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International Journal of Polymeric Materials and Polymeric Biomaterials
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Sericin and fibroin nanoparticles—natural product for cancer therapy: a comprehensive review
Mehreen Elahi, Shaukat Ali, Hafiz Muhammad Tahir, Rabia Mushtaq &
Muhammad Farooq Bhatti To cite this article: Mehreen Elahi, Shaukat Ali, Hafiz Muhammad Tahir, Rabia Mushtaq &
Muhammad Farooq Bhatti (2020): Sericin and fibroin nanoparticles—natural product for cancer therapy: a comprehensive review, International Journal of Polymeric Materials and Polymeric
Biomaterials, DOI: 10.1080/00914037.2019.1706515 To link to this article: https://doi.org/10.1080/00914037.2019.1706515
Published online: 19 Feb 2020.
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View Crossmark data Sericin and fibroin nanoparticles—natural product for cancer therapy: a comprehensive review
Mehreen Elahia, Shaukat Alia, Hafiz Muhammad Tahira, Rabia Mushtaqa, and Muhammad Farooq Bhattia,b aDepartment of Zoology, Government College University, Lahore, Pakistan; bSericulture Wing, Forest Department, Lahore, Pakistan
ABSTRACT Silk, a natural compound of silkworm contains two proteins, sericin and fibroin. These proteins can be conjugated with other compounds to form silk-derived nanoparticles. The biomedical applications of silk-based nanoparticles for drug delivery and cancer treatment are arising as they are biocompatible, biodegradable, have enhanced permeability and retention effect and less tox- icity. Nevertheless, not a single review of literature is present that could describe the anticancer potential of silk derived nanoparticles. In this review, we describe the (i) comprehensive note on fibroin and sericin based nanoparticles (ii) anticancer mechanistic accompanied by biomedical applications in diagnosis, imaging, and drug delivery.
GRAPHICAL ABSTRACT ARTICLE HISTORY Received 4 October 2019
Accepted 5 December 2019 KEYWORDS Biocompatible; cancer treatment; biodegradable; drug delivery; fibroin; sericin; silk-based nanoparticles
CONTACT Shaukat Ali dr.shaukatali@gcu.edu.pk Department of Zoology, Government College University, Lahore, 54000-Lahore, Pakistan.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpom.
2020 Taylor & Francis Group, LLC INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS https://doi.org/10.1080/00914037.2019.1706515
1. Introduction Even though great improvement has been done for the advancement in the progression and formulation of new drugs and various therapeutic approaches for cancer but still cancer continues to be the second most leading reason for death worldwide. The yearly occurrence of cancer is nearly about 2.6 million cases per year[1,2]. Necessarily, there is a crucial requirement of global measures to accompany the advantages of novel treatments in the industrialized areas and take appropriate actions to bring about the already pre- sent treatments of cancer available in the underdeveloped and developed sectors[3]. The latest studies have made con- siderable advancement in the identification of underlying mechanisms and particular causes for various forms of can- cer. Many of the cancer therapies are being used such as photodynamic therapy, radiation therapy, chemotherapy, vaccinations, stem cell transplantations and also conjugation of these treatments. Inopportunely, the majority of the trad- itional treatments are expensive and also cause harmful reac- tions[4,5]. Mainly the chemotherapy treatment causes high toxicity to the cells including both the cancerous and normal cells and thus limits its applications clinically[6].
Furthermore, another issue is the resistance of cancerous cells to these chemotherapeutic means[7], hence it becomes important to find such anti-tumor agents with biocompati- bility, biodegradability and less toxicity to cells. A drug gives optimum results when its dispersal profile is both definitive and regulated and finally, such a delivery system is required that is compatible and offers adjustability such that of the silk proteins[8]. Thus, research should be done on the gener- ation of economically suitable and efficient treatment choices that not only target the specified cancers but also does not cause any harm to the normal healthy tissues[9].
A delivery system for drugs contains a carrier containing active drug component in dispersed, dissolved or encapsu- lated on which the functional component is joined or adsorbed[10]. Drug carrier molecules are very important in drug delivery and could be administered in various forms of drugs released systems including microcapsules, nanopar- ticles, pills, microspheres, emulsions and many more.
Nanoparticles among them have fascinated much of the research because of their capability of being utilized as an effectual transporter of drug supporting drug efficiency[11].
These nanoparticles also offer new prospects to overpower the traditional methods of delivery restrictions concerning drugs[12]. Nowadays these new delivery systems utilizing nanoparticles are of great attention because this helps tar- geted introduction to the specific sites of the small bioactive molecules and drugs[13].
Recently, protein-built nanocarriers are gaining import- ance because of their biodegradability, biocompatibility, great nutritional value and less toxicity to the cells. These proteins derived nanocarriers also display great binding affinities letting remarkable uptake by the cells[14]. The scheme and formulation of effective delivery systems of a drug are central to the biomedical field[12]. Nanocarriers also offer increased anti-tumor efficiency showing minimal side effects due to their features including increased EPR effect, time in blood circulation and uptake into the cell actively[15,16]. Biopolymers varying from bioactive polymers such as heparin to the large molecular weight drug carriers including chitosan, dextran and alginates and many multiple function molecules[17,18]. One of these naturally occurring biopolymers is silk, which is being utilized in suturing and is approved by the FDA for application in humans for carry- ing the load. However, currently, silk has been rising as a prominent drug delivery biopolymer[19].
The silk originally has two key proteins including fibroin and sericin[20,21]. Silk is formed by the silkworm mainly
Bombyx mori. The sericin component is the soluble part of the cocoon and encloses and retains two filaments of fibroin together in the silk thread present in the silk cocoon[22]. The fibroin component is the insoluble protein having massive hydrophobic domains consisting of b-pleated sheets in an antiparallel direction[23]. Consequently, the requirement for biodegradable and biocompatible materials displays the ris- ing interest of silk protein components in a huge field of biomedical[22]. Sericin protein can be utilized in the drug delivery application because of its pH responsiveness and reactivity that helps in binding with other molecules and thus enabling the production of small molecules[24]. Silk fibroin component has also high binding capacity with sev- eral kinds of drugs, sample preparation requirements, con- trolled release of drug characteristics.
Both of the components of the silk have exceptional biodegradability, biocompatibility and very little or no immunogenicity[11].
Currently, nanotechnology can participate significantly in drug delivery, diagnosis and cancer treatment. Anticipating the lack of review on the usage of silk-based nanoparticles as a promising agent for cancer therapy involving the drug delivery applications, we designed this thorough review art- icle. We for the first time explained the anticipated drug delivery and anticancer activity of the silk fibroin and sericin based nanoparticles with innovative dialogue on the key advances of utilizing these nanoparticles to the clinical stage for cancer therapy (Figure 1).
2. Biomaterials The widely used pharmacological anticancer agents impart many adverse effects on the normal cells along with the can- cer tissue, so chemotherapy has many severe side effects[25].
Therefore, natural products such as biomaterials play a sig- nificant part in tissue engineering, medicine of regeneration and in the delivery of drugs[26].
3. Nanotechnology Nanotechnology has an immense role in many fields as one of its applications is nanomedicine utilized in the field of medicine. This has aided in the advancement of therapeutic carriers in the form of nanoparticles. On account of the nanoparticles enhanced the ratio of surface to volume as compared to the bulky substances impart them with fasci- nating properties like augmented mechanical strength[27].
The nanoparticle drug carriers are developed through
2 M. ELAHI ET AL. various routes depending on the application. A wide variety of materials are designed but the mutual goal of all is to explain the transfer of the drug and its enhanced bioavail- ability toward the directed cells and endorsing the response with minimized side effects. The delivery of drugs toward tumors is aggravated by harmfulness to the normal cells along with the little absorption because of less retainment of drugs by the cancerous cells at the site of the tumor[28].
Many processes like differentiation, the proliferation of cell and tissue regeneration depends on the connections between the cells and the surfaces of biomaterials[29].
The tumor microenvironment embraces cells, blood ves- sels, extracellular matrix and signaling molecules[30].
Carcinomas are the most frequent tumor types (85%). In most of the cases, these are non-vascularized and does not allow the tumor to grow greater than 2 mm and does not make new blood vessels for their feeding[31]. Angiogenesis is dysregulated for feeding the tumor cells, and thus the vessels formed vary from that of the normal tissue. Presently, nanocarriers are used efficiently for targeted therapy of can- cer and transport the desired drug component which can pass over the vasculature. Some of the vehicles of nanocar- rier having a diameter of 20–300 nm are being established for drug or medicine and many more therapeutic particle transports. These treatments are directed to extravasate selectively over the vasculature of cancer via EPR (Enhanced
Permeability and Retention) effect[32].
The Nanomedicine and Drug Delivery Symposium (nano-DDSs) drugs remain a capable approach to converse the resistance of drug, for its effective intracellular delivery.
In the meantime, earlier findings have described that the nanoparticles could be carried into compartments of endo- somes like lysosomes which are located in the nuclear per- iphery regions substantially further than the transporters of
P-gp on the membrane. This benefit of location consents release of drugs inside these compartments of endosomes to minimize efflux pumping, subsequently, the microenviron- ment of lysosomes and tumor cells with low pH might offer
Figure 1. Silk-based nanoparticles have various biomedical applications like in tissue engineering, diagnosis, imaging, drug delivery and cancer therapy.
INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
3 a strategy meant for pH-stimuli receptiveness[33]. The nano- DDSs can efficiently enter the tumor site by EPR effect during the circulation of blood in comparison to chemother- apeutic vehicles which are free[34–38]. Under these condi- tions, the drugs warped inside the nanocarriers might directly cross the cell membrane, and released toward the nucleus, therefore induced the death of most cancer cells.
Thus, nanomedicines that are taken up and released in this manner could have a more effective anti-tumor effect[39].
4. Silk fibroin The insoluble protein called silk fibroin (SF) has massive hydrophobic domains consisting of b-pleated sheets in an antiparallel direction and could be simply separated as bio- materials excluding sericin[23]. It is produced from spiders and silkworms including the Bombyx mori and Bombyx mandarins larvae along with other genera of the moth, for example, Samia, Cricula, Gonometa, and Antheraea, and many other insect’s genera. The silk fibroin primary struc- ture is categorized as a naturally occurring unit of copoly- mers which comprise of hydrophobic chunks having repeated small side-chain of amino acids like alanine and glycine and primarily comprising of repeated order of (Gly–Ser–Gly–Ala–Gly–Ala)n amino acid. The original con- dition has two key proteins including fibroin and sericin, where sericin is glue-like material coating fibroin’s two brins which are singular filaments[20,21]. This material is extremely appropriate because of its low inflammatory or immune response and promising biological response features[40]. Silk
Fibroin-based biomaterials are being explored as fibers, par- ticles, files, and scaffolds[41–44], and in practices of neural, hydrogels, bone, skin, vascular and cartilage tissue recov- ery[45–48]. Gradually, SF is being utilized in many other zones of biomedical science, because of its properties and novel knowledge about its processing such as elasticity, mechanical strength, controllable biodegradability and bio- compatibility[49]. These characteristics of SF are mainly beneficial for tissue engineering[29].
4.1. Silk fibroin nanoparticles Breast cancer has been a constant source of growing disease and death in women. Shortly, the chemotherapy of breast cancer will encompass the use of drug delivery vehicles with biocompatible high cell-targeting capacity such as silk fibroin for the betterment of these problems. The usage of silk fibroin (SF) nanoparticles for the transfer of cytotoxic drugs offers optimal entrapment, specificity, enhanced thera- peutic index, and maximum toxicity of cells of breast cancer with minimum or no harm to nearby normal cells. Silk fibroin is loaded with suitable chemotherapeutic drugs (e.g., carboplatin). Silk Fibroin has been described in numerous studies as a very valuable tool in precise passive or active delivery of a drug to targeted cancer cells, hence confirming maximal devastation and minimal harm to normal nearby cells, which enhances the drug efficacy and reduces the sys- temic toxicity[50] (Figure 2).
4.2. Silk fibroin modified chitosan nanoparticles (SF-CSNPs)
Silk fibroin modified chitosan nanoparticles (SF-CSNPs) obtained more consideration as carriers of drug or medicine on account of their low toxicity, better stability, mild prepar- ation procedures, and also offer versatile administration routes[51]. The SF-CSNPs are appropriate for the chemother- apeutic drug delivery for cancer treatment because of their
EPR effect on tumor cell surfaces. The SF-CSNPs are accu- mulated by the hydrophobic interactions around the defected cells and tissues. Additionally, numerous physico- chemical parameters of SF-CSNPs are essential to be found as favorable, as its capability to traverse the biological block- ades, to defend macromolecules breakdown and to carry the complex to the targeted location[52].
Yang et al.[29] confirmed the biological effects of uptake of SF-CSNP by the liver cells. They studied various proteins that were involved in the ubiquitin-proteasome pathway and verified that SF-CSNP might be engaged in the propagation and persistence of liver cancer cells[29].
4.3. Self-assembled silk fibroin nanoparticles The exclusive characteristics of nanoparticles can overwhelm the restrictions of using the micro molecules as representa- tives of therapeutics in biomedical applications[53]. For instance, the drug uptake can be improved by the EPR effect[54], which can surge the deposition of drugs in tar- geted cancer containing tissues and decrease the drug resist- ance by efflux pump–mediation. Moreover, the half-life and solubility of small molecular medicines or drugs could be enhanced with controllable releasing actions along with encapsulation by nanoparticles. Curcumin is a naturally existing compound derivative of turmeric with diphenolic groups and is extensively used in radio-sensitizing and chemotherapy of cancer[55–57] and other fields of biomed- ical[58–60] with nearly no toxicity[60,61], and act as a capable material in the clinical examinations for the cancer treat- ment. But, due to curcumin’s poor solubility in the physio- logical environment, it frequently displays little uptake or absorption inside the gut[62]. Lately, curcumin was encapsu- lated with the SF nanoparticles and directed to the cancer cells specific to breast and showed the highest entrapment, intracellular uptake, and regulated release[28]. Furthermore, it has been discovered that two or more drugs, when admin- istered concurrently, is also significant in the treatment of cancer. Owing to silk fibroin biocompatible and biodegrad- able features it is thought to be a promising agent in bio- medical fields[43,63–66]. SF molecules as a drug carrier have controlled breakdown in vivo and in vitro, and could be controlled through altering its molecular weight, size, level of cross-linking, and crystallinity[42,44]. Many features of SF molecules make it an excellent agent as a drug carrier. One is that its hydrophobic residues of amino acid, such as gly- cine, tyrosine, and alanine boost the curcumin entrapment and 5- fluorouracil (5-FU) by p–p wrapping and hydropho- bic interface enhance the loading efficiency of binary trans- porter of drugs. Besides, the hydrophilic residues of amino
4 M. ELAHI ET AL. acid, such as glutamate, aspartic acid, and serine enhance their solubility in water and cause the development of nano- particles in the aqueous solutions[45]. One of the studies cre- ated
SF nanoparticles acting as a biodegradable and biocompatible transporter for the efficient loading and trans- ferring of binary drugs 5-FU and curcumin and exhibited an exceptional in vivo and in vitro anticancer activity. It is being discovered that treatment with such kind of nanodrug could augment the amount of ROS (reactive oxygen species) which induces in vitro cancer cells apoptosis. Animal researches have revealed that tumors can be markedly decreased after being inoculated with the nanoparticles entrapping the drug. This demonstrated the future possibil- ity of breast cancer treatment with binary drugs loaded with nanoparticles[46].
4.4. Celastrol and triptolide loaded silk fibroin nanoparticles
Pancreatic cancer is one of the fatal diseases with a 5% sur- vival rate for 5-year. Despite many treatment options, its diagnosis is extremely poor. Hence, different therapies are employed to fight against this fatal disease such as using a combination of drugs. Celastrol (CL) and Triptolide (TPL)
Figure 2. Proposed mechanism of the role of silk fibroin-based nanoparticles in cancer therapy. Silk fibroin-based nanoparticles have enhanced drug loading cap- acity and this conjugate of silk fibroin nanoparticles loaded with drug moves through blood circulation and reach targeted site through the EPR effect and internal- ized through endocytosis into the tumor cell. The lysosomes carry them to the nucleus where the drug is released because of acidic pH and causes DNA impairment and induce apoptosis.
INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
5 are the two main compounds used in Chinese traditional medicine and have a wide range of bioactivities, one of which is the anticancer activity[48,49,51]. As silk fibroin is a natural polymer with various unique features are used as the best carrier material. One of the studies prepared CL and
TPL loaded SF nanoparticles (CL-SFNPs and TPL-SFNPs) through an improved desolvation method[47]. TPL revealed to be an efficient stimulator for the halt of the apoptosis and cell cycle in numerous categories of cancers like breast cancer, pancreatic cancer, and lung cancer[14,52,67,68]. It could efficiently reduce the in vitro viability of the pancre- atic cancer cells, as well as decrease the metastasis and growth of in vivo tumors[49,52,69].
Celastrol represses the incursion of pancreatic cancerous cells by downregulation of the chemokine receptor CXCR4 expression[70]. Nevertheless, due to their less solubility in water and severe toxicity, CL and TPL could not be employed in the clinics systemically. Hence, there was a necessity for the development of the alternative CL and TPL formulations for clinical use. Ding et al.[71] developed and characterized the CL and TPL loaded SF nanoparticles (CL- SFNPs and TPL-SFNPs) separately. This not only overcome the drawback of hydrophobicity but too enabled the passive accumulation of CL and TPL in the cancerous tissues cen- tered on the optimal dose and administration and the EPR effect. After the formulation, characterization and optimiza- tion of CL-SFPNs and TPL-SFNPs were evaluated. The SF nanoparticles cellular uptake behavior was inspected in MIA
PANC-1 and PaCA-2 cells with RITC (Rhodamine-B- Isothiocyanate) used as a fluorescent probe was established by the flow cytometer and confocal microscopy.
The advantage of the collective treatment of CL-SFNPs admixed
TPL-SFNPs were confirmed by cell apoptosis and anti-pro- liferation detection in the pancreatic cell lines of humans such as PANC-1 and MIA PaCA-2[47].
4.5. Indocyanine green encapsulated silk fibroin nanoparticles
In the earlier few decades, numerous therapeutic approaches using light were the probable alternatives to the traditional methods in the arena of healthcare for their striking proper- ties incorporating biocompatibility, minimum invasiveness, great selectivity, and favored photosensitizers localization ensuing negligible adverse effects[72–74]. Photothermal ther- apy (PTT) was the one amid them and utilizes photosensi- tizers, such as PTT mediators that function by converting absorbed energy of light at a specificwindow of wavelength to heat to show the therapeutic actions[75–79]. Lately, there has been an eminent attention in the improvement of NIR (near-infrared) triggered thermotherapy hostile to cancer because of its outstanding tissue penetration, minimal inva- siveness and high efficacy of
NIR (>750 nm)[80,81].
Indocyanine green (ICG) is a NIR fluorescent dye certi- fiedby the US Food and Drug Administration (FDA) and is used in numerous biomedical applications. ICG is particu- larly important in diagnosis, imaging, and therapeutics in the biomedical fields because of its striking features including excellent biocompatibility and important light-to- heat transformation efficiency among others[75,76,82,83]. But,
ICG still has few limitations including poor stability in aque- ous medium and absorption in the intestine, accumulation depending on the concentration in vivo ensuing poor intra- body recirculation, susceptible to photobleaching, and the absence of specificity for the target[77,82,84]. To overcome these problems, ICG being transported using various nano- carriers with enhanced stability and directing efficiency including polymeric carriers (PCs), layered double hydrox- ides (LDHs), liposomes and mesoporous silica nanoparticles (MSNs) among others[75,76,83,85–87]. The heavy chain of SF is noticeably large containing
C-terminal and N-terminal hydrophilic areas and twelve greatly recurring regions of gly- cine-alanine rich flanked by the interior hydrophilic zones[88]. The N-terminal area in this structure of fibroin (FibNT) undertakes a pH-sensitive conformational modifica- tion at below 6.0 pH to b-sheets from the random coils and results in the transfer of loaded therapeutic vehicle[88,89].
Many researches have reported the formation of silk fibroin nanoparticles including emulsification (>6 lm), poly (vinyl alcohol) blends (300 nm–10 lm), salting leaching (486–1200 nm), capillary microdot printing (25–140 nm), supercritical CO2 (50–300 nm)[22,90], and organic solvent precipitation (35–170 nm). A number of researches have observed the capability of SF nanoparticles to capture and release the drugs[12,22,88,89,91–93].
The supercritical fluid (SCF) technology has acquired much attention among them from the investigators in the earlier period for producing the polymer molecules and further therapeutic bio-actives because of its economical character and environmentally benign nature[93–95]. To achieve the production of the multi- purpose dual-triggered devices with desirable biodegradation and high therapeutic efficiency,
ICG-encapsulated silk fibroin (ICG-SF) nanoparticles were formulated by SCF technology. These ICG-SF nanoparticles formed by using this method has provided exceptional photothermal con- stancy, ICG liberation from SF by pH-responsiveness par- ticularly in the acidic tumor microenvironment, and its significant initiation with NIR light at 808 nm substantially improved PTT efficacy. Photothermal in vivo and in vitro trials have revealed that these ICG-SF nanoparticles have the capability of destroying the cancerous cells simply in the light-triggered hyperthermia. These outcomes together have proposed that ICG-SF nanoparticles formed by the SCF method gave rise to enhanced PTT efficiency and might be employed a s a favorable material in the delivery system for continuous therapy of cancer[96].
5. Silk sericin The sericin component of silk is a naturally occurring polymer that is hydrophilic and mainly formed by the insects of family
Saturniidae and Bombycidae. It is formed through epithelial cells and then collected in the generalized silk glands lumen of developed larvae of 5th instar. Then discharged from the silk gland middle and posterior segment[67]. Sericin is about
15–20% of the dry cocoon weight and adheres to the filaments
6 M. ELAHI ET AL. of fibroin of silk cocoon together. Sericin from silk is obtained during the silk fibers degumming process and is usually removed as waste material in the industry of textile. Now a days it imparts fascinating applications in the engineering of tissue and biomedical fields[14,68]. Sericin protein contains chiefly amino-acids for instance glycine (16%), serine (40%), aspartic acid, glutamic acid, tyrosine and threonine. It com- prises of polar side chains composed up of amino, carboxyl, and hydroxyl groups that allow easy copolymerization, cross- linking, and combination with more polymers to formulate better biodegradable substances[69,70,90]. The physicochemical attributes of sericin primarily depend on the way of sericin iso- lation and the families of the silkworm and this affects its func- tional features and mark sericin as a probable biocompatible material for various biomedical applications[22] (Figure 3).
5.1. Silk sericin self-assembled/poloxamer nanoparticles
In current times self-assembled micellar nanoparticles have been effectively working for directed drug delivery purposes in tissue engineering. In Mandal and Kundu[97] review article, silk protein sericin from the Antheraea mylitta non-mulberry
Tasar silk cocoons obtained from tropical region were mixed with pluronic F-87 and F-127 along with solvents to attain self-assembled nanostructures in the form of micelles that have the capability of carrying both hydrophobic (anticancer drug paclitaxel) drugs and hydrophilic (FITC-inulin). The quick intake of these units into the cells was experimented in in vitro researches using the MCF-7 cells of breast cancer. In vitro cells toxicity examination utilizing the nanoparticles loaded with paclitaxel against the breast cancer cells exhibited potential consequences compared to the paclitaxel drugs alone. Encapsulated drugs with nanoparticle have stimulated apoptosis in the
MCF-7 cells of breast cancer.
Downregulation of Bcl-2 (anti-apoptotic protein), upregula- tion of Bax (pro-apoptotic protein), and cleavage of PARP (regulatory protein) proposed more drug, provoked apoptosis in the cells. The research develops silk protein sericin as a substituted biomaterial for the production of self-built nano- particles in the occurrence of poloxamer for the effective
Figure 3. Proposed mechanism of silk sericin-based nanoparticles in cancer treatment. The diagram shows the silk sericin- nanoparticles loaded with the drug are internalized via clathrin-mediated endocytosis into the cancerous cells and carried through lysosomes into the tumor microenvironment with low pH, releasing the drug and induction of apoptosis through the cleaved caspace-3 pathway.
INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
7 distribution of both hydrophilic and hydrophobic drugs to the targeted locations. This offers a new aspect to naturally occurring sericin protein in the nanoparticles form for its effective and efficient role as a drug delivery vehicle in tissue engineering and biomedical applications[97].
5.2. Sericin-PEG nanoparticles and sericin-PBLG micelles
There are many materials used as nanocarriers, but the nat- ural polymers are chosen over current years. Among these natural polymers, sericin has obtained great consideration.
Due to its several valuable properties, sericin-based substan- ces are progressively applied in biomedicine and tissue engineering[24,41]. Presently, numerous procedures have been established to make silk centered nanoparticles such as seri- cin-PEG nanoparticles, self-built sericin nanoparticles, or other types of silk or sericin micelles[89,97–106].
Subsequently, sericin is viewed as a new material in the field of the nanocarrier. Synthetic polypeptides are broadly uti- lized in the spheres of biomedical like in the delivery of drugs[107] because of their intrinsic biodegradability and bio- compatibility degradation products. Poly (c-benzyl-L-glutam- ate) (PBLG) formed synthetically has gained consideration, and is being attached to the hydrophilic backbone of poly- saccharide identical to hyaluronic acid[108] or attaching of synthetic hydrophilic polymer like PEG[109] to develop core–shell designed micelles. In these amphiphilic unit poly- mers, the core of PBLG aids as a reservoir for hydrophobic drugs and significantly enhances the stability of therapeutic agents in the blood circulation. Furthermore, PBLG can be degraded into an amino acid such as L-glutamic acid[110].
Sericin-PBLG micelles show high stability with high drug loading capacity, which helps in extended circulation time in the blood. These micelles correspondingly had reliable biocompatibility, negative surface capacity, and suitable size distribution. The nanoparticles can be proficiently interior- ized via clathrin-facilitated endocytosis into the cells. Sericin
PBLG-DOX was carried, and then gathered within the per- ipheral nuclear lysosomes faraway from transmembrane drug pumps, and afterward releasing DOX in the micro- environment with below low pH. The DOX which is released entered directly into the nucleus following DNA impairment and greater anti-cancer effect. The principal mechanism is still to be investigated as an outcome of the pattern of these nanocarriers. The micelles of sericin-PBLG- DOX administration can accomplish an appropriately ele- vated concentration of native drug that augments the DOX chemotherapeutic impact directed toward tumors, hence reducing the unwanted cytotoxic side impacts, together with damage to brain, liver, heart, lungs, kidneys, and spleen.
The micelles of sericin-PBLG-DOX are safe and helpful in the chemotherapeutic drug delivery and thus offer a prob- able technique to reverse the multidrug resistance[39].
5.3. Sericin regulated spherical calcium phosphate nanoparticles
Calcium phosphates (CaPs) are very significant inorganic compounds of biological hard tissues in hydroxyapatite form. They have been employed as best biomaterials in the clinical inquiries because of their exceptional biocompatibil- ity function. The usage of premixed rapidly resting calcium phosphate mixtures for the bone repair can expressively improve the graft properties and cut the surgical time[111–113]. Currently, CaP nanoparticles biomedical appli- cations have spread to many other fields including gene and drug transfer and in vivo imaging reliant on progression in the nanotechnology field[114–117]. CaP has been employed as a transfecting agent for many years and its transfection effi- cacy has been enhanced by altering the size of the particle and executing surface amendments[118–122]. CaP nanopar- ticles offer a unique group of vessels for the delivery of drug as it shows sensitivity to acidic pH in the lysosomes of cell and little immunogenicity. This allows overcoming the prob- lem of drug resistance. These CaP nanoparticles could be charged with a range of molecules comprising siRNA, pDNA and chemotherapeutic drugs[123]. The dispersal along with CaP nanoparticles degradation in vivo is very import- ant for use as in vivo delivery of drug or gene[124].
The CaP nanoparticles passive targeting is still unclear after the intravenous injection and restricts its uses in the gene or drug delivery. Thus, an effective and safe approach for noticing the CaP nanoparticles delivery and tumor tar- geting in vivo is a demanding need now a days[124]. In prior studies, it was revealed that sericin can retain the amorph- ous phase of CaP nanoparticles with greater sensitivity of pH yielding it suitable for the use in the delivery of drugs or genes for the therapy of cancer[125–127]. S-CaP nanoparticles of size 80 nm were formed and tagged by near-infrared dye reagent (DiR) (S-CaP@DiR to inspect the CaP nanoparticles delivery and degradation in vivo, and the emitting NIR fluorescence from DiR offers a shallow way of in vivo imag- ing of non-invasiveness in the real time[128] to clearly detect the dispersal, breakdown or tumor targeting in in vivo which is the main reason of S-CaP nanoparticles manipulated in gene or drug delivery[124].
5.4. Multifunctional sericin nanoparticles Nanocarriers have increased the loading capacity of drugs and can be combined with hydrophobic or hydrophilic drugs. Notably, they are intended to have the capability of targeting the cancer cells actively through nanocarrier-linked ligands that explicitly attach to molecules in the cancer cells.
Natural polymers are of great attention to the use of materi- als for the nanocarriers[129]. The versatile chemical structures of these materials permit them to be suitably functionalized with the stimuli-responsive groups and tumor targeting ligands toward the design of excellent drug delivery sys- tems[130]. Such complexes release materials to the tumor sites through chemical bonds cleavage in the presence of probable external or physiological stimuli, for example, enzymatic activity[131], temperature[132], or pH[133,134] within the microenvironment of the tumor. Sericin is a abundant in polar side chains composed of carboxyl, amino and hydroxyl groups that offer it with increased chemical reactivity and not any immunogenicity[135–138] and has
8 M. ELAHI ET AL. varied bioactivities and excellent biocompatibility with the tissues and cells[139,140]. Hence, several formulations of seri- cin for the applications in biomedical have been discovered, including films[141], hydrogels[142], microparticles[143] and
3 D scaffolds[144]. In the nanocarriers field, two kinds of self- assembled sericin nanoparticles have been described for gene and drug delivery including sericin-poloxamer nano- particles[97] and sericin-PEG[69], and a kind of desolvated sericin nanoparticles[145]. All these stated sericin nanopar- ticles are a deficit in targeting the tumors in a specialized manner. Therefore, multifunctional sericin nanoparticles are a valuable tool for cancer therapy with specific targeting of the tumor and controlled release of drugs[105].
Owing to increased expression of folate receptors in sev- eral cancerous cells of humans[146], Huang et al.[105] pro- duced sericin nanoparticles with the capability of active targeting of tumor then to be favorably endocytosed through receptor-mediated endocytosis by the cancerous cells. In the meantime, endocytosis traffics nanoparticles into the intra- cellular compartments of endo-lysosomes having low pH (acidic). They designed pH sensitive hydrazone bonds to link sericin and DOX, hence bestowing controlled release of drug attribute to the nanoscale delivery approach. This cova- lent linkage helped to decrease the possible leakage of the drug. Conjugates of DOX-sericin could self-assemble to form nanoparticles because of the DOX hydrophobic nature and sericin hydrophilic nature. This approach would enable the successful liberation of DOXintracellularly, which pos- sibly will augment the anti-tumor effect of this system of nanoparticles of sericin. This plan was implemented for the successful fabrication of folate-sericin-DOX (FA-SND) based nanoparticles and was potentially employed asa carrier for drug transferfor the therapy of cancer[105].
5.5. Resveratrol-loaded sericin nanoparticles Resveratrol having the chemical name as trans-3, 5, 40-trihy- droxy-stilbene is a polyphenolic complex that has been recognized an anti-inflammatory[147], anti-carcinogenic[148], and anti-oxidant[149] characteristics which make it an inter- esting bioactive compound in pharmaceuticals. Its anti-can- cerous prospective has been broadly studied and is particularly remarkable, though its practicable uses are restricted by its poor solubility in water, quick degradability and photo-sensitivity[150,151]. One of the studies developed nanocarriers of protein by the modified-desolvation, using a retrieved protein powder of sericin from wastewater.
Manufacture of nanocarrier was carried out via a range of silk protein and concentrations of pluronic stabilizer, allow- ing the choice of optimal requirements for the development of minor sized, spherical, and stable nanoparticles. The silk protein nanoparticles were fabricated with resveratrol (RSV) by precipitation procedure involving no solvent and addition of pluronic surfactant 0.5% (w/v). These RSV-loaded SP nanoparticles effectively repressed the growth of Caco-2 (colorectal adenocarcinoma) cells while showed non-cytotox- icity to the fibroblasts of skin, as shown by the cell viability assays.
SP nanoparticles internalization cellular proved superficial and reliant on incubation time, carrier’s transfec- tion, in vitro outcomes representing continuous discharge of
RSV, and enhancements of the drug after encapsulation indicate their promising applications in the pharmaceutics and therapeutics. Therefore, sericin protein nanoparticles is a favorable attempt to be probable biological nanocarrier for the transport system for drug[152].
6. Conclusion and future perspectives The greater incidence of various types of cancer and its sev- eral treatment limitations such as high cost of drugs, resist- ance to chemotherapeutic agents and its increased toxicity has given researchers a great challenge to formulate such nanomedicines which are cost-effective, eco-friendly, bio- degradable and most importantly biocompatible. So, natural materials present such benefits. In this era, biosynthesized silk-based nanoparticles could revolutionize the nanopar- ticles in the various biomedical applications most import- antly in the cancer therapy and as a vehicle for drug delivery. The silk-based nanoparticles in cancer therapy is extensively being used and researched because of its less tox- icity, increased biodegradability and biocompatibility. The main benefit is the low cost of silk obtained easily from the silkworm cocoons and could overall decrease the production cost on greater industrial scale. Therefore, if all the results are compiled, this comprehensive review article illustrates the several biomedical applications particularly drug delivery and cancer therapy of the silk-based nanoparticles. However, in near future various effects such as biosafety and long-term cytotoxicity study, immunogenicity, detailed mechanism, and pharmacodynamics researches should be extensively examined in the animal models of the silk-based nanoparticles before taking them to the clinical trials.
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