Curcumin loaded PEG400‐OA nanoparticles: A suitable system to increase apoptosis,decrease migration,and deregulate miR‐125b/miR182 in MDA‐MB‐231 human breast cancer cells

Curcumin is an anti‐cancerous agent, but its low‐solubility limits its clinical use. The relationship between deregulation of miRNAs and their targets suggested that miRNAs can be interest targets of curcumin in treatment of different cancers. In this study, to overcome essential defects of the clinical usage of this golden drug, curcumin‐encapsulated polymersome nanoparticles (CPNs) have been developed, and the cytotoxicity effects were studied on MDA‐MB‐231 breast cancer cells. The expression level of miR‐182/125b and the expression pattern of some potential targets in apoptotic pathway, predicted by in silico approaches, were analyzed by RT‐qPCR in CPNs‐treated and untreated cells. Moreover, the amount of CASP9 and CASP8 proteins were determined by Western blotting. The effect of CPNs on cell migration were studied by scratch test and the level of EGFR, E‐cadherin, and beta‐catenin proteins were monitored in CPNs‐treated and untreated cells by western blotting. RT‐qPCR analysis identified the downregulation of miR‐125b and miR‐182 in CPNs‐treated cells and the upregulation of some predicted apoptotic target genes such as P53, CASP9 and BAX after 24 hours. Western blotting confirmed the effects of curcumin on the increase of cleaved CASP9 protein. Based on data from the current experiment, the migration of MDA‐MB‐231 cells was decreased after CPNs treatment. According to the results, CPNs, as suitable and compatible nanocarriers, can deliver curcumin into cancerous cells more effectively and can increase the therapeutic effects of curcumin on MDA‐MB‐231 cells partly by suppression of miR‐125b and miR‐182 as well as induction of apoptosis and inhibition of metastatic progression.     

Cold atmospheric plasma modification of curcumin loaded in tri‐phosphate chitosan nanoparticles enhanced breast cancer cells apoptosis

The anti‐cancer mechanisms of curcumin have been reported to include suppressions of angiogenesis and tumor proliferation. The main goal of this research is to increase the solubility of curcumin by cold atmospheric plasma (CAP) and assess the effects of modified curcumin by charging with tri‐polyphosphate chitosan nanoparticles for MCF‐7, MDA‐MB‐231 breast cancer cells, and human fibroblast cells. Curcumin modification was done by CAP and its solubility was evaluated by spectrophotometry. After loading modified curcumin into nano‐chitosan‐TPP, nanocurcumin was characterized by scanning electron microscopy. Cellular viability and apoptosis of treated cells were assessed by MTT and Annexin V. The changes of messenger RNA expression of TP5353 and VEGF genes were analyzed by real‐time PCR. CAP was able to transform the curcumin to possess hydrophilic characteristics after 90 seconds. The mean diameter of Curcumin loaded chitosannanoparticles (NPs) were determined as 48 nm. MTT results showed that the IC₅₀ of nano Cur‐chitosan‐TPP was effectively decreased compared to free curcumin in MCF‐7 (15 μg/mL at 72 hours vs 20 μg/mL at 48 hours). Additionally, nano Cur‐chitosan‐TPP had no significant effect on normal cells (Human dermal fibroblas: HDF), whereas it also decreased the viability of triple negative breast cancer cell line (MDA‐MB‐231). Real‐time PCR results showed that expression level of TP53 gene was upregulated (P = .000), whereas VEGF gene downregulated (P = .000) in treated MCF‐7 cells. Curcumin loaded chitosan nanoparticles have led to an induction of apoptosis (79.93%) and cell cycle arrest (at S and G2M). Modified‐curcumin‐tri‐polyphosphate chitosan nanoparticles using CAP can be considered as a proper candidate for breast cancer treatment.     

Synergistic Roles of Curcumin in Sensitising the Cisplatin Effect on a Cancer Stem Cell-Like Population Derived from Non-Small Cell Lung Cancer Cell Lines

Cancer stem cells (CSCs) represent a small subpopulation within a tumour. These cells possess stem cell-like properties but also initiate resistance to cytotoxic agents, which contributes to cancer relapse. Natural compounds such as curcumin that contain high amounts of polyphenols can have a chemosensitivity effect that sensitises CSCs to cytotoxic agents such as cisplatin. This study was designed to investigate the efficacy of curcumin as a chemo-sensitiser in CSCs subpopulation of non-small cell lung cancer (NSCLC) using the lung cancer adenocarcinoma human alveolar basal epithelial cells A549 and H2170. The ability of curcumin to sensitise lung CSCs to cisplatin was determined by evaluating stemness characteristics, including proliferation activity, colony formation, and spheroid formation of cells treated with curcumin alone, cisplatin alone, or the combination of both at 24, 48, and 72 h. The mRNA level of genes involved in stemness was analysed using quantitative real-time polymerase chain reaction. Liquid chromatography-mass spectrometry was used to evaluate the effect of curcumin on the CSC niche. A combined treatment of A549 subpopulations with curcumin reduced cellular proliferation activity at all time points. Curcumin significantly (p < 0.001) suppressed colonies formation by 50% and shrank the spheroids in CSC subpopulations, indicating inhibition of their self-renewal capability. This effect also was manifested by the down-regulation of SOX2, NANOG, and KLF4. Curcumin also regulated the niche of CSCs by inhibiting chemoresistance proteins, aldehyde dehydrogenase, metastasis, angiogenesis, and proliferation of cancer-related proteins. These results show the potential of using curcumin as a therapeutic approach for targeting CSC subpopulations in non-small cell lung cancer.     

Magnetically polymeric nanocarriers for targeting delivery of curcumin and hyperthermia treatments toward cancer cells

Magnetically polymeric nanocarriers, Cur‐FA‐SAMN, were designed and synthesized for targeting, therapeutic treatments to cancer cells. Amine‐group immobilized iron oxides, Fe₃O₄‐NH₂, were attached on the surface of self‐assembled tri‐block copolymer, poly[(acrylic acid)‐block‐(N‐isopropylacrylamide)‐block‐(acrylic acid)] synthesized via reversible addition‐fragmentation chain‐transfer polymerization. For the purpose of targeting effect, folic acid was grafted on the surface of Fe₃O₄‐NH₂ attached nanoparticles. The nanocarriers were characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, vibrating sample magnetometer, and UV‐Vis spectral analysis. Therefore, a hydrophobic anti‐cancer drug, curcumin, gained water dispersity, and stable storage via encapsulating into and on the magnetically polymeric nanocarriers, and the release behaviors were studied in vitro, with and without high frequency magnetic field. Biocompatibility and cytotoxicity of inherent and curcumin‐loaded nanocarriers were investigated by MTT assay. Results displayed that our nanocarriers have no cytotoxicity while curcumin‐loaded nanocarriers offered significant death to MCF‐7, human breast camcer cells. Intracellular‐uptake experiments demonstrated tremendous uptake and the destroying effect to MCF‐7 cells, most of the cancer cells were killed and the surviving ones were surrounded by the curcumin‐loaded nanocarriers. According to the aforementioned characteristics, these magnetically polymeric nanocarriers will be able to apply as a potential device for practical therapy. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2706–2713     

MicroRNA Delivery with Bioreducible Polyethylenimine as a Non‐Viral Vector for Breast Cancer Gene Therapy

Polyethylenimines (PEIs) are outstanding macromolecules belonging to the polycations used in gene transfection. The transfection efficiency and cytotoxicity of PEIs increase with the increase in their molecular weight. To break up the correlation between transfection efficiency and cytotoxicity for non‐viral gene delivery, disulfide cross‐linked polyethylenimine (PEI‐SS) has been widely employed as highly efficient gene vectors for DNA/siRNA delivery in numerous efforts. In this work, PEI‐SS is described as a non‐viral vector for miRNA delivery for the first time. PEI‐SS is synthesized via cross‐linking using disulfide bonds as the cross‐linker from low molecular weight PEI. PEI‐SS can efficiently bind anti‐miR‐155 to form the polyplex with nano‐sized spherical structures in the size range of 10–100 nm. The polyplex is degraded by glutathione (GSH, a reducing agent) in cancer cells. Anti‐miR‐155 is then released to efficiently inhibit tumor growth.     

pH‐responsive near‐infrared emitting conjugated polymer nanoparticles for cellular imaging and controlled‐drug delivery

In this article, pH‐responsive near‐infrared emitting conjugated polymer nanoparticles (CPNs) are prepared, characterized, and their stabilities are investigated under various conditions. These nanoparticles have capacity to be loaded with water insoluble, anticancer drug, camptothecin (CPT), with around 10% drug loading efficiency. The in vitro release studies demonstrate that the release of CPTs from CPNs is pH‐dependent such that significantly faster drug release at mildly acidic pH of 5.0 compared with physiological pH 7.4 is observed. Time and dose‐dependent in vitro cytotoxicity tests of blank and CPT‐loaded nanoparticles are performed by real‐time cell electronic sensing (RT‐CES) assay with hepatocellular carcinoma cells (Huh7). The results indicate that CPNs can be effectively utilized as vehicles for pH‐triggered release of anticancer drugs. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 114–122     

Conjugated Polymer Nanoparticles with Appended Photo‐Responsive Units for Controlled Drug Delivery,Release, and Imaging

Carriers that can afford tunable physical and structural changes are envisioned to address critical issues in controlled drug delivery applications. Herein, photo‐responsive conjugated polymer nanoparticles (CPNs) functionalized with donor–acceptor Stenhouse adduct (DASA) and folic acid units for controlled drug delivery and imaging are reported. Upon visible‐light (λ=550 nm) irradiation, CPNs simultaneously undergo structure, color, and polarity changes that release encapsulated drugs into the cells. The backbone of CPNs favors FRET to DASA units boosting their fluorescence. Notably, drug‐loaded CPNs exhibit excellent biocompatibility in the dark, indicating perfect control of the light trigger over drug release. Delivery of both hydrophilic and hydrophobic drugs with good loading efficiency was demonstrated. This strategy enables remotely controlled drug delivery with visible‐light irradiation, which sets an example for designing delivery vehicles for non‐invasive therapeutics.     

Screening of exon methylation biomarkers for colorectal cancer via LC‐MS/MS strategy

The identification of biomarkers would be of benefit for the diagnosis and treatment of colorectal cancer. DNA methylation in specific genomic regions, which had shown strongly association with disease genotypes, was an effective indicator to reveal the occurrence and development of cancers. To screen out methylation biomarkers for colorectal cancer (CRC), genomic DNA was isolated from colorectal cancerous and corresponding cancer‐adjacent tissues collected from 30 CRC patients and then bisulfite‐converted. The exon regions of 5 targeted genes (CNRIP1 , HIC1 , RUNX3 , p15 , and SFRP2 ) were amplified by using nested polymerase chain reaction with specific primers, and the amplicon was purified and hydrolyzed. The methylation levels of these specific regions were detected by liquid chromatography tandem mass spectrometry (LC‐MS/MS). The results showed that 5 targeted exon regions were successfully amplified and confirmed by sequencing. The methodological validations indicated that LC‐MS/MS was highly sensitive and accurate. The methylation levels of CNRIP1 and RUNX3 were remarkably high in CRC tissues with statistical difference when compared with corresponding cancer‐adjacent individuals, while that of HIC1 , p15 , and SFRP2 had no difference between 2 subjects. These findings supported CNRIP1 and RUNX3 as potential DNA methylation biomarkers for CRC diagnosis and treatment, and our LC‐MS/MS approach exhibited great advantages in the identification of regional DNA methylation biomarkers.     

Ferrocene conjugated copper(II) complexes of terpyridine and traditional Chinese medicine (TCM) anticancer ligands showing selective toxicity towards cancer cells

Six novel mixed‐ligand copper(II) complexes, namely, [Cu(R‐tpy)(L)]NO₃ ( 1–6 ), where R‐tpy is 4′‐phenyl‐2,2′:6′,2′′‐terpyridine (Ph‐tpy; 1–3 ) and 4′‐ferrocenyl‐2,2′:6′,2′′‐terpyridine (Fc‐tpy; 4–6 ), L is the bidentate O,O donor monoanion of plumbagin (5‐hydroxy‐2‐methyl‐1,4‐naphthoquinone; plum in 1 , 4 ), chrysin (5,7‐dihydroxyflavone; chry in 2 , 5 ) and curcumin (bis(4‐hydroxy‐3‐methoxyphenyl)‐1,6‐diene‐3,5‐dione; curc in 3 , 6 ) have been synthesized and characterized and their in vitro cytotoxicity against cancer cells is evaluated. The energy optimized structures and the frontier orbitals of the complexes have been obtained from the DFT calculations. Complexes 4–6 with a conjugated ferrocenyl moiety and TCM anticancer ligands, namely, plum (in 4 ), chry (in 5 ) and curc (in 6 ) showed potent cytotoxicity giving respective IC₅₀ values of 1.2 μM, 0.62 μM and 0.21 μM in HeLa and 2.0 μM and 1.0 μM and 0.34 μM in MCF‐7 cancer cells while being much less toxic to MCF‐10A normal cells (IC₅₀: 8.3‐17.1 μM). In contrast, complexes 1–3 with a conjugated phenyl moiety were appreciably less toxic to HeLa cells with respective IC₅₀ values of 10.4 μM, 8.1 μM and 5.5 μM when compared with their ferrocenyl analogues 4–6 . Mechanistic studies using Hoechst staining and Annexin‐V‐FITC assays on cancer cells revealed an apoptotic pathway of cell death induced by the complexes. Fluorescence imaging study showed that complex 6 having curcumin as ligand localized primarily in the mitochondria of HeLa cells. Thus, we demonstrate in this study that ferrocene conjugation to copper(II) complexes of TCM anticancer ligands significantly increases the selectivity and cytotoxicity of the resulting complexes towards cancer cells over normal cells.     

Unique Use of Alkylation for Chemo‐Redox Activity by a PtIV Prodrug

Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin‐based therapy. A unique dual‐acting chemotherapeutic modality, Platin‐B, a prodrug of cisplatin and pipobroman‐mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin‐B exhibited a superior cytotoxicity profile in cisplatin‐resistant cancer cells. Enhanced activity and the ability to overcome cancer‐induced resistance of Platin‐B was related to adduct formation with intracellular glutathione, followed by the activity of Platin‐B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin‐B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols.     

The cis‐Diammineplatinum(II) Complex of Curcumin: A Dual Action DNA Crosslinking and Photochemotherapeutic Agent

[Pt(cur)(NH₃)₂](NO₃) ( 1 ), a curcumin‐bound cis‐diammineplatinum(II) complex, nicknamed Platicur, as a novel photoactivated chemotherapeutic agent releases photoactive curcumin and an active platinum(II) species upon irradiation with visible light. The hydrolytic instability of free curcumin reduces upon binding to platinum(II). Interactions of 1 with 5′‐GMP and ct‐DNA indicated formation of platinum‐bound DNA adducts upon exposure to visible light (λ=400–700 nm). It showed apoptotic photocytotoxicity in cancer cells (IC₅₀≈15 μM ), thus forming ^?OH, while remaining passive in the darkness (IC₅₀>200 μM ). A comet assay and platinum estimation suggest Pt–DNA crosslink formation. The fluorescence microscopic images showed cytosolic localization of curcumin, thus implying possibility of dual action as a chemo‐ and phototherapeutic agent.     

Conjugated Polymer Nanoparticles with Appended Photo‐Responsive Units for Controlled Drug Delivery,Release, and Imaging

Carriers that can afford tunable physical and structural changes are envisioned to address critical issues in controlled drug delivery applications. Herein, photo‐responsive conjugated polymer nanoparticles (CPNs) functionalized with donor–acceptor Stenhouse adduct (DASA) and folic acid units for controlled drug delivery and imaging are reported. Upon visible‐light (λ=550 nm) irradiation, CPNs simultaneously undergo structure, color, and polarity changes that release encapsulated drugs into the cells. The backbone of CPNs favors FRET to DASA units boosting their fluorescence. Notably, drug‐loaded CPNs exhibit excellent biocompatibility in the dark, indicating perfect control of the light trigger over drug release. Delivery of both hydrophilic and hydrophobic drugs with good loading efficiency was demonstrated. This strategy enables remotely controlled drug delivery with visible‐light irradiation, which sets an example for designing delivery vehicles for non‐invasive therapeutics.     

Sequence-based analysis of 5′UTR and coding regions of CASP3 in terms of miRSNPs and SNPs in targetting miRNAs

Apoptosis is described as a mechanism of cell death occurring after adequate cellular harm. Deregulation of apoptosis occurs in many human conditions such as autoimmune disorders, ischemic damage, neurodegenerative diseases and different cancer types. Information relating miRNAs to cancer is increasing. miRNAs can affect development of cancer via many different pathways, including apoptosis. Polymorphisms in miRNA genes or miRNA target sites (miRSNPs) can change miRNA activity. Although polymorphisms in miRNA genes are very uncommon, SNPs in miRNA-binding sites of target genes are quite common. Many researches have revealed that SNPs in miRNA target sites improve or decrease the efficacy of the interaction between miRNAs and their target genes. Our aim was to specify miRSNPs on CASP3 gene (caspase-3) and SNPs in miRNA genes targeting 5′UTR and coding exons of CASP3, and evaluate the effect of these miRSNPs and SNPs of miRNA genes with respect to apoptosis. We detected 141 different miRNA binding sites (126 different miRNAs) and 7 different SNPs in binding sites of miRNA in 5′UTR and CDS of CASP3 gene. Intriguingly, miR-339-3p’s binding site on CASP3 has a SNP (rs35372903, G/A) on CASP3 5′UTR and its genomic sequence has a SNP (rs565188493, G/A) at the same nucleotide with rs35372903. Also, miR-339-3p has two other SNPs (rs373011663, C/T rs72631820, A/G) of which the first is positioned at the binding site. Here, miRSNP (rs35372903) at CASP3 5′UTR and SNP (rs565188493) at miR-339-3p genomic sequence cross-matches at the same site of binding region. Besides, miR-339-3p targets many apoptosis related genes (ZNF346, TAOK2, PIM2, HIP1, BBC3, TNFRSF25, CLCF1, IHPK2, NOL3) although it had no apoptosis related interaction proven before. This means that miR-339-3p may also have a critical effect on apoptosis via different pathways other than caspase-3. Hence, we can deduce that this is the first study demonstrating a powerful association between miR-339-3p and apoptosis upon computational analysis.     

Protective Effect of Curcumin Against Acute Ultraviolet B Irradiation‐induced Photo‐damage

Ultraviolet B (UVB) irradiation is one of the most dangerous insults for skin and causes sunburn, erythema, photoaging and photocarcinogenesis. Curcumin (diferuloylmethane), a yellow spice derived from dried rhizomes of Curcuma longa, has been shown to possess significant anti‐inflammatory, antioxidant, anticarcinogenic, antimutagenic, anticoagulant and anti‐infective effects. However, the protective effects of curcumin against acute photo‐damage are poorly understood. In this study, we investigated the photoprotective effects of curcumin against UVB‐induced acute photo‐damage in hairless mice and immortalized human keratinocytes (HaCaT). Topical application of curcumin significantly inhibited acute UVB (540 mJ cm^?2, for 3 successive days)‐induced inflammatory cells, collagen accrementition derangement and lipid peroxidation, and effectively induced NF‐E2‐related factor 2 (Nrf2) nuclear accumulation in uncovered (Uncv) hairless mice skin. Treatment of HaCaT cells with curcumin significantly attenuated acute UVB (300 mJ cm^?2)‐induced lactate dehydrogenase release, intracellular reactive oxygen species production and DNA damage, activated the expression of the phase II detoxifying enzymes and promoted DNA repair activity. The photoprotective effect provided by curcumin was potential associated with modulation of Nrf2‐dependent antioxidant response. Our study suggested that curcumin is a potential agent for preventing and/or treating UV radiation‐induced acute inflammation and photoaging.     

Combinatorial anticancer effects of curcumin and sorafenib towards thyroid cancer cells via PI3K/Akt and ERK pathways

The objective of this study was to examine the in vitro combinatorial anticancer effects of curcumin and sorafenib towards thyroid cancer cells FTC133 using a MTT cytotoxicity assay, and to test whether the mechanism involves induction of apoptosis. The present results demonstrated that curcumin at 15–25 μM dose-dependently suppressed the proliferation of FTC133. Combined treatment (curcumin (25 μM) and sorafenib (2 μM)) resulted in a reduction in cell colony formation and significantly decreased the invasion and migration of FTC133 cells compared with that treated with individual drugs. Western blot showed that the levels of p-ERK and p-Akt proteins were significantly reduced (p < 0.01) in the medicine-treated FTC133 cells. The curcumin was found to dose-dependently inhibit the apoptosis of FTC133 cells possibly via PI3K/Akt and ERK pathways. There is a synergetic antitumour effect between curcumin and sorafenib.     

Simultaneous determination of the novel thiosemicarbazone anti‐cancer agent,Bp4eT,and its main phase I metabolites in plasma: Application to a pilot pharmacokinetic study in rats

Novel thiosemicarbazone metal chelators are extensively studied anti‐cancer agents with marked and selective activity against a wide variety of cancer cells, as well as human tumor xenografts in mice. This study describes the first validated LC‐MS/MS method for the simultaneous quantification of 2‐benzoylpyridine 4‐ethyl‐3‐thiosemicarbazone (Bp4eT) and its main metabolites (E/Z isomers of the semicarbazone structure, M1‐E and M1‐Z, and the amidrazone metabolite, M2) in plasma. Separation was achieved using a C₁₈ column with ammonium formate/acetonitrile mixture as the mobile phase. Plasma samples were treated using solid‐phase extraction on 96‐well plates. This method was validated over the concentration range of 0.18–2.80 μM for Bp4eT, 0.02–0.37 μM for both M1‐E and M1‐Z, and 0.10–1.60 μM for M2. This methodology was applied to the analysis of samples from in vivo experiments, allowing for the concentration–time profile to be simultaneously assessed for the parent drug and its metabolites. The current study addresses the lack of knowledge regarding the quantitative analysis of thiosemicarbazone anti‐cancer drugs and their metabolites in plasma and provides the first pharmacokinetic data on a lead compound of this class. Copyright © 2013 John Wiley & Sons, Ltd.     

Effective Cancer Cell Killing by Hydrophobic Nanovoid‐Enhanced Cavitation under Safe Low‐Energy Ultrasound

β‐Cyclodextrin (β‐CD)‐capped mesoporous silica nanoparticles with hydrophobic internal nanovoids were prepared and used for effective cancer cell killing in synergistic combination with low‐energy ultrasound (≤1.0 W cm^?2, 1 MHz). The water‐dispersible nanoparticles with hydrophobic internal nanovoids can be taken up by cancer cells and subsequently evoke a remarkable cavitation effect under irradiation with mild low‐energy ultrasound (≤1.0 W cm^?2, 1 MHz). A significant cancer cell killing effect was observed in cancer cells and in a mouse xenograft tumor model treated with the nanoagents together with the low‐energy ultrasound, showing a distinct dependence on the concentration of nanoagents and ultrasound intensity. By contrast, an antitumor effect was not observed when either low‐energy ultrasound or nanoagents were applied alone. These findings are significant as the technique promises a safe, low‐cost, and effective treatment for cancer therapy.     

Discovery of cancer cell proliferation inhibitors from Salviae miltiorrhizae radix et rhizoma by a trace peak enrichment approach

Salviae miltiorrhizae radix et rhizoma is a traditional herbal medicine with anti‐cancer activities. In this work, a trace peak enrichment approach combined with a cell proliferation assay was applied for screening cancer cell proliferation inhibitors from the extract of S. miltiorrhiza. A set of 123 peak fractions were prepared, and by comprehensive screening, 21 tanshinones were screened out as cancer cell proliferation inhibitors and their structures were tentatively identified by liquid chromatography coupled with quadrupole time‐of‐flight tandem mass spectrometry analysis. The inhibitory activities of nine available screened tanshinones were validated, with their IC₅₀ values ranging from 0.63 to 28.40 μM, indicating their activities strongly inhibit the proliferation of cancer cells. This study presents tanshinones that are potential cancer cell proliferation inhibitors and may explain the anti‐cancer activity of S. miltiorrhiza.     

Enzyme and pH dual responsive l‐amino acid based biodegradable polymer nanocarrier for multidrug delivery to cancer cells

We report a new pH and enzyme dual responsive biodegradable polymer nanocarrier to deliver multiple anticancer drugs at the intracellular compartment in cancer cells. Natural l ‐aspartic acid was converted into multifunctional monomer and polymerized to yield new classes of biodegradable aliphatic polyester in‐build with pH responsiveness. The transformation of side chain BOC urethanes into cationic in the acidic endosomal environment disassembled the polymers nanoparticles (pH trigger‐1). The biodegradation of aliphatic polyester backbone by esterase enzyme ruptured the nanoassemblies and released the drugs in the cytoplasm (trigger‐2). The polymer scaffolds were capable of delivering multiple drugs such as doxorubicin, topotecan, and curcumin (CUR). The cytotoxicity of the nascent and drug‐loaded nanoparticles were tested in cervical (HeLa) and breast (MCF‐7) cancer cell lines. The nascent polymer nanoscaffolds were found to be nontoxic to cells whereas their drug‐loaded nanoparticles exhibited excellent killing. Confocal microscopic images revealed that the drug‐loaded polymer nanoparticles were taken up by the cells and the dual degradation process delivered the drugs to nucleus and established the proof‐of‐concept. The present investigation opens up new platform for l ‐amino acid based polyester scaffolds, for the first time, in the intracellular drug delivery in cancer treatment. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3279–3293