Sulfoxide-containing polymers conjugated prodrug micelles with enhanced anticancer activity and reduced intestinal toxicity.

Poly(ethylene glycol) (PEG) is widely utilized as a hydrophilic coating to extend the circulation time and improve the tumor accumulation of polymeric micelles. Nonetheless, PEGylated micelles often activate complement proteins, leading to accelerated blood clearance and negatively impacting drug efficacy and safety. Here, we have crafted amphiphilic block copolymers that merge hydrophilic sulfoxide-containing polymers (psulfoxides) with the hydrophobic drug 7-ethyl-10-hydroxylcamptothecin (SN38) into drug-conjugate micelles. Our findings show that the specific variant, PMSEA-PSN38 micelles, remarkably reduce protein fouling, prolong blood circulation, and improve intratumoral accumulation, culminating in significantly increased anti-cancer efficacy compared with PEG-PSN38 counterpart. Additionally, PMSEA-PSN38 micelles effectively inhibit complement activation, mitigate leukocyte uptake, and attenuate hyperactivation of inflammatory cells, diminishing their ability to stimulate tumor metastasis and cause inflammation. As a result, PMSEA-PSN38 micelles show exceptional promise in the realm of anti-metastasis and significantly abate SN38-induced intestinal toxicity. This study underscores the promising role of psulfoxides as viable PEG substitutes in the design of polymeric micelles for efficacious anti-cancer drug delivery.

Neutrophil Extracellular Traps-Inhibiting and Fouling-Resistant Polysulfoxides Potently Prevent Postoperative Adhesion, Tumor Recurrence, and Metastasis.

Peritoneal metastasis (PM) is considered one of the most dreaded forms of cancer metastases for both patients and physicians. Aggressive cytoreductive surgery (CRS) is the primary treatment for peritoneal metastasis. Unfortunately, this intensive treatment frequently causes clinical complications, such as postoperative recurrence, metastasis, and adhesion formation. Emerging evidence suggests that neutrophil extracellular traps (NETs) released by inflammatory neutrophils contribute to these complications. Effective NET-targeting strategies thus show considerable potential in counteracting these complications but remain challenging. Here, one type of sulfoxide-containing homopolymer, PMeSEA, with potent fouling-resistant and NET-inhibiting capabilities, is synthesized and screened. Hydrating sulfoxide groups endow PMeSEA with superior nonfouling ability, significantly inhibiting protein/cell adhesion. Besides, the polysulfoxides can be selectively oxidized by ClO- which is required to stabilize the NETs rather than H2O2, and ClO- scavenging effectively inhibits NETs formation without disturbing redox homeostasis in tumor cells and quiescent neutrophils. As a result, PMeSEA potently prevents postoperative adhesions, significantly suppresses peritoneal metastasis, and shows synergetic antitumor activity with chemotherapeutic 5-Fluorouracil. Moreover, coupling CRS with PMeSEA potently inhibits CRS-induced tumor metastatic relapse and postoperative adhesions. Notably, PMeSEA exhibits low in vivo acute and subacute toxicities, implying significant potential for clinical postoperative adjuvant treatment.

RNA-based modulation of macrophage-mediated efferocytosis potentiates antitumor immunity in colorectal cancer.

Tumor-associated macrophages play pivotal roles in tumor progression and metastasis. Macrophage-mediated clearance of apoptotic cells (efferocytosis) supports inflammation resolution, contributing to immune evasion in colorectal cancers. To reverse this immunosuppressive process, we propose a readily translatable RNA therapy to selectively inhibit macrophage-mediated efferocytosis in tumor microenvironment. A clinically approved lipid nanoparticle platform (LNP) is employed to encapsulate siRNA for the phagocytic receptor MerTK (siMerTK), enabling selective MerTK inhibition in the diseased organ. Decreased MerTK expression in tumor-associated macrophages results in apoptotic cell accumulation and immune activation in tumor microenvironment, leading to suppressed tumor growth and better survival in both liver and peritoneal metastasis models of colorectal cancers. siMerTK delivery combined with PD-1 blockade further produces enhanced antimetastatic efficacy with reactivated intratumoral immune milieu. Collectively, LNP-based siMerTK delivery combined with immune checkpoint therapy may present a feasible modality for metastatic colorectal cancer therapy.

Activation of TRPV1 by capsaicin-loaded CaCO3 nanoparticle for tumor-specific therapy.

Capsaicin is a natural non-toxic small molecular organic substance, which is often used clinically to reduce inflammation and pain. Here, we report an acid-responsive CaCO3 nanoparticle loaded with capsaicin that can specifically activate TRPV1 channels and trigger tumor calcium ion therapy. The excellent acid responsiveness of calcium carbonate enables it to precisely target the tumor sites. The released capsaicin can specifically activate TRPV1 channel, overloading the intracellular calcium ion concentration and causing cell apoptosis, which provides a new safer and cheaper treatment. We proved that the naturalness and non-toxicity of capsaicin make the CaCO3@CAP nanoparticles have excellent biocompatibility, which has good development prospects and clinical application potential.

Light-Induced Caspase-3-Responsive Chimeric Peptide for Effective PDT/Chemo Combination Therapy with Good Compatibility.

Activated doxorubicin (DOX) often has severe systemic toxicity and side effects due to its inability to distinguish tumor cells from normal cells, which seriously affects the prognosis of patients. Here, we synthesized an inactivated a DOX prodrug that could be selectively activated by a light-induced caspase-3 enzyme in the tumor site. In the absence of light, this uniformly dispersed nanoparticle avoided the unnecessary toxicity under physiological conditions. Upon the laser irradiating to the tumor area of interest, the nanoparticles can produce a large amount of reactive oxygen species (ROS) to induce cell apoptosis and activate caspase-3 enzyme to release DOX selectively. Meanwhile, the produced ROS can also combine with activated DOX to cause more potent tumor damage. The experiments demonstrated that the light can effectively activate DOX drug through a series of cascade events and the subsequent synergistic therapy both in vitro and in vivo. This strategy achieved excellent therapeutic outcomes and minimal adverse effects, which should significantly improve the dilemma of traditional chemotherapy.

Au Hollow Nanorods-Chimeric Peptide Nanocarrier for NIR-II Photothermal Therapy and Real-time Apoptosis Imaging for Tumor Theranostics.

The strategy that combines photodynamic therapy (PDT) and photothermal therapy (PTT) is widely used to achieve strong antitumor efficiency. Since light in the NIR-II window possesses ideal penetration ability, developing NIR-II PTT and NIR-II light triggered photosensitizer release for combined PDT and PTT is very promising in nanomedicine. Methods: We develop a novel nanocarrier (termed AuHNRs-DTPP) by conjugating photosensitizer contained chimeric peptide (DTPP) to Au hollow nanorods (AuHNRs). AuHNRs was obtained by a Te-templated method with the assistance of L-cysteine. The chimeric peptide PpIX-PEG8-GGK(TPP)GRDEVDGC (DTPP) was obtained through a solid-phase peptide synthesis (SPPS) method. Results: Under the 1064 nm laser irradiation, the nanocarrier can accumulate heat quickly for efficient PTT, and then release activated photosensitizer for real-time apoptosis imaging. Thereafter, supplementary PDT can be conducted to kill tumor cells survived from the PTT, and meanwhile the normal tissue can be protected from photo-toxicity. Conclusion: This designed AuHNRs-DTPP nanocarrier with remarkable therapy effect, real-time apoptosis imaging ability and reduced skin damage is of great potential in nanomedicine application.

Reasonably retard O2 consumption through a photoactivity conversion nanocomposite for oxygenated photodynamic therapy.

Photodynamic therapy (PDT) brings excellent treatment outcome while also causing poor tumor microenvironment and prognosis due to the uncontrolled oxygen consumption. To solve this issue, a novel PDT strategy, oxygenated PDT (maintain the tumor oxygenation before and after PDT) was carried out by a tumor and apoptosis responsive photoactivity conversion nanocomposite (MPPa-DP). Under physiological conditions, this nanocomposite has a low photoactivity. While at H2O2-rich tumor microenvironment, the nanocomposite could react with overexpressed H2O2 to produce O2 and release high photoactivity chimeric peptide PPa-DP for oxygenated tumor and PDT. Importantly, when the PDT mediates cell apoptosis, the photoactivity of PPa-DP be effectively quenched and the O2 consumption appeared retard, which avoided further consumption of residual O2 on apoptotic cells. In vitro and vivo studies revealed that this nanocomposite could efficiently change photoactivity, reasonable control O2 consumption and increase residual O2 content of tumor after PDT.

Tumor-triggered transformation of chimeric peptide for dual-stage-amplified magnetic resonance imaging and precise photodynamic therapy.

Despite the great success in clinical magnetic resonance imaging (MRI), Gd3+-based contrast agents still suffer from low proton relaxation efficiency, rapid metabolic clearance as well as poor sensitivity. In this work, we designed a matrix metalloproteinase-2 (MMP-2) responsive chimeric peptide for dual-stage-amplified MRI and precise photodynamic therapy. Both in vitro and in vivo studies indicated that this chimeric peptide could self-assembly into spherical nanoparticles at physiological condition with r1 value of 28.17 mM-1s-1. Meanwhile, the spherical shape endowed chimeric peptide with efficient tumor accumulation via enhanced penetration and retention (EPR) effect. Importantly, the overexpressed MMP-2 in tumor region could specifically hydrolyze chimeric peptide, leading to sphere-to-fiber transformation. This transformation enhanced both the tumor accumulation and the relaxivity of contrast agent. Consequently, the r1 value was remarkably elevated to 51.52 mM-1s-1, which guided precise photodynamic therapy. This tumor microenvironment-triggered transformable strategy should show great potential for tumor-targeted imaging and phototherapy.