Molecularly Precise Dendrimer–Drug Conjugates with Tunable Drug Release for Cancer Therapy

The structural preciseness of dendrimers makes them perfect drug delivery carriers, particularly in the form of dendrimer–drug conjugates. Current dendrimer–drug conjugates are synthesized by anchoring drug and functional moieties onto the dendrimer peripheral surface. However, functional groups exhibiting the same reactivity make it impossible to precisely control the number and the position of the functional groups and drug molecules anchored to the dendrimer surface. This structural heterogeneity causes variable pharmacokinetics, preventing such conjugates to be translational. Furthermore, the highly hydrophobic drug molecules anchored on the dendrimer periphery can interact with blood components and alter the pharmacokinetic behavior. To address these problems, we herein report molecularly precise dendrimer–drug conjugates with drug moieties buried inside the dendrimers. Surprisingly, the drug release rates of these conjugates were tailorable by the dendrimer generation, surface chemistry, and acidity.     

Antibody–Drug Conjugates: An Emerging Concept in Cancer Therapy

Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor‐selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody–drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent approval of two ADCs, brentuximab vedotin and ado‐trastuzumab emtansine, for cancer treatment has spurred tremendous research interest in this field. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first‐generation ADCs have led to improvements in every aspect of this technology, i.e., the antibody, the cytotoxic compound, and the linker connecting them, leading to the current successes. The design of ADCs currently in clinical development, and results from mechanistic studies and preclinical and clinical evaluation are discussed. Emerging technologies that seek to further advance this exciting area of research are also discussed.     

Synchronous Chemoradiation Nanovesicles by X‐Ray Triggered Cascade of Drug Release

The approach of concurrent‐to‐synchronous chemoradiation has now been advanced by well‐designed nanovesicles that permit X‐ray irradiation‐triggered instant drug release. The nanovesicles consist of Au nanoparticles tethered with irradiation labile linoleic acid hydroperoxide (LAHP) molecules and oxidation‐responsive poly(propylene sulfide)‐poly(ethylene glycol) (PPS‐PEG) polymers, where DOX were loaded in the inner core of the vesicles (Au‐LAHP‐vDOX). Upon irradiation, the in situ formation of hydroxyl radicals from LAHP molecules triggers the internal oxidation of PPS from being hydrophobic to hydrophilic, leading to degradation of the vesicles and burst release of cargo drugs. In this manner, synchronous chemoradiation showed impressive anticancer efficacy both in vitro and in a subcutaneous mouse tumor model by one‐dose injection and one‐time irradiation.     

Lessons To Be Learned: The Molecular Basis of Kinase‐Targeted Therapies and Drug Resistance in Non‐Small Cell Lung Cancer

The treatment of non‐small cell lung cancer (NSCLC) is currently experiencing a revolution. Over the last decade, the knowledge gained about the biochemical features of biomarkers and their predictive abilities has led to the development of targeted small‐molecule inhibitors that present an alternative to harsh chemotherapy. The use of these new therapies has improved the quality of life and increased the survival of patients. The occurrence of inevitable drug resistance requires the constant development of precision medicine. The detailed understanding of the target biology and the search for innovative chemical approaches has encouraged investigations in this field. Herein, we review selected aspects of the molecular targets and present an overview of current topics and challenges in the rational development of small molecules to target NSCLC.     

Upconverting Nanoparticles with a Mesoporous TiO2 Shell for Near‐Infrared‐Triggered Drug Delivery and Synergistic Targeted Cancer Therapy

Malignant tumors remain a major health burden throughout the world and effective therapeutic strategies are urgently needed. Herein, we report the synthesis of upconverting nanoparticles with a mesoporous TiO₂ (mTiO₂) shell for near‐infrared (NIR)‐triggered drug delivery and synergistic targeted cancer therapy. The NaGdF₄:Yb,Tm could convert NIR light to UV light, which activated the mTiO₂ to produce reactive oxygen species for photodynamic therapy (PDT). Due to the large surface area and porous structure, the mTiO₂ shell endowed the nanoplatform with another functionality of anticancer drug loading for chemotherapy. The hyaluronic acid modified on the surface not only promised controlled drug release but also conferred targeted ability of the system toward cluster determinant 44 overexpressed cancer cells. More importantly, cytotoxicity experiments demonstrated that combined therapy mediated the highest rate of death of breast carcinoma cells compared with that of single chemotherapy or PDT.     

Tumour‐Targeted Drug Delivery with Mannose‐Functionalized Nanoparticles Self‐Assembled from Amphiphilic β‐Cyclodextrins

Multivalent mannose‐functionalized nanoparticles self‐assembled from amphiphilic β‐cyclodextrins (β‐CDs) facilitate the targeted delivery of anticancer drugs to specific cancer cells. Doxorubicin (DOX)‐loaded nanoparticles equipped with multivalent mannose target units were efficiently taken up via receptor‐mediated endocytosis by MDA‐MB‐231 breast cancer cells that overexpress the mannose receptor. Upon entering the cell, the intracellular pH causes the release of DOX, which triggers apoptosis. Targeting by multivalent mannose significantly improved the capability of DOX‐loaded nanoparticles to inhibit the growth of MDA‐MB‐231 cancer cells with minimal side effects in vivo. This targeted and controlled drug delivery system holds promise as a nanotherapeutic for cancer treatment.     

PPI Modulators of E6 as Potential Targeted Therapeutics for Cervical Cancer: Progress and Challenges in Targeting E6

Advanced cervical cancer is primarily managed using cytotoxic therapies, despite evidence of limited efficacy and known toxicity. There is a current lack of alternative therapeutics to treat the disease more effectively. As such, there have been more research endeavors to develop targeted therapies directed at oncogenic host cellular targets over the past 4 decades, but thus far, only marginal gains in survival have been realized. The E6 oncoprotein, a protein of human papillomavirus origin that functionally inactivates various cellular antitumor proteins through protein–protein interactions (PPIs), represents an alternative target and intriguing opportunity to identify novel and potentially effective therapies to treat cervical cancer. Published research has reported a number of peptide and small-molecule modulators targeting the PPIs of E6 in various cell-based models. However, the reported compounds have rarely been well characterized in animal or human subjects. This indicates that while notable progress has been made in targeting E6, more extensive research is needed to accelerate the optimization of leads. In this review, we summarize the current knowledge and understanding of specific E6 PPI inhibition, the progress and challenges being faced, and potential approaches that can be utilized to identify novel and potent PPI inhibitors for cervical cancer treatment.     

ZnO‐Functionalized Upconverting Nanotheranostic Agent: Multi‐Modality Imaging‐Guided Chemotherapy with On‐Demand Drug Release Triggered by pH

Limited therapeutic efficiency and severe side effects in patients are two major issues existing in current chemotherapy of cancers in clinic. To design a proper theranostic platform seems thus quite needed to target cancer cells accurately by bioimaging and simultaneously release drugs on demand without premature leakage. A novel ZnO‐functionalized upconverting nanotheranostic platform has been fabricated for clear multi‐modality bioimaging (upconversion luminescence (UCL), computed tomography (CT), and magnetic resonance imaging (MRI)) and specific pH‐triggered on‐demand drug release. In our theranostic platform multi‐modality imaging provides much more detailed and exact information for cancer diagnosis than single‐modality imaging. In addition, ZnO can play the role of a “gatekeeper” to efficiently block the drug in the mesopores of the as‐prepared agents until it is dissolved in the acidic environment around tumors to realize sustained release of the drug. More importantly, the biodegradable ZnO, which is non‐toxic against normal tissues, endows the as‐prepared agents with high therapeutic effectiveness but very low side effects. These findings are of great interests and will inspire us much to develop novel effective imaging‐guided on‐demand chemotherapies in cancer treatment.     

The Prodrug Platin‐A: Simultaneous Release of Cisplatin and Aspirin

Cancer‐associated inflammation induces tumor progression to the metastatic stage, thus indicating that a chemo‐anti‐inflammatory strategy is of interest for the management of aggressive cancers. The platinum(IV) prodrug Platin‐A was designed to release cisplatin and aspirin to ameliorate the nephrotoxicity and ototoxicity caused by cisplatin. Platin‐A exhibited anticancer and anti‐inflammatory properties which are better than a combination of cisplatin and aspirin. These findings highlight the advantages of combining anti‐inflammatory treatment with chemotherapy when both the drugs are delivered in the form of a single prodrug.     

Polymeric Nanoparticles with a Glutathione‐Sensitive Heterodimeric Multifunctional Prodrug for In Vivo Drug Monitoring and Synergistic Cancer Therapy

Polymeric micelle‐based drug delivery systems have dramatically improved the delivery of small molecular drugs, yet multiple challenges remain to be overcome. A polymeric nanomedicine has now been engineered that possesses an ultrahigh loading (59 %) of a glutathione (GSH)‐sensitive heterodimeric multifunctional prodrug (HDMP) to effectively co‐deliver two synergistic drugs to tumors. An HDMP comprising of chemotherapeutic camptothecin (CPT) and photosensitizer 2‐(1‐hexyloxyethyl)‐2‐devinyl pyropheophorbide‐α (HPPH) was conjugated via a GSH‐cleavable linkage. The intrinsic fluorogenicity and label‐free radio‐chelation (⁶⁴Cu) of HPPH enabled direct drug monitoring by fluorescence imaging and positron emission tomography (PET). Through quantitative PET imaging, HDMP significantly improves drug delivery to tumors. The high synergistic therapeutic efficacy of HDMP‐loaded NPs highlights the rational design of HDMP, and presents exciting opportunities for polymer NP‐based drug delivery.     

An Enzyme‐Responsive Prodrug with Inflammation‐Triggered Therapeutic Drug Release Characteristics

Long‐term use of nonsteroidal anti‐inflammatory drugs (NSAIDs) for relieving inflammatory reactions can lead to severe side effects. It is of great importance to configure new dosing strategies for alleviating the side effects of NSAIDs. In this work, an enzyme‐responsive anti‐inflammatory prodrug capable of generating indomethacin upon the trigger of inflammation is developed. A monomer is first prepared after the esterification of carboxyl groups of indomethacin by hydroxyl groups of N‐(2‐hydroxyethyl) acrylamide. Then, a polymer prodrug, with indomethacin linked through ester bonds on the side chain, is synthesized by free radical polymerization of the monomer. The therapeutic drug component can be triggered to release from the prodrug under the stimulation of cholesterol esterase, mimicking the inflammation environment. On the contrary, there is only a small amount of drug released in the absence of the enzyme. Therefore, the drug can be triggered to release under the stimulation of an environment mimicking inflammation. Furthermore, the in vitro studies at the cellular level indicate that the enzyme‐responsive prodrug can efficiently relieve inflammatory responses induced by lipopolysaccharide in RAW264.7 macrophage cells while indicating no cytotoxicity.     

Polymer‐Chlorambucil Drug Conjugates: A Dynamic Platform of Anticancer Drug Delivery

Recently, polymer drug conjugates (PDCs) have attracted considerable attention in the treatment of cancer. In this work, a simple strategy has been developed to make PDCs of an antitumor alkylating agent, chlorambucil, using a biocompatible disulphide linker. Chlorambucil‐based chain transfer agent was used to prepare various homopolymers and block copolymers in a controlled fashion via reversible addition–fragmentation chain transfer polymerization. Chlorambucil conjugated block copolymer, poly(polyethylene glycol monomethyl ether methacrylate)‐b‐poly(methyl methacrylate), formed nanoaggregates in aqueous solutions, which are characterized by dynamic light scattering and field emission‐scanning electron microscopy. Finally, the simplicity of the design is exemplified by performing a release study of chlorambucil under reducing condition by using D,L‐dithiothreitol.

     

Conjugates of Antibody‐Targeted PEG Multiblock Polymers with Doxorubicin in Cancer Therapy

The synthesis and physico‐chemical characterisation of biodegradable multiblock polymer drug carriers based on poly(ethylene glycol) (PEG) are described. The blocks of PEG ( = 2 000) are interconnected by an enzymatically degradable tripeptide derivative consisting of one Lys and two Glu residues. An anticancer drug, doxorubicin (Dox), was attached to the polymer carrier by a Gly‐Phe‐Leu‐Gly tetrapeptide spacer, which is also susceptible to degradation by lysosomal enzymes. A targeting polyclonal antibody was covalently linked to the polymer‐Dox conjugate by the aminolytic reaction of reactive sulfosuccinimidyl ester groups of the polymer with the protein. The resulting antibody‐polymer‐drug conjugates were characterised by SEC, UV/VIS spectrophotometry and amino acid analysis. Although the studied polymers show only a moderate antiproliferative activity against concanavalin A‐stimulated murine splenocytes and a murine T‐cell EL 4 lymphoma in vitro, they exhibited significant antitumour efficiency against murine T‐cell EL 4 lymphoma in vivo.

     

Reactivity Study of Pyridyl‐Substituted 1‐Metalla‐2,5‐diaza‐cyclopenta‐2,4‐dienes of Group 4 Metallocenes

In this work the reactivity of 1‐metalla‐2,5‐diaza‐cyclopenta‐2,4‐dienes of group 4 metallocenes, especially of the pyridyl‐substituted examples, towards small molecules is investigated. The addition of H₂, CO₂, Ph?C≡N, 2‐py?C≡N, 1,3‐dicyanobenzene or 2,6‐dicyanopyridine results in exchange reactions, which are accompanied by the elimination of a nitrile. For CO₂, a coordination to the five‐membered cycle occurs in case of Cp*₂Zr(N=C(2‐py)?C(2‐py)=N). A 1,4‐diaza‐buta‐1,3‐diene complex is formed by H‐transfer in the conversion of the analogous titanocene compound with CH₃?C≡N, PhCH₂?C≡N or acetone. For CH₃?C≡N a coupling product of three acetonitrile molecules is established additionally. In order to split off the metallocene from the coupled nitriles, we examined reactions with HCl, PhPCl₂, PhPSCl₂ and SOCl₂. In the last case, the respective thiadiazole oxides and the metallocene dichlorides were obtained. A subsequent reaction produced thiadiazoles.     

Gold Nanorods with Phase‐Changing Polymer Corona for Remotely Near‐Infrared‐Triggered Drug Release

Herein, we report a new drug‐delivery system (DDS) that is comprised of a near‐infrared (NIR)‐light‐sensitive gold‐nanorod (GNR) core and a phase‐changing poly(ε‐caprolactone)‐b‐poly(ethylene glycol) polymer corona (GNR@PCL‐b‐PEG). The underlying mechanism of the drug‐loading and triggered‐release behaviors involves the entrapment of drug payloads among the PCL crystallites and a heat‐induced phase change, respectively. A low premature release of the pre‐loaded doxorubicin was observed in PBS buffer (pH 7.4) at 37 °C (<10 % of the entire payload after 48 h). However, release could be activated within 30 min by conventional heating at 50 °C, above the T_m of the crystalline PCL domain (43.5 °C), with about 60 % release over the subsequent 42 h at 37 °C. The NIR‐induced heating of an aqueous suspension of GNR@PCL‐b‐PEG under NIR irradiation (802 nm) was investigated in terms of the irradiation period, power, and concentration‐dependent heating behavior, as well as the NIR‐induced shape‐transformation of the GNR cores. Remotely NIR‐triggered release was also explored upon NIR irradiation for 30 min and about 70 % release was achieved in the following 42 h at 37 °C, with a mild warming (<4 °C) of the surroundings. The cytotoxicity of GNR@PCL‐b‐PEG against the mouse fibroblastic‐like L929 cell‐line was assessed by MTS assay and good compatibility was confirmed with a cell viability of over 90 % after incubation for 72 h. The cellular uptake of GNR@PCL‐b‐PEG by melanoma MEL‐5 cells was also confirmed, with an averaged uptake of 1250(±110) particles cell^?1 after incubation for 12 h (50 μg mL^?1). This GNR@PCL‐b‐PEG DDS is aimed at addressing the different requirements for therapeutic treatments and is envisaged to provide new insights into DDS targeting for remotely triggered release by NIR activation.