Peroxynitrite-Promoted Persulfide Prodrugs with Protective Potential against Paracetamol Poisoning

The newly emerging persulfide prodrugs provide additional options for the profound study of persulfide, a fascinating molecule expected to intervene in biological functions and even diseases. Peroxynitrite is often the culprit in pathological processes characterized by oxidative stress, while the persulfide prodrug responsive to it is still pending. To enrich the family of redox-activated prodrugs, we designed prodrugs with a 2-oxo-2-phenylacetamide trigger, which achieved the release of persulfide via 1, 6-N, S-relay. The degradation of prodrugs and the formation of persulfides were confirmed to be peroxynitrite-responsible by the qualitative and quantitative studies based on LC-MS/MS methods and a spectrophotometry-based tag-switch strategy. Furthermore, these prodrugs showed potent peroxynitrite scavenging activity, cellular therapeutic potential against paracetamol poisoning in HepG2 and oxidative stress in H9c2, as well as desirable in vitro metabolic properties.     

Esterase‐Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide

Prodrugs that release hydrogen sulfide upon esterase‐mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H₂S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H₂S donors. Additionally, such prodrugs can easily be conjugated to another non‐steroidal anti‐inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H₂S prodrugs, the anti‐inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS‐induced TNF‐α production in RAW 264.7 cells. This type of H₂S prodrugs shows great potential as both research tools and therapeutic agents.     

A Persulfide Donor Responsive to Reactive Oxygen Species: Insights into Reactivity and Therapeutic Potential

Persulfides (RSSH) have been hypothesized as critical components in sulfur‐mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H₂S). Hindering the study of persulfides is a lack of persulfide‐donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS‐responsive (ROS=reactive oxygen species), self‐immolative persulfide donor. The donor, termed BDP‐NAC, showed selectivity towards H₂O₂ over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N‐acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS. Exposure of H9C2 cardiomyocytes to H₂O₂ revealed that BDP‐NAC mitigated the effects of a highly oxidative environment in a dose‐dependent manner over relevant controls and to a greater degree than common H₂S donors sodium sulfide (Na₂S) and GYY4137. BDP‐NAC also rescued cells more effectively than a non‐persulfide‐releasing control compound in concert with common H₂S donors and thiols.     

Photoactivatable Prodrugs of Highly Potent Duocarmycin Analogues for a Selective Cancer Therapy

A main problem of common cancer chemotherapy is the occurrence of severe side effects caused by insufficient selectivity of the applied drugs. A possible concept to overcome this limitation is light‐driven prodrug monotherapy. The synthesis as well as photochemical and biological evaluation of new photoactivatable prodrugs is described. Best results were obtained with prodrug (S,S)‐ 7 a . The photochemical labile protecting groups in (S,S)‐ 7 a can easily be removed by irradiation with UV‐A light in 30 min with a power of only 2 J cm^?2. The determination of the in vitro cytotoxicity by using an HTCFA‐test reveals a QIC₅₀ value of 8200 and the prodrug is more than two million times less cytotoxic than the corresponding seco‐drug (?)‐(S,S)‐ 5 with an IC₅₀ value of about 110 fM . The big therapeutic window makes (S,S)‐ 7 a very suitable for its use in selective cancer therapy.     

Lysosome‐Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs

Cancer cells produce elevated levels of reactive oxygen species, which has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, in which a prodrug reacts with ROS. However, at low micromolar concentrations of the prodrugs and ROS, the activation is usually inefficient. Herein, we propose and validate a potentially general approach for solving this intrinsic problem of ROS‐dependent prodrugs. In particular, known prodrug 4‐(N ‐ferrocenyl‐N ‐benzylaminocarbonyloxymethyl)phenylboronic acid pinacol ester was converted into its lysosome‐specific analogue. Since lysosomes contain a higher concentration of active ROS than the cytoplasm, activation of the prodrug was facilitated with respect to the parent compound. Moreover, it was found to exhibit high anticancer activity in a variety of cancer cell lines (IC₅₀=3.5–7.2 μm ) and in vivo (40 mg kg⁻¹, NK/Ly murine model) but remained weakly toxic towards non‐malignant cells (IC₅₀=15–30 μm ).     

Alleviating Cellular Oxidative Stress through Treatment with Superoxide‐Triggered Persulfide Prodrugs

Overproduction of superoxide anion (O₂^.?), the primary cellular reactive oxygen species (ROS), is implicated in various human diseases. To reduce cellular oxidative stress caused by overproduction of superoxide, we developed a compound that reacts with O₂^.? to release a persulfide (RSSH), a type of reactive sulfur species related to the gasotransmitter hydrogen sulfide (H₂S). Termed SOPD‐NAC , this persulfide donor reacts specifically with O₂^.?, decomposing to generate N‐acetyl cysteine (NAC) persulfide. To enhance persulfide delivery to cells, we conjugated the SOPD motif to a short, self‐assembling peptide (Bz‐CFFE‐NH₂) to make a superoxide‐responsive, persulfide‐donating peptide ( SOPD‐Pep ). Both SOPD‐NAC and SOPD‐Pep delivered persulfides/H₂S to H9C2 cardiomyocytes and lowered ROS levels as confirmed by quantitative in vitro fluorescence imaging studies. Additional in vitro studies on RAW 264.7 macrophages showed that SOPD‐Pep mitigated toxicity induced by phorbol 12‐myristate 13‐acetate (PMA) more effectively than SOPD‐NAC and several control compounds, including common H₂S donors.     

Reduction of Cisplatin and Carboplatin Pt(IV) Prodrugs by Homocysteine: Kinetic and Mechanistic Investigations

Pt(IV) anticancer active complexes are commonly regarded as prodrugs, and the reduction of the prodrugs to their Pt(II) analogs is the activation process. The reduction of a cisplatin prodrug cis‐[Pt(NH₃)₂Cl₄] and a carboplatin prodrug cis,trans‐[Pt(cbdca)(NH₃)₂Cl₂] by dl ‐homocysteine (Hcy) has been investigated kinetically in a wide pH range in this work. The reduction process follows overall second‐order kinetics: −d [Pt(IV)]/dt = k ′[Hcy]_tot[Pt(IV)], where [Hcy]_tot stands for the total concentration of Hcy and k ′ pertains to the observed second‐order rate constants. The k ′ versus pH profiles have been established for both prodrugs. Spectrohotometric titrations reveal a stoichiometry of Δ[Pt(IV)]:Δ[Hcy]_tot = 1:2; homocystine is identified as the major oxidation product of Hcy by high‐resolution mass spectrometry. A reaction mechanism has been proposed, which involves all the four protolysis species of Hcy attacking the Pt(IV) prodrugs in parallel. Moreover, these parallel attacks are the rate‐determining steps, resulting in a Cl⁺ transfer from the Pt(IV) prodrugs to the attacking sulfur atom. Rate constants of the rate‐determining steps have been derived, indicating that the two prodrugs are reduced with a very similar rate in spite of the difference between the coordination ligands in their equatorial positions. The reactivity analysis in the case of cis,trans‐[Pt(cbdca)(NH₃)₂Cl₂] unravels that one species of Hcy (form III ) is almost exclusively responsible for the reductions at the physiological pH (7.4), although it is existing only 5.2% of the total Hcy. On the other hand, the dominant existing form II of Hcy virtually does not make a contribution to the overall reactivity at pH 7.4.     

Monochalcoplatin: An Actively Transported,Quickly Reducible,and Highly Potent PtIV Anticancer Prodrug

Recently, Pt^IV prodrugs have attracted much attention as the next generation of platinum‐based antineoplastic drug candidates. Here we report the discovery and evaluation of monochalcoplatin, a monocarboxylated Pt^IV prodrug that is among the most cytotoxic Pt^IV prodrugs to date. Compared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells, which is not ascribed to its lipophilicity. The prodrug is quickly reduced, causes DNA damage, and induces apoptosis, resulting in superior cytotoxicity with IC₅₀ values in the nanomolar range in both cisplatin‐sensitive and ‐resistant cells; these IC₅₀ values are up to 422‐fold higher than that of cisplatin. A detailed mechanistic study reveals that monochalcoplatin actively enters cells through a transporter‐mediated process. Moreover, monochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies a practical strategy for the design of more effective Pt^IV prodrugs to conquer drug resistance by tuning both cellular uptake pathways and activation processes.     

Monochalcoplatin: An Actively Transported,Quickly Reducible,and Highly Potent PtIV Anticancer Prodrug

Recently, Pt^IV prodrugs have attracted much attention as the next generation of platinum‐based antineoplastic drug candidates. Here we report the discovery and evaluation of monochalcoplatin, a monocarboxylated Pt^IV prodrug that is among the most cytotoxic Pt^IV prodrugs to date. Compared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells, which is not ascribed to its lipophilicity. The prodrug is quickly reduced, causes DNA damage, and induces apoptosis, resulting in superior cytotoxicity with IC₅₀ values in the nanomolar range in both cisplatin‐sensitive and ‐resistant cells; these IC₅₀ values are up to 422‐fold higher than that of cisplatin. A detailed mechanistic study reveals that monochalcoplatin actively enters cells through a transporter‐mediated process. Moreover, monochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies a practical strategy for the design of more effective Pt^IV prodrugs to conquer drug resistance by tuning both cellular uptake pathways and activation processes.     

Alleviating Cellular Oxidative Stress through Treatment with Superoxide-Triggered Persulfide Prodrugs

Overproduction of superoxide anion (O₂^.−), the primary cellular reactive oxygen species (ROS), is implicated in various human diseases. To reduce cellular oxidative stress caused by overproduction of superoxide, we developed a compound that reacts with O₂^.− to release a persulfide (RSSH), a type of reactive sulfur species related to the gasotransmitter hydrogen sulfide (H₂S). Termed SOPD-NAC , this persulfide donor reacts specifically with O₂^.−, decomposing to generate N-acetyl cysteine (NAC) persulfide. To enhance persulfide delivery to cells, we conjugated the SOPD motif to a short, self-assembling peptide (Bz-CFFE-NH₂) to make a superoxide-responsive, persulfide-donating peptide ( SOPD-Pep ). Both SOPD-NAC and SOPD-Pep delivered persulfides/H₂S to H9C2 cardiomyocytes and lowered ROS levels as confirmed by quantitative in vitro fluorescence imaging studies. Additional in vitro studies on RAW 264.7 macrophages showed that SOPD-Pep mitigated toxicity induced by phorbol 12-myristate 13-acetate (PMA) more effectively than SOPD-NAC and several control compounds, including common H₂S donors.     

Synthesis of α-Methyldopa Prodrugs Containing Dipeptide Moieties as Tools for Intestinal Delivery

Dipeptides containing D-phenylglycine or D-p-hydroxyphenylglycine were attached onto the antihypertensive agent α-methyldopa to form prodrugs 1a , 1b and 1c . The nonessential amino acids were introduced into the prodrug molecules as tools of chemical delivery to improve the intestinal absorption of the parent drug. Preliminary tests revealed that the prodrugs were stable in phosphate buffer solutions at pH 7.4 (t_1/2 > 10 h). These compounds also demonstrated satisfactory stability toward enzymatic degradation in a mucosa preparation isolated from rat intestine, indicating that they might be feasibly formulated as an oral prodrug of α-methyldopa.     

Isolable Boron Persulfide: Activation of Elemental Sulfur with a 2‐Chloro‐Azaborolyl Anion

The novel boron persulfide 2 LB(η²‐S₂) (L=[ArNC(R)CHC(R)]^?; Ar=2,6‐Me₂C₆H₃, R=tBu) was obtained by the reaction of the 2‐chloro‐azaborolyl anion 1 (LBCl)K(THF) with 0.25 equiv of elemental sulfur (S₈). Persulfide 2 is labile in solution and could be converted to the cyclic tetrasulfide LBS₄ ( 3 ) and hexasulfide LBS₆ ( 4 ) in the presence of sulfur at room temperature and 50 °C, respectively. Desulfination of 2 with triphenylphosphine resulted in the formation of the thioxoborane LB=S ( 5) . Alternatively, 3 and 4 could be obtained by the reaction of 1 with an excess of sulfur. Structural analysis of 2 disclosed the relatively long S?S bond of 2.1004(8) Å due to the lone‐pair repulsions of the two sulfur atoms, as disclosed by DFT calculations.     

Facile preparation of pH-responsive PEGylated prodrugs for activated intracellular drug delivery

PEGylated prodrug, covalent attaching polyethylene glycol (PEG) polymer chains to therapeutic drugs, is one of the most promising techniques to improve the water-solubility, stability, and therapeutic effect of drugs. In this study, three PEGylated acid-sensitive prodrugs DOX-PEG-DOX with different molecular weights, were prepared via Schiff-base reaction between aldehyde-modified PEG and the amino groups of doxorubicin (DOX). This kind of amphiphilic polymeric prodrug could be self-assemble into nanoparticles in aqueous solution. The average particle size and morphologies of the prodrug nanoparticles under different pH conditions were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. It turned out that the nanoparticles could be kept stable in the physiological environment, but degraded in acidic medium. Subsequently, we also investigated in vitro drug release behavior and found that the prodrug had acid-sensitive property. The cytotoxicity and intracellular uptake assays revealed that the prodrugs could rapidly internalized by HeLa or HepG2 cells to release DOX and effectively inhibited the proliferation of the tumor cells, which have the potential for use in cancer therapy.     

Porous CuxCoyS Supraparticles for In Vivo Telomerase Imaging and Reactive Oxygen Species Generation

In this study, we successfully synthesized Cu_xCo_yS supraparticles (SPs) on the nanoscale featuring multiple pores inside and strong absorption from 400 to 900 nm. Porous Cu_xCo_yS SPs produced the highest reactive oxygen species (ROS) yield (1.39) when illuminated with near‐infrared (NIR) light. Furthermore, we demonstrated that Cu_xCo_yS SPs could be used to identify cancer cells through intracellular telomerase‐responsive fluorescence (FL) imaging in living cells. Because the Cu_xCo_yS SPs were associated with telomerase‐responsive bioimaging and high ROS production, they can be efficiently used in the diagnosis and therapy of tumors with high selectivity and excellent therapeutic effects in vivo. This study provides a new vision for the creation of multifunctional SPs, which can be used as cellular sensors and control tools for pathologies across a broad range of biological systems.     

Design of Block Copolymer Micellar Aggregates for Co‐Delivery of Enzyme and Anticancer Prodrug

Traditional enzyme–prodrug therapy (EPT) is a two‐step strategy, which has many serious deficiencies, so having a one‐step EPT treatment becomes a problem of immediate interest. This study aims to achieve an effective co‐delivery of horseradish peroxidase (HRP) as a kind of enzyme for prodrug activation and ethyl 3‐indoleacetate (EIA) as anticancer prodrug. A ternary block copolymer PEG‐PAsp(AED)‐CA consisting of poly(ethylene glycol) (PEG), reduction‐sensitive poly (N ‐(2,2′‐dithiobis(ethylamine)) aspartamide) PAsp(AED), and cholic acid (CA) was synthesized and assembled into spherical micelles which encapsulated EIA in its hydrophobic core and HRP in a reduction‐sensitive interlayer. TEM photographs show that the polymer micelle is around 40 nm, and the cell survival rate test shows that the EIA/HRP polymer micelle is highly lethal to human lung adenocarcinoma cells. Thus, co‐delivery of EIA and HRP demonstrates great potential in cancer therapy, offering a structurally simple and highly tunable platform for the synchronous delivery of enzymes and prodrugs in EPT.     

A Bis(dipyridophenazine)(2‐(2‐pyridyl)pyrimidine‐4‐carboxylic acid)ruthenium(II) Complex with Anticancer Action upon Photodeprotection

Improving the selectivity of anticancer drugs towards cancer cells is one of the main goals of drug optimization; the prodrug strategy has been one of the most promising. A light‐triggered prodrug strategy is presented as an efficient approach for controlling cytotoxicity of the substitutionally inert cytotoxic complex [Ru(dppz)₂(CppH)](PF₆)₂ ( C1 ; CppH=2‐(2‐pyridyl)pyrimidine‐4‐carboxylic acid; dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine). Attachment of a photolabile 3‐(4,5‐dimethoxy‐2‐nitrophenyl)‐2‐butyl (DMNPB) ester (“photocaging”) makes the otherwise active complex C1 innocuous to both cancerous (HeLa and U2OS) and non‐cancerous (MRC‐5) cells. The cytotoxic action can be successfully unleashed in living cells upon light illumination (350 nm), reaching similar level of activity as the parent cytotoxic compound C1 . This is the first substitutionally inert cytotoxic metal complex to be used as a light‐triggered prodrug candidate.     

A Lock-and-Kill Anticancer Photoactivated Chemotherapy Agent†

Photosubstitutionally active ruthenium complexes show high potential as prodrugs for the photoactivated chemotherapy (PACT) treatment of tumors. One of the problems in PACT is that the localization of the ruthenium compound is hard to trace. Here, a ruthenium PACT prodrug, [Ru(3)(biq)(STF-31)](PF₆)₂ (where 3 = 3-(([2,2′:6′,2″-ter- pyridin]-4′-yloxy)propyl-4-(pyren-1-yl)butanoate) and biq = 2,2′-biquinoline), has been prepared, in which a pyrene tracker is attached via an ester bond. The proximity between the fluorophore and the ruthenium center leads to fluorescence quenching. Upon intracellular hydrolysis of the ester linkage, however, the fluorescence of the pyrene moiety is recovered, thus demonstrating prodrug cellular uptake. Further light irradiation of this molecule liberates by photosubstitution STF-31, a known cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, as well as singlet oxygen via excitation of the free pyrene chromophore. The dark and light cytotoxicity of the prodrug, embedded in liposomes, as well as the appearance of blue emission upon uptake, were evaluated in A375 human skin melanoma cells. The cytotoxicity of the liposome-embedded prodrug was indeed increased by light irradiation. This work realizes an in vitro proof-of-concept of the lock-and-kill principle, which may ultimately be used to design strategies aimed at knowing where and when light irradiation should be realized in vivo.     

Synthesis and structures of photoactive rhenium carbonyl complexes derived from 2‐(pyridin‐2‐yl)‐1,3‐benzothiazole, 2‐(quinolin‐2‐yl)‐1,3‐benzothiazole and 1,10‐phenanthroline

Carbon monoxide (CO) has recently been identified as a gaseous signaling molecule that exerts various salutary effects in mammalian pathophysiology. Photoactive metal carbonyl complexes (photoCORMs) are ideal exogenous candidates for more controllable and site‐specific CO delivery compared to gaseous CO. Along this line, our group has been engaged for the past few years in developing group‐7‐based photoCORMs towards the efficient eradication of various malignant cells. Moreover, several such complexes can be tracked within cancerous cells by virtue of their luminescence. The inherent luminecscent nature of some photoCORMs and the change in emission wavelength upon CO release also provide a covenient means to track the entry of the prodrug and, in some cases, both the entry and CO release from the prodrug. In continuation of the research circumscribing the development of trackable photoCORMs and also to graft such molecules covalently to conventional delivery vehicles, we report herein the synthesis and structures of three rhenium carbonyl complexes, namely, fac‐tricarbonyl[2‐(pyridin‐2‐yl)‐1,3‐benzothiazole‐κ²N ,N ′](4‐vinylpyridine‐κN )rhenium(I) trifluoromethanesulfonate, [Re(C₇H₇N)(C₁₂H₈N₂S)(CO)₃](CF₃SO₃), ( 1 ), fac‐tricarbonyl[2‐(quinolin‐2‐yl)‐1,3‐benzothiazole‐κ²N ,N ′](4‐vinylpyridine‐κN )rhenium(I) trifluoromethanesulfonate, [Re(C₇H₇N)(C₁₆H₁₀N₂S)(CO)₃](CF₃SO₃), ( 2 ), and fac‐tricarbonyl[1,10‐phenanthroline‐κ²N ,N ′](4‐vinylpyridine‐κN )rhenium(I) trifluoromethanesulfonate, [Re(C₇H₇N)(C₁₂H₈N₂)(CO)₃](CF₃SO₃), ( 3 ). In all three complexes, the Re^I center resides in a distorted octahedral coordination environment. These complexes exhibit CO release upon exposure to low‐power UV light. The apparent CO release rates of the complexes have been measured to assess their comparative CO‐donating capacity. The three complexes are highly luminescent and this in turn provides a convenient way to track the entry of the prodrug molecules within biological targets.     

d‐ Versus l‐Glucose Conjugation: Mitochondrial Targeting of a Light‐Activated Dual‐Mode‐of‐Action Ruthenium‐Based Anticancer Prodrug

Light‐activated ruthenium polypyridyl anticancer prodrugs often suffer from poor water solubility, poor selectivity, and/or ill‐defined intracellular targets. Coordination of the d ‐ or l ‐glucose thioether ligand 3 (2‐(2‐(2‐(methylthio)ethoxy)ethoxy)ethyl‐β‐glucopyranoside) to the highly lipophilic ruthenium complex [Ru(tpy)(dppn)(H₂O)]²⁺ ([ 1 ]²⁺; dppn=benzo[i]dipyrido‐[3,2‐a:2′,3′‐c]phenazine, tpy=2,2′:6′,2′′‐terpyridine) solved all these problems at once. The two enantiomers of [Ru(tpy)(dppn)( 3) ][PF₆]₂, [d ‐ 2 ][PF₆]₂ and [l ‐ 2 ][PF₆]₂, were soluble in water, which allowed the influence of the chirality of the glucose moiety on uptake, toxicity, and intracellular localization of the prodrug to be probed without changing any other physicochemical properties. Both compounds showed mild, but different, cytotoxicity in A549 (human lung carcinoma) and MCF‐7 (human breast adenocarcinoma) cancer cells in the dark, whereas following low doses of visible light irradiation (3.1 J cm^?2 at λ = 454 nm), a similar, but high cytotoxicity (EC₅₀ < 1 μm ), was observed. Irrespective of the chirality, both slightly emissive Ru complexes were found in the mitochondria, and two modes of action may contribute to light‐induced cell death: 1) the glucose thioether ligand is photosubstituted by water, thus [ 1 ]²⁺, which interacts with DNA at an exceptionally high 400:1 base pair/Ru ratio, is released; 2) both [ 1 ]²⁺ and [ 2 ]²⁺ produce massive amounts of singlet oxygen, which leads to very efficient photodynamic DNA cleavage.     

Targeting Cancer with PCPA‐Drug Conjugates: LSD1 Inhibition‐Triggered Release of 4‐Hydroxytamoxifen

Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer‐targeting methods. Herein, we focused on lysine‐specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans‐2‐phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA‐drug conjugate (PDC) prototypes, we designed PCPA‐tamoxifen conjugates 1 a and 1 b , which released 4‐hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells.