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Introduction Recent advances in long‐acting antiretroviral therapy (LA‐ART) could provide new options for HIV treatment and reduce adherence barriers, if regimens are acceptable to patients. We elicited preferences for key attributes of potential LA‐ART regimens among people with HIV (PWH) in the United States, focusing on four treatment modes (oral tablets, subcutaneous injections, intramuscular injections, and implants), product characteristics and location of administration. Methods A discrete choice experiment was conducted among PWH aged ≥18 years recruited from HIV clinics in Washington State and Atlanta, Georgia from March 2021 to June 2022. Participants responded to 17 choice scenarios, each with three options: two systematically generated hypothetical LA‐ART regimens and a constant opt‐out (their current daily oral treatment). LA‐ART regimen descriptions included treatment mode, pain, dosing frequency, location, pre‐treatment time with undetectable viral load, pre‐treatment negative reaction testing and “late‐dose leeway” (i.e. flexibility or forgiveness in timing the next dose). We used conditional logistic regression, with an interaction between treatment mode and pain, to estimate preference weights for all attribute levels. Results Seven hundred participants (350 at each site) enrolled, with median age 51 years (range 18–73); 70% identified as cisgender male, 24% as cisgender female and 6% as non‐binary or transgender. LA oral tablets were the only mode preferred over current daily oral treatment, with annual implants and injections the next most preferred LA‐ART option. Longer time between doses was preferred, and administration at home was preferred to clinics, which were preferred to pharmacies. Attributes with less impact on preferences included oral lead‐in treatment to achieve viral suppression or test for negative reactions and late‐dose leeway around the prescribed dosing interval. Participants in Atlanta were more likely to prefer their current daily oral ART than participants from Seattle. Conclusions PWH in the United States may soon have several options for LA‐ART. Our results suggest that LA oral tablets will be preferred by many patients over their current daily oral treatment, while implants and injections with longer duration may be acceptable to some. Future research should investigate sources of preference heterogeneity and actual uptake of and adherence to LA‐ART products, when available.

Preclinical models of cancer are vital for assessing and predicting efficacies and toxicities of novel treatments prior to testing in human subjects. Current pancreatic tumor models exhibit variable growth rates, unpredictable tumor size after implantation in non-native tissues, or require surgical implantation. Surgical implantation in the pancreas may produce not only unpredictable tumor uptake but could also elicit additional inflammatory responses. In searching for a pancreatic carcinoma cell that can be introduced into a mouse via simple injection, we found that Pan02, a murine ductal pancreatic adenocarcinoma derived from a pancreatic lesion of a C57BL/6 mouse, inoculated peritoneally can consistently produce pancreatic tumors. This intraperitoneal, but not intravenous, introduction of Pan02 cells leads to the attachment and growth of Pan02 in the pancreas before spreading to other tissues. Time-course tissue analysis indicates that the Pan02 cells first find, infiltrate, and grow within the pancreas, producing a pancreatic tumor model. This model appears to mimic pancreatic cancer development in humans and is the first reported use of Pan02 cells to produce orthotopic pancreatic and metastatic neoplasms in a mouse model without the need for tumor implantation within matrices or survival surgeries. This orthotopic pancreatic tumor model, with consistent tumor uptake, synchronized tumor development and survival, and predictable outcomes may enable and accelerate the preclinical evaluation of treatment candidates for pancreatic cancer.

Early diagnosis along with new drugs targeted to cancer receptors and immunocheckpoints have improved breast cancer survival. However, full remission remains elusive for metastatic breast cancer due to dose-limiting toxicities of heavily used, highly potent drug combinations such as gemcitabine and paclitaxel. Therefore, novel strategies that lower the effective dose and improve safety margins could enhance the effect of these drug combinations. To this end, we developed and evaluated a novel drug combination of gemcitabine and paclitaxel (GT). Leveraging a simple and scalable drug-combination nanoparticle platform (DcNP), we successfully prepared an injectable GT combination in DcNP (GT DcNP). Compared to a Cremophor EL/ethanol assisted drug suspension in buffer (CrEL), GT DcNP exhibits about 56-fold and 8.6-fold increases in plasma drug exposure (area under the curve, AUC) and apparent half-life of gemcitabine respectively, and a 2.9-fold increase of AUC for paclitaxel. Using 4T1 as a syngeneic model for breast cancer metastasis, we found that a single GT (20/2 mg/kg) dose in DcNP nearly eliminated colonization in the lungs. This effect was not achievable by a CrEL drug combination at a 5-fold higher dose (i.e., 100/10 mg/kg GT). A dose-response study indicates that GT DcNP provided a therapeutic index of ~15.8. Collectively, these data suggest that GT DcNP could be effective against advancing metastatic breast cancer with a margin of safety. As the DcNP formulation is intentionally designed to be simple, scalable, and long-acting, it may be suitable for clinical development to find effective treatment against metastatic breast cancer.

Timosaponin AIII (TAIII), as a steroid saponin in , has favorable potential as an antitumor candidate. However, its hydrophobicity and low bioavailability severely limit its in vivo antitumor efficacy. To overcome this drawback, TAIII-loaded liposomes (LP) were prepared to improve TAIII solubility and extend its circulation time. Furthermore, anti-CD44 antibody-modified LP (CD44-LP) was prepared to enhance the therapeutic index of TAIII. The LP and CD44-LP were also characterized through their biological activity, target selective binding and uptake, and in vivo pharmacokinetics. Compared with free TAIII, both LP and CD44-LP possessed a desirable sustained-release profile in vitro, with ~14.2- and 10.7-fold longer TAIII half-life, respectively, and 1.7- and 1.9-fold larger area under the curve, respectively. LP and CD44-LP enhanced TAIII antitumor activity against HepG2 cells and in a xenograft mouse model without detectable toxicity. In particular, CD44-LP exhibited notably higher cytotoxicity than did LP, with a lower half-maximal inhibitory concentration (48 h). CD44-LP exhibited stronger tumor inhibition, and the tumor inhibitory effect was 1.3-fold that of LP. Furthermore, confocal laser scanning microscopy and in vivo near-infrared imaging of a xenograft mouse model revealed that compared with LP, CD44-LP could effectively enhance tumor accumulation. Taken together, the results indicate that both CD44-LP and LP can considerably extend TAIII circulation time, increase tumor-targeted accumulation, and enhance antitumor activity. Thus, the anti-CD44 antibody-modified liposome is a promising candidate for treating CD44-positive cancer with considerable antitumor effects.

To avoid undefined metabolic mechanisms and to eliminate potential side effects of traditional nanocarriers, new green carriers are urgently needed in cancer treatment. Carrier-free nanoparticles (NPs) based on ursolic acid (UA) have attracted significant attention, but the UA NPs targeting the folate receptor have never been explored. We designed a novel self-assembled UA-Methotrexate (MTX) NPs targeting the folate-receptor and its synergetic anticancer activity was studied in vitro and in vivo. UA-MTX NPs were prepared using the solvent precipitation method. Characterization of the UA-MTX NPs preparation was performed using a size analyzer, transmission electron microscopy, and UV-vis spectrophotometry. The in vitro pH-responsive drug release capability of UA-MTX NPs was tested at different pH values. The UA-MTX NPs targeting of folates was determined by comparing the endocytosis rates of cell lines with low or overexpression of the folate receptor (A549 and MCF-7 cells). The cytotoxicity and cell apoptosis of UA-MTX NPs were also studied to determine the in vitro synergistic effects. Combination chemotherapy of UA-MTX NPs in vivo was evaluated using MCF-7 xenografted tumor models. Compared with free UA or MTX, the water solubility of UA-MTX NPs improved significantly. Drug-release from the UA-MTX NPs was faster at pH 5.0 than pH 7.4, suggesting MTX-UA NPs could rapidly release MTX in the acidic conditions of the tumor microenvironment. Confocal laser scanning microscopy revealed the excellent folate receptor targeting of UA-MTX NPs in MCF-7 cells. Cytotoxicity and cell apoptosis results demonstrated greater antiproliferative capacity of UA-MTX NPs than that of free drug in folate receptor overexpressing MCF-7 cells. Anticancer effects in vivo suggested MTX-UA NPs exhibited good biological safety and could enhance antitumor efficacy due to the combination therapy. Our findings indicate that the UA-MTX NPs targeting folate-receptors is an efficient strategy for combination chemotherapy.

Artemisinin (ART) dimers show potent anti-proliferative activities against breast cancer cells. To facilitate their clinical development, novel pH-responsive artemisinin dimers were synthesized for liposomal nanoparticle formulations. A new ART dimer was designed to become increasingly water-soluble as pH declines. The new artemisinin dimer piperazine derivatives (ADPs) remained tightly associated with liposomal nanoparticles (NPs) at neutral pH but were efficiently released at acidic pH's that are known to exist within solid tumors and organelles such as endosomes and lysosomes. ADPs incorporated into nanoparticles down regulated the anti-apoptotic protein, survivin, and cyclin D1 when incubated at low concentrations with breast cancer cell lines. We demonstrate for the first time, for any ART derivative, that ADP NPs can down regulate the oncogenic protein HER2, and its counterpart, HER3 in a HER2+ cell line. We also show that the wild type epidermal growth factor receptor (EGFR or HER1) declines in a triple negative breast cancer (TNBC) cell line in response to ADP NPs. The declines in these proteins are achieved at concentrations of NP109 at or below 1 µM. Furthermore, the new artemisinin derivatives showed improved cell-proliferation inhibition effects compared to known dimer derivatives.

Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth—by 100 to 140 times—in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy.

Gadolinium (Gd), with its 7 unpaired electrons in 4f orbitals that provide a very large magnetic moment, is proven to be among the best agents for contrast enhanced MRI. Unfortunately, the most potent MR contrast agent based on Gd requires relatively high doses of Gd. The Gd-chelated to diethylene-triamine-penta-acetic acid (DTPA), or other derivatives (at 0.1 mmole/kg recommended dose), distribute broadly into tissues and clear through the kidney. These contrast agents carry the risk of Nephrogenic Systemic Fibrosis (NSF), particularly in kidney impaired subjects. Thus, Gd contrast agents that produce higher resolution images using a much lower Gd dose could address both imaging sensitivity and Gd safety. To determine whether a biocompatible lipid nanoparticle with surface bound Gd can improve MRI contrast sensitivity, we constructed Gd-lipid nanoparticles (Gd-LNP) containing lipid bound DTPA and Gd. The Gd-LNP were intravenously administered to rats and MR images collected. We found that Gd in Gd-LNP produced a greater than 33-fold higher longitudinal (T(1)) relaxivity, r(1), constant than the current FDA approved Gd-chelated contrast agents. Intravenous administration of these Gd-LNP at only 3% of the recommended clinical Gd dose produced MRI signal-to-noise ratios of greater than 300 in all vasculatures. Unlike current Gd contrast agents, these Gd-LNP stably retained Gd in normal vasculature, and are eliminated predominately through the biliary, instead of the renal system. Gd-LNP did not appear to accumulate in the liver or kidney, and was eliminated completely within 24 hrs. The novel Gd-nanoparticles provide high quality contrast enhanced vascular MRI at 97% reduced dose of Gd and do not rely on renal clearance. This new agent is likely to be suitable for patients exhibiting varying degrees of renal impairment. The simple and adaptive nanoparticle design could accommodate ligand or receptor coating for drug delivery optimization and in vivo drug-target definition in system biology profiling, increasing the margin of safety in treatment of cancers and other diseases.

Leukemia remains incurable partly due to difficulties in reaching and maintaining therapeutic drug concentrations in the target tissues and cells. Next-generation drugs targeted to multiple cell checkpoints, including the orally active venetoclax (Bcl-2 target) and zanubrutinib (BTK target), are effective and have improved safety and tolerability compared to conventional, nontargeted chemotherapies. However, dosing with a single agent frequently leads to drug resistance; asynchronous coverage due to the peak-and-trough time-course of two or more oral drugs has prevented drug combinations from simultaneously knocking out the respective drugs’ targets for sustained leukemia suppression. Higher doses of the drugs may potentially overcome asynchronous drug exposure in leukemic cells by saturating target occupancy, but higher doses often cause dose-limiting toxicities. To synchronize multiple drug target knockout, we have developed and characterized a drug combination nanoparticle (DcNP), which enables the transformation of two short-acting, orally active leukemic drugs, venetoclax and zanubrutinib, into long-acting nanoformulations (VZ-DCNPs). VZ-DCNPs exhibit synchronized and enhanced cell uptake and plasma exposure of both venetoclax and zanubrutinib. Both drugs are stabilized by lipid excipients to produce the VZ-DcNP nanoparticulate (d ~ 40 nm) product in suspension. The VZ-DcNP formulation has enhanced uptake of the two drugs (VZ) in immortalized leukemic cells (HL-60), threefold over that of its free drug counterpart. Additionally, drug-target selectivity of VZ was noted with MOLT-4 and K562 cells that overexpress each target. When given subcutaneously to mice, the half-lives of venetoclax and zanubrutinib were extended by approximately 43- and 5-fold, respectively, compared to an equivalent free VZ. Collectively, these data suggest that VZ in VZ-DcNP warrant consideration for preclinical and clinical development as a synchronized and long-acting drug-combination for the treatment of leukemia.

Despite the availability of molecularly targeted treatments such as antibodies and small molecules for human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and programmed death-ligand 1 (PD-L1), limited treatment options are available for advanced metastatic breast cancer (MBC), which constitutes ~90% mortality. Many of these monotherapies often lead to drug resistance. Novel MBC-targeted drug-combination therapeutic approaches that may reduce resistance are urgently needed. We investigated intercellular adhesion molecule-1 (ICAM-1), which is abundant in MBC, as a potential target to co-localize two current drug combinations, gemcitabine (G) and paclitaxel (T), assembled in a novel drug-combination nanoparticle (GT DcNP) form. With an ICAM-1-binding peptide (referred to as LFA1-P) coated on GT DcNPs, we evaluated the role of the LFA1-P density in breast cancer cell localization in vitro and in vivo. We found that 1–2% LFA1-P peptide incorporated on GT DcNPs provided optimal cancer cell binding in vitro with ~4× enhancement compared to non-peptide GT DcNPs. The in vivo probing of GT DcNPs labeled with a near-infrared marker, indocyanine green, in mice by bio-imaging and G and T analyses indicated LFA1-P enhanced drug and GT DcNP localization in breast cancer cells. The target/healthy tissue (lung/gastrointestinal (GI)) ratio of particles increased by ~60× compared to the non-ligand control. Collectively, these data indicated that LFA1 on GT DcNPs may provide ICAM-1-targeted G and T drug combination delivery to advancing MBC cells found in lung tissues. As ICAM-1 is generally expressed even in breast cancers that are triple-negative phenotypes, which are unresponsive to inhibitors of nuclear receptors or HER2/estrogen receptor (ER) agents, ICAM-1-targeted LFA1-P-coated GT DcNPs should be considered for clinical development to improve therapeutic outcomes of MBCs.