Search

Although important advances have been achieved in the development of radiolabeled prostate-specific membrane antigen (PSMA)-targeting ligand constructs for both diagnosis and therapy of prostate cancer (PCa) over the past decade, challenges related to off-target effects and limited treatment responses persist. In this study, which builds upon the successful clinical translation of a series of ultrasmall, dye-encapsulating core-shell silica nanoparticles, or Cornell Prime Dots (C′ dots), for cancer management, we sought to address these limitations by designing a dual-modality, PSMA-targeting platform that evades undesirable accumulations in the salivary glands, kidneys, and reticuloendothelial system, while exhibiting bulk renal clearance. This versatile PCa-targeted particle imaging probe offers significant clinical potential to improve future theranostic applications in a variety of patient care settings.

Key Points Question Can the favorable properties of an ultrasmall fluorescent core-shell silica nanoparticle aid real-time image-guided detection, localization, and surgical management of sentinel lymph nodes (SLNs) in patients with head and neck melanoma? Findings In this nonrandomized clinical trial of 24 patients, real-time, particle-based fluorescence imaging of SLNs was feasible and safe at the microdosing level and enabled deep-tissue nodal detection. There was high concordance in identifying nodes between preoperative lymphoscintigraphy and particle-based fluorescence-guided biopsy. Meaning The findings of this study suggest that ultrabright, optical contrast–conferring particles for SLN identification hold promise for overcoming current probe limitations and improving surgical outcomes., This nonrandomized clinical trial evaluates whether an ultrasmall, molecularly targeted core-shell silica nanoparticle can safely and reliably identify optically avid SLNs in head and neck melanoma during fluorescence-guided biopsy., Importance Sentinel lymph node (SLN) mapping agents approved for current surgical practice lack sufficient brightness and target specificity for high-contrast, sensitive nodal visualization. Objective To evaluate whether an ultrasmall, molecularly targeted core-shell silica nanoparticle (Cornell prime dots) can safely and reliably identify optically avid SLNs in head and neck melanoma during fluorescence-guided biopsy. Design, Setting, and Participants This nonrandomized clinical trial enrolled patients aged 18 years or older with histologically confirmed melanoma in whom SLN mapping was indicated. Exclusion criteria included known pregnancy, breast-feeding, or medical illness unrelated to the tumor. The trial was conducted between February 2015 and March 2018 at Memorial Sloan Kettering Cancer Center, with postoperative follow-up of 2 years. Data analysis was conducted from February 2015 to March 2018. Interventions Patients received standard-of-care technetium Tc 99m sulfur colloid followed by a microdose administration of integrin-targeting, dye-encapsulated nanoparticles, surface modified with polyethylene glycol chains and cyclic arginine-glycine–aspartic acid–tyrosine peptides (cRGDY-PEG-Cy5.5-nanoparticles) intradermally. Main Outcomes and Measures The primary end points were safety, procedural feasibility, lowest particle dose and volume for maximizing nodal fluorescence signal, and proportion of nodes identified by technetium Tc 99m sulfur colloid that were optically visualized by cRGDY-PEG-Cy5.5-nanoparticles. Secondary end points included proportion of patients in whom the surgical approach or extent of dissection was altered because of nodal visualization. Results Of 24 consecutive patients enrolled (median [interquartile range] age, 64 [51-71] years), 18 (75%) were men. In 24 surgical procedures, 40 SLNs were excised. Preoperative localization of SLNs with technetium Tc 99m sulfur colloid was followed by particle dose-escalation studies, yielding optimized doses and volumes of 2 nmol and 0.4 mL, respectively, and maximum SLN signal-to-background ratios of 40. No adverse events were observed. The concordance rate of evaluable SLNs by technetium Tc 99m sulfur colloid and cRGDY-PEG-Cy5.5-nanoparticles was 90% (95% CI, 74%-98%), 5 of which were metastatic. Ultrabright nanoparticle fluorescence enabled high-sensitivity SLN visualization (including difficult-to-access anatomic sites), deep tissue imaging, and, in some instances, detection through intact skin, thereby facilitating intraoperative identification without extensive dissection of adjacent normal tissue or nerves. Conclusions and Relevance This study found that nanoparticle-based fluorescence-guided SLN biopsy in head and neck melanoma was feasible and safe. This technology holds promise for improving lymphatic mapping and SLN biopsy procedures, while potentially mitigating procedural risks. This study serves as a first step toward developing new multimodal approaches for perioperative care. Trial Registration ClinicalTrials.gov Identifier: NCT02106598

Purpose: Small-molecule inhibitors have had a major impact on cancer care. While treatments have demonstrated clinically promising results, they suffer from dose-limiting toxicities and the emergence of refractory disease. Considerable efforts made to address these issues have more recently focused on strategies implementing particle-based probes that improve drug delivery and accumulation at target sites, while reducing off-target effects. Experimental Design: Ultrasmall ( Results: Gefitinib-bound C′ dots (DFO-Gef-C′ dots), synthesized using the gefitinib analogue, APdMG, at a range of drug-to-particle ratios (DPR; DPR = 11–56), demonstrated high stability for DPR values≤ 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD50 = 6.21 nmol/L vs. 3 μmol/L, respectively). In human non–small cell lung cancer mice, efficacious Gef-C′ dot doses were at least 200-fold lower than that needed for gefitinib (360 nmoles vs. 78 μmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C′ dot–treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wild-type EGFR target inhibition, unlike free drug. Conclusions: Results underscore the clinical potential of DFO-Gef-C′ dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose.

The poor prognosis associated with malignant melanoma has not changed substantially over the past 30 years. Targeted molecular therapies, such as immunotherapy, have shown promise but suffer from resistance and off-target toxicities, underscoring the need for alternative therapeutic strategies that can be used in combination with existing protocols. Moreover, peptides targeting melanoma-specific markers, like the melanocortin-1 receptor (MC1-R), for imaging and therapy exhibit high renal uptake that limits clinical translation. In the current study, the application of ultrasmall fluorescent (Cy5) silica nanoparticles (C' dots), conjugated with MC1-R targeting alpha melanocyte stimulating hormone (αMSH) peptides on the polyethylene glycol (PEG) coated surface, is examined for melanoma-selective imaging. αMSH peptide sequences, evaluated for conjugation to the PEG-Cy5-C' dot nanoparticles, bound to MC1-R with high affinity and targeted melanoma in syngenetic and xenografted melanoma mouse models. Results demonstrated a 10-fold improvement in MC1-R affinity over the native peptide alone following surface attachment of the optimal αMSH peptide. Systematic in vivo studies further demonstrated favorable in vivo renal clearance kinetics as well as receptor-mediated tumor cell internalization of as-developed radiolabeled particle tracers in B16F10 melanoma bearing mice. These findings highlight the ability of αMSH-PEG-Cy5-C' dots to overcome previous hurdles that prevented clinical translation of peptide and antibody-based melanoma probes and reveal the potential of αMSH-PEG-Cy5-C' dots for melanoma-selective imaging, image-guided surgery, and therapeutic applications.

Spectrally distinct ultrasmall fluorescence silica particles as multiplexing tools address cancer heterogeneity and aid surgery., Accurate detection and quantification of metastases in regional lymph nodes remain a vital prognostic predictor for cancer staging and clinical outcomes. As intratumoral heterogeneity poses a major hurdle to effective treatment planning, more reliable image-guided, cancer-targeted optical multiplexing tools are critically needed in the operative suite. For sentinel lymph node mapping indications, accurately interrogating distinct molecular signatures on cancer cells in vivo with differential levels of sensitivity and specificity remains largely unexplored. To address these challenges and demonstrate sensitivity to detecting micrometastases, we developed batches of spectrally distinct 6-nm near-infrared fluorescent core-shell silica nanoparticles, each batch surface-functionalized with different melanoma targeting ligands. Along with PET imaging, particles accurately detected and molecularly phenotyped cancerous nodes in a spontaneous melanoma miniswine model using image-guided multiplexing tools. Information afforded from these tools offers the potential to not only improve the accuracy of targeted disease removal and patient safety, but to transform surgical decision-making for oncological patients.

Purpose: Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood–brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy. Experimental Design: Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with αv integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (124I, 89Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with 124I-cRGD- or 124I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood–brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle–drug conjugates (Das-NDCs). Imaging findings were confirmed with ex vivo autoradiography, fluorescence microscopy, and p-S6RP IHC. Results: Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition. Conclusions: These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.

CDCs are novel ultra-small (6-7 nm) nanoparticle drug conjugates that have been demonstrated to be capable of faster tumor targeting and deeper tumor penetration than antibody drug conjugates in animal models. CDCs are capable of targeting tumors in the brain and pancreas that are difficult to access, while exhibiting limited exposure to normal tissues due their efficient renal elimination. CDCs are composed of a silica core, in which Cy5, a far red dye is covalently encapsulated. The silica core is covalently coated with a layer of polyethylene glycol which is then functionalized with targeting moieties and payloads. ELU001 is a CDC functionalized with ~20 molecules of the topoisomerase-1 inhibitor exatecan linked via a proteolytic cleavable linker as a payload and ~15 folic acids to provide targeting to FRα overexpressing cancers. ELU001 is rapidly internalized into FRα expressing cells and is trafficked to the lysosome where the payload is released from the CDC. ELU001 exhibits potency in the low single digit nanomolar to sub-nanomolar range against cancer cells that express 3+ (KB, IGROV-1) and 2+ (SK-OV-3, HCC827 and OVCAR-3) levels of FRα after a 6-hr exposure in a 7-day viability study. In contrast, an anti-FRα ADC based ADC mirvetuximab soravtansine exhibits lower potency (>100 nM IC50) against SK-OV-3 and HCC827 cells and 40 nM IC50 against OVCAR-3 cells. ELU001 exhibits potent efficacy against established s.c. KB human cervical tumor xenografts in immunodeficient mice with significantly better efficacy and safety than free exatecan payload. It is also effective in treating established SK-OV-3 tumors with lower (2+) FRα expression, a setting where the ADC is again less effective. IND-enabling nonclinical studies are currently underway to prepare for initiation of a first-in-human phase 1 clinical trial in subjects with FRα overexpressing cancers in the second half of 2021. Citation Format: Gregory Paul Adams, Kai Ma, Aranapakam Venkatesan, Feng Chen, Fei Wu, Melik Turker, Thomas Gardinier, Peiming Chen, Vaibhav Patel, Eliel Bayever, Paul Rudick, Geno Germano. ELU001, a targeted C'Dot drug conjugate (CDC) for the treatment of folate receptor alpha (FRα) overexpressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 305.

Lutetium-177 (177Lu) radiolabeled ultrasmall (~6 nm dia.) fluorescent core-shell silica nanoparticles (Cornell prime dots or C′ dots) were developed for improving efficacy of targeted radiotherapy in melanoma models. PEGylated C′ dots were surface engineered to display 10–15 alpha melanocyte stimulating hormone (αMSH) cyclic peptide analogs for targeting the melanocortin-1 receptor (MC1-R) over-expressed on melanoma tumor cells. The 177Lu-DOTA-αMSH-PEG-C′ dot product was radiochemically stable, biologically active, and exhibited high affinity cellular binding properties and internalization. Selective tumor uptake and favorable biodistribution properties were also demonstrated, in addition to bulk renal clearance, in syngeneic B16F10 and human M21 xenografted models. Prolonged survival was observed in the treated cohorts relative to controls. Dosimetric analysis showed no excessively high absorbed dose among normal organs. Correlative histopathology of ex vivo treated tumor specimens revealed expected necrotic changes; no acute pathologic findings were noted in the liver or kidneys. Collectively, these results demonstrated that 177Lu-DOTA-αMSH-PEG-C′ dot targeted melanoma therapy overcame the unfavorable biological properties and dose-limiting toxicities associated with existing mono-molecular treatments. The unique and tunable surface chemistries of this targeted ultrasmall radiotherapeutic, coupled with its favorable pharmacokinetic properties, substantially improved treatment efficacy and demonstrated a clear survival benefit in melanoma models, which supports its further clinical translation.

Controlling the biodistribution of nanoparticles upon intravenous injection is the key to achieving target specificity. One of the impediments in nanoparticle-based tumor targeting is the inability to limit the trafficking of nanoparticles to liver and other organs leading to smaller accumulated amounts in tumor tissues, particularly via passive targeting. Here we overcome both these challenges by designing nanoparticles that combine the specificity of antibodies with favorable particle biodistribution profiles, while not exceeding the threshold for renal filtration as a combined vehicle. To that end, ultrasmall silica nanoparticles are functionalized with anti-human epidermal growth factor receptor 2 (HER2) single-chain variable fragments to exhibit high tumor-targeting efficiency and efficient renal clearance. This ultrasmall targeted nanotheranostics/nanotherapeutic platform has broad utility, both for imaging a variety of tumor tissues by suitably adopting the targeting fragment and as a potentially useful drug delivery vehicle., One of the major obstacles in nanoparticle-based therapy is to achieve tumour targeting, limiting non-specific accumulation of the nanoparticles. Here the authors propose the conjugation of anti-HER2 scFv fragments to the silica nanoparticles, increasing specificity and limiting the final size of the immunoconjugates below the renal clearance threshold.

The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (