A stimuli‐responsive polymeric prodrug‐based nanotheranostic system with imaging agents (cyanine5.5 and gadolinium‐chelates) and a therapeutic agent paclitaxel (PTX) is prepared via polymerization and conjugating chemistry. The branched polymeric PTX‐Gd‐based nanoparticles (BP‐PTX‐Gd NPs) demonstrate excellent biocompatibility, and high stability under physiological conditions, but they stimuli‐responsively degrade and release PTX rapidly in a tumor microenvironment. The in vitro behavior of NPs labeled with fluorescent dyes is effectively monitored, and the NPs display high cytotoxicity to 4T1 cells similar to free PTX by impairing the function of microtubules, downregulating anti‐apoptotic protein Bcl‐2, and upregulating the expression of Bax, cleaved caspase‐3, cleaved caspase‐9, cleaved‐PARP, and p53 proteins. Great improvement in magnetic resonance imaging (MRI) is demonstrated by these NPs, and MRI accurately maps the temporal change profile of the tumor volume after injection of NPs and the tumor treatment process is also closely correlated with the T1 values measured from MRI, demonstrating the capability of providing real‐time feedback to the chemotherapeutic treatment effectiveness. The imaging‐guided chemotherapy to the 4T1 tumor in the mice model achieves an excellent anti‐tumor effect. This stimuli‐responsive polymeric nano‐agent opens a new door for efficient breast cancer treatment under the guidance of fluorescence/MRI.

Herein, two water‐soluble PROXYL‐based magnetic resonance imaging (MRI) macromolecular organic contrast agents (mORCAs) are designed and synthesized: linear and cross‐linked PCE‐mPEG‐Ppa‐PROXYL. They are prepared by conjugating linear and cross‐linked poly(carboxylate ester) (PCE) with poly(ethylene glycol) (mPEG 2000 )‐modified nitroxides (PROXYL), respectively. Both mORCAs form self‐assembled aggregates in an aqueous phase and PROXYL is protected inside a hydrophobic core to achieve great resistance to reduction in the physiological environment, and they have low toxicity. Since cross‐linked PCE‐mPEG‐Ppa‐PROXYL possess a branched architecture, its self‐assembled aggregate is more stable and compact with a greater particle size. Cross‐linked PCE‐mPEG‐Ppa‐PROXYL outperform the linear one in the following aspects: 1) its longitudinal relaxivity ( r 1 = 0.79 m m −1 s −1 ) is higher than that of the linear one ( r 1 = 0.64 m m −1 s −1 ) and both excel the best mORCA reported so far ( r 1 = 0.42 m m −1 s −1 ); 2) its blood retention time (≈48 h) is longer than that of its linear counterpart (≈10 h); 3) cross‐linked PCE‐mPEG‐Ppa‐PROXYL provided better MR imaging contrast resolution in normal organs (liver and kidney) and tumor of mice than the linear one. Overall, cross‐linked PCE‐mPEG‐Ppa‐PROXYL may have great potential to be a novel metal‐free macromolecular contrast agent for MR imaging.

reported that the optimized size may also improve the delivery efficiency in tumors [4] and NPs with moderate rigidity could enhance the multibiological barrier penetrating capability for drug delivery in comparison with their soft and hard counterparts. [5] NPs with poly(ethylene glycol) (PEG) modification can effectively transport across various biological barriers. [6] The hydrophile-lipophile balance (HLB) is a key factor in the formation of self-assembled NPs and its morphology, [7] however, the role of HLB of NPs in drug delivery, particularly in penetration and retention in tumors, remains unclear.One of the challenges is to prepare NPs with a tunable ratio of hydrophilic to hydrophobic units, or a tunable HLB value, which governs the self-assembling behavior of the NPs. In our previous work, we have reported a linear-peptide dendritic copolymer and its conjugated hydrophobic drug (doxorubicin) could self-assemble into stable and tumor microenvironment-responsive NPs by nonbonding interactions, such as π-π stacking, hydrophobic interaction, and hydrogen bonding. [8] However, it is a challenge to obtain NPs from the linear dendritic copolymers with tunable HLB values.Herein, we employed 2,2-bis(hydroxymethyl)propionic acid (Bis-MPA) hyperbranched PEG-OH dendrimer as a hydrophilic unit and pyropheophorbide-a (Ppa) as a hydrophobic unit to Hydrophile-lipophile balance (HLB) has a great influence on the selfassembly and physicochemical properties of amphiphiles, thus affecting their biological effects. It is shown that amphiphilic nanoparticles (NPs) with a moderate HLB value display enhanced stability and highly efficient tumor retention. 2,2-Bis(hydroxymethyl)propionic acid hyperbranched poly(ethylene glycol) (PEG)-pyropheophorbide-a (Ppa) amphiphiles (G320P, G310P, G220P, and G210P) are synthesized with a tunable HLB value from 6.1 to 9.9 by manipulating the number of generation of dendrons (G2 or G3) and the molecular weight of PEG chains (10 or 20 kDa). Molecular dynamics simulations reveal that G320P and G210P with a moderate HLB value (8.0 and 7.8) self-assemble into very stable NPs with a small solvent accessible surface area and high nonbonding interactions. G320P with a moderate HLB value (8.0) and a long PEG chain excels against other NPs in prolonging the blood circulation time of Ppa (up to 13-fold), penetrating deeply into multicellular tumor spheroids and accumulating in tumors, and enhancing the PDT efficacy with a tumor growth inhibition of 96.0%. Rational design of NPs with a moderate HLB value may be implemented in these NP-derived nanomedicines to achieve high levels of retention in tumors. Hydrophile-Lipophile BalanceRational designs of nanomedicine aid in overcoming physiological barriers of solid tumors for achieving enhanced therapeutic efficacy, [1] including manipulating physical, chemical, and biological properties of nanoparticles. [2] Negatively charged nanoparticles (NPs) are very stable in the blood circulatory system, thereby allowing NPs accumulation in tumors through enha...

compositions and molecular structures. Recently, hyaluronic acid (HA), a natural polysaccharide, has been exploited to mimic viral or bacterial capsules and HA-derived drug/DNA delivery systems have achieved superior antitumor effects. [2] Saccharides, an important component unit in nature, can form complexes with proteins to play critical roles in activities such as cell adhesion, substance transportation and immune regulation. Their unique structures and multiple weak interactions within peptides have been found to be important factors on these activities. [3] Beyond the use of saccharides as envelopes to improve the targeting ability of drug delivery systems, these saccharides can be a structure unit in the saccharide-based drug delivery system with unique weak interactions with proteins/peptides, which could open new opportunities in developing novel nanomedicines for cancer therapy.Saccharide-based polymers, such as glycopolymers with a polyhydroxyl-aldehyde/ ketone structure, can form numerous intermolecular hydrogen bonds which are beneficial for building stable nanostructures. [4] It has also been shown that most monosaccharides have a nonpolar plane composed of several CH groups, which enable carbohydrate/aromatic stacking (CH-π) interactions between CH groups and benzene or indole in amino acid residues. [3c,5] These interactions play an essential role in Inspired by natural saccharide-protein complexes, a stimuli-responsive biodegradable and branched glycopolymer-pyropheophorbide-a (Ppa) conjugate (BSP) with saccharide units for cancer therapy is constructed. A linear glycopolymeric conjugate (LSP), a branched glycopolymeric conjugate (BShP) from Ppa with long carbon chains, and a branched conjugate (BHSP) based on poly[N-(2-hydroxypropyl) methacrylamide] (polyHPMA) without saccharide units are prepared as controls. Through structure-activity relationship studies, BSP with a 3D network structure forms stable nanostructures via weak intermolecular interactions, regulating the stacking state of Ppa to improve the singlet oxygen quantum yield and the corresponding photodynamic therapy (PDT) effect. BSP shows high loading of olaparib, and are further coated with tumor cell membranes, resulting in a biomimetic nanomedicine (CM-BSPO). CM-BSPO shows highly efficient tumor targeting and cellular internalization properties. The engulfment of CM-BSPO accompanied with laser irradiation results in a prominent antitumor effect, evidenced by disruption of cell cycles in tumor cells, increased apoptosis and DNA damage, and subsequent inhibition of repair for damaged DNA.The mechanism for the synergistic effect from PDT and olaparib is unveiled at the genetic and protein level through transcriptome analysis. Overall, this biodegradable and branched glycopolymer-drug conjugate could be effectively optimized as a biomimetic nanomedicine for cancer therapy.

Owing to the low efficacy of clinically used small-molecule gadolinium (Gd)-based magnetic resonance imaging (MRI) agents, we designed and explored biodegradable macromolecular conjugates as MRI contrast agents. The linear polymeric structure and core-cross-linked formulation possessed different characteristics and features, so we prepared and comparatively studied the two kinds of Gd-based N-(2-hydroxypropyl) methacrylamide (HPMA) polymeric systems (the core-cross-linked pHPMA-DOTA-Gd and the linear one) using the clinical agent diethylene-triamine pentaacetic acid-Gd(III) (DTPA-Gd) as a control. This study was aimed to find the optimal polymeric formulation as a biocompatible and efficient MRI contrast agent. The high molecular weight (MW, 181 kDa) and core-cross-linked copolymer was obtained via the cross-linked block linear copolymer and could be degraded to low-MW segments (29 kDa) in the presence of glutathione (GSH) and cleaned from the body. Both core-cross-linked and linear pHPMA-DOTA-Gd copolymers displayed 2-3-fold increased relaxivity (r value) than that of DTPA-Gd. Animal studies demonstrated that two kinds of macromolecular systems led to much longer blood circulation time, higher tumor accumulation, and much higher signal intensity compared with the linear and clinical ones. Finally, in vivo and in vitro toxicity studies indicated that the two macromolecular agents had great biocompatibility. Therefore, we performed preliminary but important studies on the Gd-based HPMA polymeric systems as biocompatible and efficient MRI contrast agents and found that the biodegradable core-cross-linked pHPMA-DOTA-Gd copolymer might have greater benefits for the foreground.

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Multiple sclerosis (MS) is a neurodegenerative disease with a high morbidity and disease burden. It is characterized by the loss of the myelin sheath, resulting in the disruption of neuron electrical signal transmissions and sensory and motor ability deficits. The diagnosis of MS is crucial to its management, but the diagnostic sensitivity and specificity are always a challenge. To overcome this challenge, nanomedicines have recently been employed to aid the diagnosis of MS with an improved diagnostic efficacy. Advances in nanomedicine-based contrast agents in magnetic resonance imaging scanning of MS lesions, and nanomedicine-derived sensors for detecting biomarkers in the cerebrospinal fluid biopsy, or analyzing the composition of exhaled breath gas, have demonstrated the potential of using nanomedicines in the accurate diagnosis of MS. This review aims to provide an overview of recent advances in the application of nanomedicines for the diagnosis of MS and concludes with perspectives of using nanomedicines for the development of safe and effective MS diagnostic nanotools.

Hepatic fibrosis is induced by chronic hepatic injuries before it turns into hepatic cirrhosis/carcinoma. It is characterized by the formation of collagen and other extracellular matrices around damaged hepatic tissues; consequently, the normal architecture of liver would be disrupted and its function impaired. Diagnosis of hepatic fibrosis, especially at the early stage, is crucial because most fibrotic changes are reversible during the hepatic fibrosis stage. However, early and more accurate diagnosis of hepatic fibrosis still remains a great challenge. With their promising structural adjustability and targeting ability, nanomedicines have recently been introduced to improve diagnosis of hepatic fibrosis. By targeting fibrogenic cells, receptors, and extracellular matrix components, these nanomedicines can achieve detection of hepatic tissues with high sensitivity and specificity at the early stage. The use of nanomedicines can also enable theranostics of this chronic hepatic disease. This review aims to present an overview of recent advances of nanomedicines in diagnosis and theranostics of hepatic fibrosis.