Excellent efficacy in Phase II study in women’s group with HPV-positive vulval and vaginal intraepithelial neoplasia	[176]
	Recombinant human TNF-related apoptosis-inducing ligand (rhTRAIL)		Effective in cervical cancer	[177]
	TPGS-b-(PCL-ran-PGA) nanoparticle	Polyethyleneimine (PEI) carrying TRAIL and/or endostatin genes	Enhanced cytotoxicity towards HeLa cells	[178]

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