Polymeric Micelles with Pendant Dicarboxylato Chelating Ligands Prepared via a Michael Addition for <i>cis</i>-Platinum Drug Delivery

A new monomer with a neighboring carboxylate functional group was prepared via carbon Michael addition between ethylene glycol dimethacrylate and malonate. The monomer, 1,1-di-tert-butyl 3-(2-(methacryloyloxy)ethyl) butane-1,1,3-tricarboxylate (MAETC), was polymerized in a controlled manner using RAFT polymerization. After deprotection and the conjugation of platinum drugs, a macromolecular Pt complex was created, which was found to be insoluble in water. 195Pt NMR revealed that the desired complex has been formed next to a minor fraction of other Pt complexes. Block copolymers were prepared using poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMEMA) as macroRAFT agent for chain extension with the synthesized monomer to yield three different block copolymers with varying PMAETC block lengths. Subsequent conjugation to platinum resulted in amphiphilic block copolymers, which can ultimately generate micelles. The length of the core block had significant contribution to the micelle sizes with the micelle size increasing with an increase of the hydrophobic block length. The polymers prior to platinum conjugation were found to be nontoxic when in contact with A549, a lung cancer cell line. After conjugation with the platinum drug, the micelle with the shortest PMAETC block length was found to have the highest toxicity, which may be due to the fastest cisplatin release when compared to the longer PMAETC block lengths

Core-Cross-Linked Micelles Synthesized by Clicking Bifunctional Pt(IV) Anticancer Drugs to Isocyanates

Most low molecular weight platinum-based anticancer drugs have a short circulation time in the bloodstream. One of the potential strategies to improve the targeted delivery of cisplatin and prolong its circulation is via the use of nanocarriers. An improved drug delivery system was developed via reversible addition−fragmentation chain transfer (RAFT) polymerization. In a one-pot reaction, the incorporation of anticancer drug and core cross-linking was simultaneously carried out by using the highly effective reaction of isocyanate groups in the core of the polymeric micelles poly(oligo(ethylene glycol) methyl ether methacrylate)-block-poly(styrene-co-3-isopropenyl-α,α-dimethylbenzyl isocyanate) (POEGMA-block-P(STY-co-TMI)) with amine groups in the prepared platinum(IV) drug. The micelles with platinum(IV) incorporated with a size of 36 nm were very stable in water. In a reductive environment, in this study simulated using ascorbate, the drug was released at a slow rate of 82% in 22 days and at the same time the cross-linked micelle broke down into free block copolymers as evidenced using inductively coupled plasma-mass spectrometer (ICP-MS), size exclusion chromatography (SEC), and dynamic light scattering (DLS). The in vitro study also revealed the promising antitumor activity of prepared platinum(IV) drugs encapsulated into the micelle structure

Thiol–yne and Thiol–ene “Click” Chemistry as a Tool for a Variety of Platinum Drug Delivery Carriers, from Statistical Copolymers to Crosslinked Micelles

Statistical and block copolymers based on poly(2-hydroxyethyl methacrylate) (PHEMA) and poly[oligo(ethylene glycol) methylether methacrylate] (POEGMEMA) were modified with 4-pentenoic anhydride or 4-oxo-4-(prop-2-ynyloxy)butanoic anhydride to generate polymers with pendant vinyl or acetylene, respectively. Subsequent thiol–ene or thiol–yne reaction with thioglycolic acid or 2-mercaptosuccinic acid leads to polymers with carboxylate functionalities, which were conjugated with cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) to generate a drug carrier for Pt-drugs. Only the polymers modified with 2-mercaptosuccinic acid resulted in the formation of soluble well-defined polymers with gel formation being prevented. Due to the hydrophobicity of the drug, the block copolymers took on amphiphilic character leading to micelle formation. The micelles were in addition crosslinked to further stabilize their structure. Pt-containing statistical copolymer, micelles, and crosslinked micelles were then tested regarding their cellular uptake by the A549 lung cancer cell line to show a superior uptake of crosslinked micelles. However, due to the better Pt release of the statistical copolymer, the highest cytotoxicity was observed with this type of polymer architecture

Acid Degradable Cross-Linked Micelles for the Delivery of Cisplatin: A Comparison with Nondegradable Cross-Linker

Well-defined and nontoxic cross-linked polymeric micelles, containing either permanent or acid degradable cross-linkers, were employed for efficient intracellular delivery of cisplatin. The self-assembled structures were generated from triblock copolymers of poly­(oligo­(ethylene glycol) methylether methacrylate)-<i>block</i>-poly­(<i>N</i>-hydroxysuccinic methacrylate)-<i>block</i>-poly­(1,1-di-<i>tert</i>-butyl 3-(2-(methacryloyloxy)­ethyl) butane-1,1,3-tricarboxylate) (POEGMEMA-<i>b</i>-PNHSMA-<i>b</i>-PMAETC) loaded with cisplatinum. The polymeric micelles were subsequently cross-linked via a reaction between pendant activated esters at the nexus core of the triblock copolymer using acid degrdabale ketal diamino cross-linkers. An in vitro study confirmed that both uncross-linked and cross-linked micelles prior to the loading of the platinum drug were nontoxic against OVCAR-3 cells even at high polymer concentration (around 300 μg mL^–1). The drug loaded cross-linked platinum polymeric micelles were superior to the uncross-linked platinum polymeric micelles in terms of cytotoxicity against OVCAR-3, due to a higher cellular uptake. Although there was no significant difference in cytotoxicity of cross-linked platinum polymeric micelles using different cross-linkers (permanent and acid cleavable) after 72 h of exposure, the difference was noticeable after 24 h of incubation, highlighting a much higher activity for acid degradable cross-linked micelles with conjugated platinum drugs. Moreover, the clonogenic assay suggested that cross-linked micelle loaded platinum drugs, in contrast to uncross-linked micelles, can effectively inhibit the OVCAR-3 cell regrowth for an extended period of time (10 days), even at very low micellar concentrations. In summary, acid degradable linkers ensure high cellular uptake compared to uncross-linked micelles but also lead to a faster drug action in comparison to a permanently cross-linked micelle

Block Copolymer Micelles with Pendant Bifunctional Chelator for Platinum Drugs: Effect of Spacer Length on the Viability of Tumor Cells

Three monomers with 1,3-dicarboxylate functional groups but varying spacer lengths were synthesized via carbon Michael addition using malonate esters and ethylene- (MAETC), butylene- (MABTC), and hexylene (MAHTC) glycol dimethacrylate, respectively. Poly­[oligo-(ethylene glycol) methylether methacrylate] (POEGMEMA) was prepared in the presence of a RAFT (reversible addition–fragmentation chain transfer) agent, followed by chain extension with the prepared monomers to generate three different block copolymers (BP-E80, BP-B82, and BP-H79) with similar numbers of repeating units, but various spacer lengths as distinguishing features. Conjugation with platinum drugs created macromolecular platinum drugs resembling carboplatin. The amphiphilic natures of these Pt-containing block copolymers led to the formation micelles in solution. The rate of drug release of all micelles was similar, but a noticeable difference was the increasing stability of the micelle against dissociation with increasing spacer length. The platinum conjugated polymer showed high activity against A549, OVCAR3, and SKOV3 cancer cell lines exceeding the activity of carboplatin, but only the micelle based on the longest spacer had IC₅₀ values as low as cisplatin. Cellular uptake studies identified a better micelle uptake with increasing micelle stability as a possible reason for lower IC₅₀ values. The clonogenic assay revealed that micelles loaded with platinum drugs, in contrast to low molecular weight carboplatin, have not only better activity within the frame of a 72 h cell viability study, but also display a longer lasting effect by preventing the colony formation A549 for more than 10 days

Nanodiamonds with Surface Grafted Polymer Chains as Vehicles for Cell Imaging and Cisplatin Delivery: Enhancement of Cell Toxicity by POEGMEMA Coating

Nanodiamonds (NDs) are highly promising drug carriers due to their biocompatibility, manipulable surface chemistry, and nonbleaching flourescence. In this communication, we compare the cytotoxicity of three ND-cisplatin systems in which cisplatin was incorporated via direct attachment to the ND surface, physical adsorption within a poly­(oligo­(ethylene glycol) methyl ether methacrylate) POEGMEMA surface coating, or complexation to 1,1-di-<i>tert</i>-butyl 3-(2-methacryloyloxy)­ethyl)­butane-1,1,3-tricarboxylate (MAETC) groups of a POEGMEMA-<i>st</i>-PMAETC surface layer. The polymer layers were introduced by grafting from RAFT-functionalized ND particles. All three ND systems displayed lower IC₅₀ values than free cisplatin in A2870 and A2870cis ovarian cancer cells. The two polymer-containing systems outperformed their “naked” counterpart, with the POEGMEMA-coated particles the most cytotoxic, displaying an IC₅₀ of 1.5 μM, more than an order of magnitude lower than that of cisplatin. The enhanced cytotoxicity is attributed to promotion of cellular uptake by the hydrophilic surface polymer

Aqueous Polymeric Hollow Particles as an Opacifier by Emulsion Polymerization Using Macro-RAFT Amphiphiles

A robust polymerization technique that enables the surfactant-free aqueous synthesis of a high solid content latex containing polymeric hollow particles is presented. Uniquely designed amphiphilic macro-reversible addition fragmentation chain transfer (RAFT) copolymers were used as sole stabilizers for monomer emulsification as well as for free-radical emulsion polymerization. The polymerization was found to be under RAFT control, generating various morphologies from spherical particles, wormlike structures to polymer vesicles. The final particles were dominantly polymeric vesicles which had a substantially uniform and continuous polymer layer around a single aqueous filled void. They produced hollow particles once dried and were successfully used as opacifiers to impart opacity into polymer paint films. This method is simple, can be performed in a controllable and reproducible manner, and may be performed using diverse procedures

Fluorescence Enhancement through Confined Oligomerization in Nanochannels: An Anthryl Oligomer in a Metal-Organic Framework

Nanoconfinement offers opportunities to tune physical properties of molecular entities by altering their assembled structures. This also applies to acene-based molecules with potentially rich π–π interactions. Unlike most of the previous cases with acene-based guests directly incorporated into hosts, we take a further step by oligomerizing a fluorescent anthryl monomer, 9-vinylanthracene, inside nanochannels of a metal–organic framework, which is a pillared three-dimensional kagome net of [Zn2(bdc)2(dabco)] (bdc2– = 1,4-benzenedicarboxylate; dabco = 1,4-diazabicyclo[2.2.2]­octane). The fluorescence emission of the guest can be significantly enhanced after oligomerization, which is likely due to the suppressed nonemissive interaction between the oligomerized molecules in the nanospace and the MOF wall. The case we have demonstrated for fluorescence enhancement via confined oligomerization provides inspiration for the design of luminescent composites and is encouraging for further exploration of molecules in a nanoconfined space

Fluorescence Enhancement through Confined Oligomerization in Nanochannels: An Anthryl Oligomer in a Metal-Organic Framework

Nanoconfinement offers opportunities to tune physical properties of molecular entities by altering their assembled structures. This also applies to acene-based molecules with potentially rich π–π interactions. Unlike most of the previous cases with acene-based guests directly incorporated into hosts, we take a further step by oligomerizing a fluorescent anthryl monomer, 9-vinylanthracene, inside nanochannels of a metal–organic framework, which is a pillared three-dimensional kagome net of [Zn2(bdc)2(dabco)] (bdc2– = 1,4-benzenedicarboxylate; dabco = 1,4-diazabicyclo[2.2.2]­octane). The fluorescence emission of the guest can be significantly enhanced after oligomerization, which is likely due to the suppressed nonemissive interaction between the oligomerized molecules in the nanospace and the MOF wall. The case we have demonstrated for fluorescence enhancement via confined oligomerization provides inspiration for the design of luminescent composites and is encouraging for further exploration of molecules in a nanoconfined space

Fluorescence Enhancement through Confined Oligomerization in Nanochannels: An Anthryl Oligomer in a Metal-Organic Framework

Nanoconfinement offers opportunities to tune physical properties of molecular entities by altering their assembled structures. This also applies to acene-based molecules with potentially rich π–π interactions. Unlike most of the previous cases with acene-based guests directly incorporated into hosts, we take a further step by oligomerizing a fluorescent anthryl monomer, 9-vinylanthracene, inside nanochannels of a metal–organic framework, which is a pillared three-dimensional kagome net of [Zn2(bdc)2(dabco)] (bdc2– = 1,4-benzenedicarboxylate; dabco = 1,4-diazabicyclo[2.2.2]­octane). The fluorescence emission of the guest can be significantly enhanced after oligomerization, which is likely due to the suppressed nonemissive interaction between the oligomerized molecules in the nanospace and the MOF wall. The case we have demonstrated for fluorescence enhancement via confined oligomerization provides inspiration for the design of luminescent composites and is encouraging for further exploration of molecules in a nanoconfined space