it is definitely not a matter of dispute that chemotherapy and its constituent cytotoxic agents play a vital role in the clinical management of the vast majority of cancer conditions . chemotherapy measures focus on eradication of tumour presence or ( at least ) control the degree of tumour progression and metastasis . however , this therapy has its own critical flaws due to two major issues , namely , dose - dependent adverse conditions and the emergence of chemoresistance properties within the tumour . the issue of dose - dependent cumulative adverse effects derives from the pharmacological properties of cytotoxic chemotherapeutic agents , which are not tissue - specific and thus affect all tissues in a widespread manner . in addition , tissues having increased turnover rates , such as the gastro - intestinal system and skin , are more vulnerable to cytotoxic drug activity and are the most prevalent dose - limiting cumulative adverse effects in patients undergoing chemotherapy . table 1 describes in brief the pharmacology and adverse effects of a few of the most commonly prescribed chemotherapeutic agents that are implemented in many cancer chemotherapy strategies . the emergence of chemoresistance within tumour cells of solid tissues is sadly one of the main reasons for treatment failure and relapse in patients suffering from metastatic cancer conditions . resistance of the tumour cell to chemotherapeutic agent exposure may be innate , whereby the genetic characteristics of the tumour cells are naturally resistant to chemotherapeutic drug exposure . alternatively , chemoresistance can be acquired through development of a drug resistant phenotype over a defined time period of exposure of the tumour cell to individual / multiple chemotherapy combinations [ 1 , 2 ] ( see figure 1 ) . the biological routes by which the tumour cell is able to escape death by chemotherapy are numerous and complex . however , the major pathways enabling chemoresistance in cancer have been studied in detail and are summarised in table 2 . the introduction of nanotechnology in the last few decades has led to an undisputed boom in the conception and development of innovative methods for effective and safe delivery of small - molecule drugs and gene - based therapies to their intended target tissues . the advantages of exploiting nanoparticle delivery systems are many , such as the possibility to protect nuclease - labile drug therapies , such as short interfering rnas ( sirnas ) and micrornas ( mirnas ) during transit within the bloodstream [ 87 , 88 ] . in addition , implementation of nanoparticle - based delivery systems has led to improved pharmacokinetic profiles for the specific drug being carried within such a system , together with enhanced targeting of the site of action of the drug [ 8991 ] . the excellent review by hu and zhang   highlighted that nanoparticles also have the capacity to carry combination therapies of two drugs / small molecules and have demonstrated to be particularly effective in circumventing multidrug resistance ( mdr ) issues in multiple cancer models . the chemical composition of nanoparticles , both from natural occurring compounds ( see figure 2 ) and synthetic ones ( see table 3 ) , is varied and the selection of which nanoparticle to utilize for any individual drug delivery system is very much dependent on a multitude of factors such as the chemical nature of the drug to be transported , the loading capacity of the nanoparticle , and resultant pharmacokinetic and pharmacodynamics properties of the nanoparticle following drug loading . it is beyond the scope of this review to delve into the specific technical details regarding each individual type of nanoparticle utilized at present , as this has been already discussed extensively in other technical reviews and research articles within the literature [ 83 , 84 , 94 , 95 ] . however , a brief summary encompassing the spectrum of varying nanoparticle compositions , key advantages together with toxicity profiles can be viewed in table 3 and figure 3 . the study carried out by kang et al .   demonstrated that administration of solid lipid nanoparticles containing doxorubicin ( sln - dox ) to the adriamycin - resistant breast cancer cell line mcf-7/adr , which also overexpressed p - glycoprotein ( p - gp ) , allowed for chemosensitisation of the cell line . this was induced due to enhanced accumulation of doxorubicin within the cell line , contributed by the nanoparticle - based delivery method , and thus the degree of apoptosis was enhanced .   the same principle of exploiting nanoparticle delivery to substantiate chemotherapeutic drug accumulation within the target cancer cell , with the ultimate goal of enhancing tumour chemosensitivity , polymer - cisplatin conjugate nanoparticles were developed and consequently delivered to a2780 human ovarian carcinoma cell line . the added potential of this delivery system relied on the cisplatin analogue prodrug covalently linked to a poly(ethylene glycol)-based polymer , which only released its therapeutic payload in a low ph environment . consequently , clinical administration of such a delivery system would ensure that the drug will remain complexed whilst in transit within the bloodstream due to its neutral ph environment . additionally , rnai therapeutics have come to rely much further on the utilization of nanoparticle delivery systems to exert their biological effects . the study by dickerson et al .   elucidated the efficiency to knock - down genes such as epidermal growth factor receptor ( egfr ) by the delivery of egfr - specific sirnas contained within core / shell hydrogel nanoparticles ( nanogels ) . the nanogels were also coated with peptides targeting the epha2 receptor to enhance delivery of anti - egfr sirnas within the targeted hey tumour cells . consequently , the knock - down effect on egfr led to enhanced chemosensitivity of cancer cells to taxane chemotherapy . the implementation of nanoparticle technology has also demonstrated to aid the clinical effect of other therapies that were previously unsuccessful due to poor drug delivery issues . developed transferrin conjugated ph - sensitive lipopolyplex nanoparticles with the capacity to bind specific oligodeoxynucleotides ( gti-2040 in this case ) . this delivery system allowed gti-2040 to exert its effect on the r2 subunit of the chemoresistance factor ribonucleotide reductase in acute myeloid leukaemia cell line models . the influence of ultilising such a delivery system was evident in that the 50% inhibitory concentration ( ic(50 ) ) for 1  m gti-2040 decreased from 47.69  nm to 9.05  nm . an additional nanoparticle delivery system , adopted against mdr in leukaemic conditions , was investigated by cheng et al . . this system combined magnetic iron oxide nanoparticles together with daunorubicin and 5-bromotetrandrin , which proved to possess a sustained release pharmacokinetic drug profile when administered to k562/a02 multidrug resistant leukaemic cell lines . the principle behind the utilization of magnetic nanoparticles is due to the effects of magnetic field gradients positioned in a nonparallel manner with respect to flow direction within the tumour vasculature . this allows for physical ( magnetic ) enhancement of the passive mechanisms implemented for the extravastation and accumulation of such magnetically responsive nanoparticles within the tumour microenvironment , followed by cellular uptake of the nanoparticles within the target tumour cell cytoplasm . the magnetically responsive nanoparticle itself is composed of one or a combination of the three ferromagnetically active elements at physiological temperature , namely , iron , nickel , and cobalt . the delivery system described by cheng et al .   also aided in providing a dose - dependent antiproliferative effect on such cell lines , together with enhanced intracellular accumulation of daunorubicin and downregulated transcript expression of mdr1 gene , the main factor for induction of mdr in most cancer models . these factors all contributed to a reduction in mdr and were directed by the level of endosomal - mediated cellular uptake properties of such nanoparticles . in chronic myelogenous leukaemia ( cml ) , a bcr - abl positive status induces mdr properties through multiple pathways , including resistance to p53 and fas ligand - induced apoptotic pathways . the delivery system devised by singh et al .   consisted of magnetic nanoparticles combined with paclitaxel and was consequently administered to bcr - abl positive k562 leukaemic cell lines . the addition of lectin functional groups to the nanoparticle complex served to aid cellular uptake by the target k562 cell line and also demonstrated a reduction in the ic(50 ) for paclitaxel within this cell line model . multiple myeloma is an additional tumour model that has seen benefit from the exploitation of nanoparticle technology in its therapeutic avenues . the study by kiziltepe et al .   succeeded in developing a micelle - based nanoparticle delivery system containing doxorubicin and very late antigen-4 ( vla-4 ) antagonist peptides . this delivery method not only accomplished enhanced cytotoxic activity when compared to doxorubicin alone , but also the addition of vla-4 antagonist peptides served well in circumventing the phenomenon of cell - adhesion - mediated drug resistance due to the resultant impaired vla-4 mediated adhesion of multiple myeloma cells to the stroma of bone marrow within cb.17 scid murine multiple myeloma xenograft models . additionally , drug accumulation within the stroma of the multiple myeloma murine xenograft models was also tenfold higher than the control murine model . yet another tumour model that has been investigated for the application of nanoparticle - based chemotherapy , for the purpose of avoidance of chemoresistance , is prostate cancer . gold nanoparticles are an attractive avenue for drug delivery researchers primarily due to their lack of complexity in their synthesis , characterization , and surface functionality . the endosomal - based route for gold nanoparticle cellular uptake can be viewed as the primary advantage for circumventing mdr within the tumour cell , since the drug efflux pump is bypassed and the nanoparticle - held chemotherapeutic agent is released within the acidic environment of the endosome and allowed to penetrate the tumour cell cytoplasm . consequently , tumour progression phenotypes such as cell proliferation and level of apoptosis are affected to direct an amelioration of patient prognosis . , with the capacity to selectively bind to two surface receptors which are upregulated in prostate tumour cell surface . thus allowing accumulation of the nanoparticle conjugate specifically within treatment - resistant prostate tumour cells . gold nanoparticles were also exploited in the study conducted by tomuleasa et al .   for the purpose of reducing mdr hepatocellular carcinoma - derived cancer cells . the gold nanoparticles were loaded with doxorubicin , capecitabine , and cisplatin , followed by nanoparticle stabilization by l - aspartate . the resultant cellular proliferation rates of the hepatocellular carcinoma cells treated with this nanoparticle - based therapy were found to be lowered drastically .   in the study carried out by punfa et al . , the cytotoxic properties of curcumin on multidrug resistant cervical tumours were maximized through the development of a nanoparticle - curcumin drug delivery system . curcumin was successfully entrapped within poly ( dl - lactide - co - glycolide ) ( plga ) nanoparticles , followed by the incorporation of the amino - terminal of anti - p - gp . consequently , the curcumin - nanoparticle conjugates were deployed onto the kb - v1 cervical cancer cell line , having upregulated p - gp expression , together with the kb-3 - 1 cell line that has a reduced p - gp expression level . the results of this study demonstrated that nanoparticle conjugates bearing anti - p - gp surface markers were highly efficient in binding to the mdr - inducing surface protein , allowing enhanced cellular uptake and ultimately aid in the cytotoxic efficacy of curcumin due to increased accumulation of the drug , particularly within the kb - v1 cell line due to its exacerbated p - gp expression status . curcumin / doxorubicin - laden composite polymer nanoparticles were also developed in other studies   as a means of enhancing the pharmacokinetic and pharmacodynamics properties of curcumin , thus enhancing its mdr - modulating effect in the target tumour cells . the resultant nanoparticle complex was deployed onto several mdr tumour models such as acute leukaemia , multiple myeloma , and ovarian cancers , both in vitro and in vivo . the results of this study highlighted the possibility of administration of lower doses of doxorubicin due to the circumvention of tumour mdr by efficient curcumin activity , thus enhancing the toxicity profile for doxorubicin in clinical use stemming from the reduction in cardiotoxicity and haematological toxicity dose - dependent adverse effects . retinoblastoma therapeutic avenues have also been increased due to the introduction of nanoparticle drug delivery technology . the study by das and sahoo demonstrated the effectiveness of utilising a nanoparticle delivery system which was dual loaded with curcumin together with nutlin-3a ( which has been proven to stimulate the activity of the tumour suppressor protein p53 ) . the results of this particular investigation highlighted an enhanced level of therapeutic efficacy on utilizing the nanoparticle - curcumin - nutlin-3a conjugates on the target retinoblastoma y79 cell lines . in addition , a downregulation of bcl2 and nfb was also observed following cell line exposure to the nanoparticle conjugates . the nanoparticle - based drug delivery system designed by saxena and hussain   for its application against multidrug resistant breast tumours was novel in that the actual components of the nanoparticle biomaterials , namely , poloxamer 407 and d--tocopheryl polyethylene glycol 1000 succinate ( tpgs ) , are both known to exert pharmacological activity against p - gp . the drug utilized for nanoparticle loading in this case was gambogic acid , a naturally occurring cytotoxic agent though laden with issues of poor bioavailability and severe dose - limiting adverse effects . similarly to other studies mentioned above , the incorporation of a nanoparticle - based drug delivery system allowed for enhanced cellular uptake by the target breast cancer cell line mcf-7 , thus leading to elevated drug accumulation on the intracellular level and ultimately inducing enhanced cytotoxic effects in the target breast cancer cell line . a separate nanoparticle - based drug delivery system for use in circumventing mdr effects in breast cancer is the one developed by li et al . . in this study , the nanoparticle drug delivery system consisted of a dimethyldidodecylammonium bromide ( dmab)-modified poly(lactic - co - glycolic acid ) ( plga ) nanoparticle core that was conjugated to doxorubicin , then consequently coated with a 1,2-dipalmitoyl - sn - glycero-3-phosphocholine ( dppc ) shell . this system has been described to be specifically effective against mcf-7 breast cancer cell lines overexpressing p - gp . the results obtained from this particular study indicated an elevated accumulation of doxorubicin released from the nanoparticle complex , within the nuclei of the drug resistant mcf-7 cell line . in comparison , the level of accumulation of freely administered ( i.e. , not utilising a nanoparticle - based drug delivery system ) doxorubicin attained lower drug concentration levels within the same cell line . finally , the ic(50 ) levels for doxorubin on adriamycin - resistant mcf-7 have been observed to be lowered by 30-fold following the incorporation of this nanoparticle delivery system . apart from delivery of conventional chemotherapeutic drugs in drug resistant breast cancer cell line models , researchers also delved into the possibility of adopting sirna therapeutic approaches , using the aid of nanoparticle drug delivery systems . the study conducted by navarro et al .   developed a nanoparticle - based delivery system for sirnas targeting p - gp expression , with the nanoparticle constituent biomaterials being dioleoylphosphatidylethanolamine and polyethylenimine ( pei ) . again , the reduction in p - gp expression led the path to enhanced cytoxic effects brought about by the exposure of the mcf-7 cell line to doxorubicin , thus this nanoparticle - sirna therapy was successful in drastically reducing mdr in this cancer model . quantum dots have also been implemented as novel and effective drug delivery systems for circumventing multidrug resistance in cancer chemotherapy . researchers in this study developed a quantum dot - based drug delivery system that allowed anti - mdr1 sirna and doxorubicin incorporation to two cadmium - selenium / zinc - selenium quantum dots that were eventually functionalized by -cyclodextrin coupling to l - arginine or l - histamine . following deployment of these dual loaded quantum dots in the hela cervical cancer cell line model , elevated accumulation of doxorubicin within the tumour cells was denoted , together with a marked reduction in mdr1 and p - gp expression on analysis by reverse transcription real time quantitative polymerase chain reaction and western blotting . in line with magnetic and gold nanoparticle platforms , quantum dots rely mainly on the endosomal method of tumour cellular uptake and therefore the drug efflux pump system is bypassed , with consequent reduction in mdr properties by the tumour cells . finally , the additional benefit of utilizing quantum dots as a drug delivery system is their capacity to be tracked in real time within specific areas of the target cells , due to their intrinsic fluorescence properties . apart from cell line studies , researchers have also looked into the feasibility of implementing nanoparticle - based drug delivery systems within in vivo models . investigated the efficacy of utilising a egfr - targeting polymer blend nanoparticles , loaded with paclitaxel and the mitochondrial hexokinase 2 inhibitor lonidamine . the nanoparticle polymer blend consisted of 70% polycaprolactone ( pcl ) incorporating a plga - polyethylene glycol - egfr specific peptide that helped enable nanoparticle active targeting efficiency . following nanoparticle development , four groups of orthotopic mdr breast cancer murine models ( mda - mb-231 in nude mice ) were treated with free paclitaxel , free lonidamine , free paclitaxel / lonidamine combination , or nanoparticle complexes containing paclitaxel / lonidamine combination . the degree of toxicity of such treatments was also monitored through body weight change measurements , liver enzyme plasma levels , and white blood cell / platelet counts , together with h & e staining of tumour sections was carried out . tumour weight and other clinical parameters such as mdr protein marker ( p - gp , hypoxia inducible factor  , hexokinase 2 , egfr , stem cell factor ) were observed over the course of 28 days after - treatment . following this 28-day period , the results demonstrated that only the murine model sample group exposed to the nanoparticle - based paclitaxel / lonidamine combination treatment was the only group to experience statistically significant tumour volume and density reduction , together with overall alteration of the mdr phenotype . toxicity effects due to paclitaxel and lonidamine were also drastically reduced when administered within the nanoparticle - based delivery system , which can ultimately provide enhanced tolerance by the cancer patient . other in vivo studies in this field include the investigations carried out by shen et al . , which focused on the codelivery of paclitaxel and survivin short hairpin rna ( shrna ) for circumventing chemoresistance in lung cancer . the investigators utilized the pluronic block co - polymer p85 combined with d--tocopheryl polyethylene glycol 1000 succinate ( p85-pei / tpgs ) for developing the nanoparticles to be implemented in this study . these nanoparticles were based upon triblock structural formation of hydrophilic poly(ethylene oxide ) ( peo ) blocks and hydrophobic poly(propylene oxide ) ( ppo ) blocks , which also gives enhanced capacity to revert chemoresistance due to drug efflux pump inhibition properties , downregulation of atpase activity and p85-induced inhibition of the gluthathione s - transferase compound detoxification enzyme at the subcellular level . paclitaxel and surviving shrna were selected as the ideal drugs for nanoparticle delivery due to the former having poor efficacy due to chemoresistance within the tumour , and survivin was identified as highly expressed within chemoresistant tumours . the in vivo activity of such nanoparticle systems ( with / without paclitaxel and survivin shrna ) was evaluated on balb / c nude mice injected with viable , paclitaxel - resistant , a549/t lung adenocarcinoma epithelial cells . the results of this study demonstrated that deployment of the nanoparticle - based chemotherapeutic drug proved to have distinct enhancement of antitumour efficacy , when compared to deployment of the drug / s alone . chemoresistance to the aromatase inhibitor letrozole in postmenopausal breast cancer is another major therapeutic hurdle which was investigated in vivo . biodegradable plga - polyethylene glycol copolymer nanoparticles were developed by nanoprecipitation and designed to incorporate hyaluronic acid - bound letrozole ( ha - letr - nps ) . the addition of hyaluronic acid served to enhance letrozole binding specificity to cd44 on the target tumour cell surface , with the expected consequences of enhanced drug accumulation within the target tumour cell cytoplasm and resultant re - sensitization of the target tumour cells to letrozole activity . such ha - letr - nps , once produced at a size of less than 100  nm diameter , were deployed within a letrozole - resistant murine xenograft tumour model . the results of this study demonstrated a highly efficient nanoparticle - based drug delivery system , with the ic(50 ) for ha - letr - nps within the murine xenograft model being only 5  m when compared to the control groups , thus enhancing the in vivo aromatase enzyme activity within the xenograft and ultimately inducing a prolonged resensitising of the breast cancer tumour to letrozole activity . the naturally occurring compound chitosan was also utilized for the development of in vivo nanoparticle - based therapies to circumvent ovarian cancer chemoresistance properties induced by overexpression of the jagged1 notch ligand . murine orthotopic models , utilising female athymic nude mice , were injected with skov3trip2 taxane - resistant ovarian cancer cell line and consequently , following one week , subjected to anti - jagged1 sirna / chitosan nanoparticle complexes ( 5  g dose of sirna ) with / without taxane , applied via intraperitoneal route twice weekly for a total period of five weeks . the results of this study indicated that such nanoparticle - based complexes had the capacity to reduce tumour weight by over 70% within such murine models and also induced taxane sensitization within the tumour . in a similar study , cationic liposome - polycation - dna ( lpd ) and anionic liposome - polycation - dna ( lpd ii ) nanoparticle systems were developed to incorporate doxorubicin and vegf sirna within a murine ovarian cancer animal model . female , athymic nude mice were treated with 5  10 cells of the mdr ovarian cancer cell line nci / adr - res . once the murine tumours reached a size of approximately 1625  mm , the mice were consequently injected with individual nanoparticle complexes bearing either sirna or doxorubicin at a dose of 1.2  mg / kg in both cases , once daily for three consecutive days . the results of this study demonstrated the effectiveness of such nanoparticle complexes for inhibiting tumour progression within the treated murine model groups , mainly due to impaired vegf expression - related mdr . other human cancer conditions which were investigated for circumvention of tumour mdr properties through nanoparticle delivery include uterine sarcomas . in the study carried out by huang et al . , ph - sensitive mesoporous silica nanoparticles incorporating hydrazine and doxorubicin were developed for in vivo testing on murine models of doxorubicin - resistant uterine sarcoma . since the composition of such nanoparticles specifically allow for cellular uptake through endocytosis , bypassing of the p - gp efflux pump induced a marked reduction in p - gp dependent mdr properties . consequently , the murine mdr tumour model treated with such nanoparticles demonstrated enhanced tumour apoptotic effects which were clearly confirmed by active caspase-3 immunohistochemical validation analysis . the latest studies described above undoubtedly serve as a testament to the immense clinical value represented by nanoparticle technology . the ability of such nanoparticles , irrelevant of biomaterial composition to efficiently load individual or combinations of chemotherapeutic drugs and/or chemosensitising agents ( such as curcumin ) and novel rna interference - based therapies has been clearly demonstrated above . this property provides an excellent escape mechanism for circumventing target tumour cell multidrug resistance properties based on drug efflux pump activity on the tumour cell surface , such as that exerted by p - gp . the overall advantage of deploying nanoparticles includes the drastic reduction in the ic(50 ) parameter for most of the carried chemotherapy agents , due to marked intracellular accumulation pharmacodynamics . this in turn would lead to a reduction in the clinical doses of the conventional cytotoxic agents required for chemotherapy , ultimately demonstrating a striking reduction in dose - dependent adverse effects in the oncology patient . presently , this does not mean that nanotechnology - based translational therapies are not fraught with challenges , such as biocompatibility issues of the nanoparticle components and the level of complexity required for cost - effectively translating these novel therapies to the patient bedside . however , it is the firm belief of the authors that through constant accumulation of marginal gains in knowledge , derived from persistent and motivated researchers on a global scale , will ultimately overcome such scientific hurdles , thus nanoparticle - based drug delivery aided therapies will eventually become commonplace in the oncology clinic in the near future .