Programmable Delivery of Synergistic Cancer Drug Combinations Using Bicompartmental Nanoparticles.

Delivery of multiple therapeutics has become a preferred method of treating cancer, albeit differences in the biodistribution and pharmacokinetic profiles of individual drugs pose challenges in effectively delivering synergistic drug combinations to and at the tumor site. Here, bicompartmental Janus nanoparticles comprised of domains are reported with distinct bulk properties that allow for independent drug loading and release. Programmable drug release can be triggered by a change in the pH value and depends upon the bulk properties of the polymers used in the respective compartments, rather than the molecular structures of the active agents. Bicompartmental nanoparticles delivering a synergistic combination of lapatinib and paclitaxel result in increased activity against HER2+ breast cancer cells. Surprisingly, the dual drug loaded particles also show significant efficacy toward triple negative breast cancer, even though this cancer model is unresponsive to lapatinib alone. The broad versatility of the nanoparticle platform allows for rapid exploration of a wide range of drug combinations where both their relative drug ratios and temporal release profiles can be optimized.

A hyaluronic acid conjugate engineered to synergistically and sequentially deliver gemcitabine and doxorubicin to treat triple negative breast cancer.

Combination chemotherapy is commonly used to treat advanced breast cancer. However, treatment success is often limited due to systemic toxicity. To improve therapeutic efficacy, polymer drug conjugates carrying synergistic pairs of chemotherapy drugs can be used to reduce drug administration dose. Here, we systematically evaluated the effect of temporal scheduling of doxorubicin (DOX) and gemcitabine (GEM) on drug synergy. Hyaluronic acid (HA) drug conjugates with distinct linkers conjugating both DOX and GEM were synthesized to control relative release kinetics of each drug. We show that polymer conjugates that release GEM faster than DOX are more effective at killing triple negative breast cancer cells in vitro. We further show that the optimal dual drug conjugate more effectively inhibits the growth of an aggressive, orthotopic 4T1 tumor model in vivo than free DOX and GEM and the single drug HA conjugates. The dual drug HA conjugate can inhibit 4T1 tumor growth in vivo during treatment through both intravenous and non-local subcutaneous injections. These results emphasize the importance of understanding the effect release rates have on the efficacy of synergistic drug carriers and motivate the use of HA as a delivery platform for multiple cancer types.

Voluntary and involuntary ligature of the bile duct in iatrogenic injuries: a nonadvisable approach.

BACKGROUND: Bile duct injuries related to laparoscopic and/or open cholecystectomy are a frequent finding and require surgical treatment. Complete obstruction is due to either intentionally or unintentionally placed ligatures or clips. The intentional application is usually performed to "facilitate identification of the duct by bile duct dilation." Considering that we are a national referral center for such injuries, we decided to analyze our cases of voluntary and involuntary duct ligation after iatrogenic bile duct injury. METHODS: We reviewed the files of patients with voluntary or involuntary bile duct ligation. Results of preoperative evaluation of the ducts, operative treatment, and postoperative results were analyzed. RESULTS: A total of 413 patients were included. Forty-five patients presented with complete obstruction. In 15 cases, the ligature was intentional, and in 30 cases, occlusion was involuntary. Bile duct dilation (>10 mm) was demonstrated in one case of voluntary (6%) and three cases of involuntary ligations (10%). The remaining cases in both groups had no duct dilation and developed necrosis at the blinded duct and leakage proximal to the ligature, with different degrees of bilioperitoneum and/or biloma. In all cases, a Roux-en-Y hepatojejunostomy was performed. CONCLUSION: Bile duct ligature produces dilation in a very small number of patients (less than 10%) and usually produces necrosis of the blinded stump with subsequent bile leakage. Placement of a subhepatic drain and transference of the patient to a qualified center for reconstruction is the best approach if the primary surgeon is not able to do the repair.